# US 9,750,701 B2 · Pharmaceutical dosage form > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,750,701 B2 - Document ID: US9750701B2 - Status: Granted - Kind: B2 - Application number: 14/965,935 - Filed: 2015-12-11 - Published: 2016-07-14 - Granted: 2017-09-05 - Earliest claimed: 2008-01-25 - Assignees: GrüNenthal GmbH - Applicants: GrüNenthal GmbH - Inventors: Eugeen Marie Jozef Jans; Filip René Irena Kiekens; Jody Firmin Marceline Voorspoels; Anne Faure; Iris Ziegler; Elisabeth Arkenau-Maric; Lutz Barnscheid; Johannes Bartholomäus; Marc Frevel; Eric Galia; Andrea Schüessele - Web page: https://patentgrep.com/patent/US9750701B2 ## CPC - A61K 9/2072: {characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms (A61K9/0004, A61K9/0056, A61K9/0065 take precedence)} - A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates} - A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers} - A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose} - A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin} - A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} - A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} - A61P 25/04: Centrally acting analgesics, e.g. opioids - A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia - Y10T 428/24479: including variation in thickness - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION ## Abstract The invention relates to a pharmaceutical dosage form, preferably with controlled release of a pharmacologically active compound (A) contained therein, the pharmaceutical dosage form very preferably being tamper-resistant and most preferably having a breaking strength B1 of at least 500 N in direction of extension E1 and having a breaking strength B2 of less than 500 N in direction of extension E2. ## Claims ### Claim 1 A pharmaceutical dosage form with controlled release of a pharmacologically active compound (A) contained therein, the pharmaceutical dosage form having a first breaking strength (B1) of at least 500 N in a first direction of extension (E1) and having a second breaking strength (B2) of less than 500 N in a second direction of extension (E2), wherein the pharmacologically active compound (A) is tapentadol or a physiologically acceptable salt thereof and/or the pharmaceutical dosage form comprises a polyalkylene oxide. ### Claim 2 (depends on 1) A pharmaceutical dosage form according to claim 1, having a shape comprising a longitudinal axis and two opposite longitudinal edges, a transversal axis perpendicular to the longitudinal axis and two opposite transversal edges, a front side, an opposite back side and a circumferential rim between said front and back side, wherein the front side and/or the back side comprise a basis area and wherein the front side and/or the back side comprise at least one bulge which extends above said basis area, said at least one bulge being present at and/or adjacent to at least a section of one or both longitudinal edges and/or at and/or adjacent to at least a section of one or both transversal edges and/or between both longitudinal edges and both transversal edges. ### Claim 3 (depends on 2) The pharmaceutical dosage form according to claim 2, which is a tablet having an oblong shape. ### Claim 4 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein the front side and the back side each comprise at least one bulge at least along a section at and/or adjacent to both longitudinal edges and/or at least along a section at and/or adjacent to both transversal edges. ### Claim 5 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein said front side and said back side comprise an at least essentially continuous bulge at and/or adjacent to at least two thirds of both opposite longitudinal edges. ### Claim 6 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein one or both longitudinal edges are essentially straight over at least a major part of their length and/or wherein one or both transversal edges are curved over a major part of their length. ### Claim 7 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein the front side and/or the back side comprise an essentially circumferential bulge at and/or adjacent to the circumferential edge of the front side and/or the back side of said pharmaceutical dosage form. ### Claim 8 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein said pharmaceutical dosage form has an oblong form, and in its oblong form comprises at and/or adjacent to major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at and/or adjacent to major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at and/or adjacent to the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at and/or adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 9 (depends on 8) The pharmaceutical dosage form according to claim 8, wherein said pharmaceutical dosage form in its oblong form comprises at major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 10 (depends on 8) The pharmaceutical dosage form according to claim 8, wherein said pharmaceutical dosage form in its oblong form comprises adjacent to major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge adjacent to major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 11 (depends on 8) The pharmaceutical dosage form according to claim 8, wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 12 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein the front side and/or the back side comprise, in addition to at least one bulge on the front side and/or the back side, at least one indentation. ### Claim 13 (depends on 12) The pharmaceutical dosage form according to claim 12, wherein the front and the back side comprise at least one indentation. ### Claim 14 (depends on 13) The pharmaceutical dosage form according to claim 13, wherein the indentation(s) in the front side and the back side are at least once at least partially off-set. ### Claim 15 (depends on 13) The pharmaceutical dosage form according to claim 13, wherein all the indentations of the front side and all the indentations of the back side are at least partially off-set. ### Claim 16 (depends on 13) The pharmaceutical dosage form according to claim 13, wherein at least one indentation of the front side and at least one indentation of the back side are positioned in a congruent manner. ### Claim 17 (depends on 16) The pharmaceutical dosage form according to claim 16, wherein all indentations of the front side and all indentations of the back side are positioned in a congruent manner. ### Claim 18 (depends on 12) The pharmaceutical dosage form according to claim 12, wherein the indentations have a cylindrical or cube-like or cuboid-like shape or the shape of a half-sphere. ### Claim 19 (depends on 2) The pharmaceutical dosage form according to claim 2, comprising one or more hydrophilic polymers. ### Claim 20 (depends on 19) The pharmaceutical dosage form according to claim 19, wherein the one or more hydrophilic polymers are hydroxypropyl methyl cellulose and/or hydroxypropyl cellulose. ### Claim 21 (depends on 19) The pharmaceutical dosage form according to claim 19, further comprising pregelatinized starch. ### Claim 22 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein the length of the pharmaceutical dosage form does not exceed 30 mm. ### Claim 23 (depends on 2) The pharmaceutical dosage form according to claim 2, having an average thickness over the basis areas of the front and the back side of about at least 1 mm. ### Claim 24 (depends on 2) The pharmaceutical dosage form according to claim 2, wherein the bulge extends perpendicular from the basis area of the front side and/or from the basis area of the back side in average from about 0.5 mm to about 2 mm. ### Claim 25 (depends on 2) The pharmaceutical dosage form according claim 2, having a length in the range of about 5 mm to about 30 mm, a width in the range of about 5 mm to about 15 mm, and a thickness over the basis areas in the range of about 1 mm to about 6 mm. ### Claim 26 (depends on 2) The pharmaceutical dosage form according to claim 2, further comprising at least partially a coating. ### Claim 27 (depends on 1) The pharmaceutical dosage form according to claim 1, which is tamper-resistant and has a retarded release profile for pharmaceutical application as an oral dosage form, comprising at least one pharmaceutically active ingredient with potential for abuse, and having a shape comprising a longitudinal axis and two opposite longitudinal edges, a transversal axis perpendicular to the longitudinal axis and two opposite transversal edges, a front side, an opposite back side and a circumferential rim between said front and back side, wherein the front side and/or the back side comprise a basis area and wherein the front side and/or the back side comprise at least one bulge which extends above said basis area, said at least one bulge being present at and/or adjacent to at least a section of one or both longitudinal edges and/or at and/or adjacent to at least a section of one or both transversal edges and/or between both longitudinal edges and both transversal edges. ### Claim 28 (depends on 27) The pharmaceutical dosage form according to claim 27, which is a tablet having an oblong shape. ### Claim 29 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein the front side and the back side each comprise at least one bulge at least along a section at and/or adjacent to both longitudinal edges and/or at least along a section at and/or adjacent to both transversal edges. ### Claim 30 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein said front side and said back side comprise an at least essentially continuous bulge at and/or adjacent to at least two thirds of both opposite longitudinal edges. ### Claim 31 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein one or both longitudinal edges are essentially straight over at least a major part of their length and/or wherein one or both transversal edges are curved over a major part of their length. ### Claim 32 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein the front side and/or the back side comprise an essentially circumferential bulge at and/or adjacent to the circumferential edge of the front side and/or the back side of said pharmaceutical dosage form. ### Claim 33 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein said pharmaceutical dosage form has an oblong form, and in its oblong form comprises at and/or adjacent to major portions of both opposite longitudinal edges of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at and/or adjacent to major portions of both opposite longitudinal edges of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at and/or adjacent to the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at and/or adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 34 (depends on 33) The pharmaceutical dosage form according to claim 33, wherein said pharmaceutical dosage form in its oblong form comprises at major portions of both opposite longitudinal edge of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge at major portions of both opposite longitudinal edge of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge at the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge at the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 35 (depends on 33) The pharmaceutical dosage form according to claim 33, wherein said pharmaceutical dosage form in its oblong form comprises adjacent to major portions of both opposite longitudinal edge of the front side at least one bulge, or wherein said pharmaceutical dosage form in its oblong form comprises at least one bulge adjacent to major portions of both opposite longitudinal edge of both the front side and the back side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form comprises in its oblong form a circumferential bulge adjacent to the circumferential edge of the front side of said pharmaceutical dosage form, or wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 36 (depends on 33) The pharmaceutical dosage form according to claim 33, wherein said pharmaceutical dosage form in its oblong form comprises a circumferential bulge adjacent to the circumferential edge of both the front side and the back side of said pharmaceutical dosage form. ### Claim 37 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein the front side and/or the back side comprise, in addition to at least one bulge on the front side and/or the back side, at least one indentation. ### Claim 38 (depends on 37) The pharmaceutical dosage form according to claim 37, wherein the front and the back side comprise at least one indentation. ### Claim 39 (depends on 38) The pharmaceutical dosage form according to claim 38, wherein the indentation(s) in the front side and the back side are at least once at least partially off-set. ### Claim 40 (depends on 38) The pharmaceutical dosage form according to claim 38, wherein all the indentations of the front side and all the indentations of the back side are at least partially off-set. ### Claim 41 (depends on 37) The pharmaceutical dosage form according to claim 37, wherein at least one indentation of the front side and at least one indentation of the back side are positioned in a congruent manner. ### Claim 42 (depends on 41) The pharmaceutical dosage form according to claim 41, wherein all indentations of the front side and all indentations of the back side are positioned in a congruent manner. ### Claim 43 (depends on 37) The pharmaceutical dosage form according to claim 37, wherein the indentations have a cylindrical or cube-like or cuboid-like shape or the shape of a half-sphere. ### Claim 44 (depends on 27) The pharmaceutical dosage form according to claim 27, comprising a polyalkylene oxide. ### Claim 45 (depends on 27) The pharmaceutical dosage form according to claim 27, comprising at least one cellulose ether derivative. ### Claim 46 (depends on 45) The pharmaceutical dosage form according to claim 45, wherein the cellulose ether derivative is hydroxypropyl methyl cellulose. ### Claim 47 (depends on 44) The pharmaceutical dosage form according to claim 44, wherein the polyalkylene oxide is polyethylene oxide. ### Claim 48 (depends on 47) The pharmaceutical dosage form according to claim 47, wherein the polyethylene oxide has a molecular weight in the range of about 2,000,000 g mol−1 to about 7,000,000 g mol−1. ### Claim 49 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein the pharmaceutical dosage form further comprises a polyalkylene glycol. ### Claim 50 (depends on 49) The pharmaceutical dosage form according to claim 49, wherein the polyalkylene glycol is polyethylene glycol. ### Claim 51 (depends on 27) The pharmaceutical dosage form according to claim 27, comprising at least one pharmaceutically active ingredient with potential for abuse; at least one poly(alkylene oxide), at least one cellulose ether derivative; and at least one polyalkylene glycol; and optionally an additive. ### Claim 52 (depends on 51) The pharmaceutical dosage form according to claim 51, wherein the active ingredient with potential for abuse is present in an amount of at least 5 weight percent; poly(alkylene oxide) is present in an amount of at least 15 weight percent; cellulose ether derivative is present in an amount of at least 5 weight percent; and polyalkylene glycol, is present in an amount of at least 5 weight percent. ### Claim 53 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein the length of the pharmaceutical dosage form does not exceed 30 mm. ### Claim 54 (depends on 27) The pharmaceutical dosage form according to claims 27, having an average thickness over the basis areas of the front and the back side of about at least 1 mm. ### Claim 55 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein the bulge extends perpendicular from the basis area of the front side and/or from the basis area of the back side in average from about 0.5 mm to about 2 mm. ### Claim 56 (depends on 27) The pharmaceutical dosage form according to claim 27, having a length in the range of about 5 mm to about 30 mm, a width in the range of about 5 mm to about 15mm, and a thickness over the basis areas in the range of about 1 mm to about 6 mm. ### Claim 57 (depends on 27) The pharmaceutical dosage form according to claim 27, wherein said pharmaceutical dosage form is a monolith. ### Claim 58 (depends on 27) The pharmaceutical dosage form according to claim 27, which has been prepared via compression using a die and a punch from a monolithic mass obtained by melt extrusion. ### Claim 59 (depends on 57) The pharmaceutical dosage form according to claim 57, wherein said pharmaceutical dosage form has been obtained by compressing a melt extruded monolithic mass which exhibits ambient temperature. ### Claim 60 (depends on 59) The pharmaceutical dosage form according to claim 59, wherein the extruded monolithic mass has been cut prior to compression. ### Claim 61 (depends on 58) The pharmaceutical dosage form according to claim 58, wherein melt extrusion has been conducted with a twin-screw extruder. ### Claim 62 (depends on 27) The pharmaceutical dosage form according to claim 27, further comprising at least partially a coating. ### Claim 63 (depends on 1) The pharmaceutical dosage form according to claim 1, wherein E1 is orthogonal to E2. ### Claim 64 (depends on 1) The pharmaceutical dosage form according to claim 1, which has a main direction of extension, wherein E2 is the main direction of extension of the pharmaceutical dosage form. ### Claim 65 (depends on 1) The pharmaceutical dosage form according to claim 1, which provides fragments when exerting a force higher than B2 in direction of extension E2, said fragments in turn having a breaking strength of at least 500 N in any of their directions of extension. ### Claim 66 (depends on 65) The pharmaceutical dosage form according to claim 65, wherein the volume of each fragment is at least 5% of the volume of the pharmaceutical dosage form. ### Claim 67 (depends on 1) The pharmaceutical dosage form according to claim 1, which is deformed when exerting a force in direction of extension E2 so that, when the amount of force reaches the breaking strength B2, deformation causes tractive forces that lead to disruption of the dosage form. ### Claim 68 (depends on 1) The pharmaceutical dosage form according to claim 1, which has released under in vitro conditions after 0.5 h 1.0 to 35 wt.-%, after 1 h 5.0 to 45 wt.-%, after 2 h 10 to 60 wt.-%, after 4 h at least 15 wt.-%, after 6 h at least 20 wt.-%, after 8 h at least 25 wt.-% and after 12 h at least 30 wt.-% of the pharmacologically active compound (A) that was originally contained in the pharmaceutical dosage form. ### Claim 69 (depends on 1) The pharmaceutical dosage form according to claim 1, which is not radially symmetric about its principal direction of extension. ### Claim 70 (depends on 1) The pharmaceutical dosage form according to claim 1, which exhibits a maximum extension of the dosage form orthogonal to a main area of extension of the dosage form spaced from a centre of mass of the dosage form parallel to said main area of extension. ### Claim 71 (depends on 1) The pharmaceutical dosage form according to claim 1, wherein a portion of its surface is convex, and another portion of its surface is concave. ### Claim 72 (depends on 1) The pharmaceutical dosage form according to claim 1, which contains a polymer (C) having a weight average molecular weight of at least 100,000 g mol−1. ### Claim 73 (depends on 72) The pharmaceutical dosage form according to claim 72, wherein the polymer (C) comprises a polyalkylene oxide. ### Claim 74 (depends on 1) The pharmaceutical dosage form according to claim 1, wherein a portion of the surface of the pharmaceutical dosage form is convex, another portion of its surface is concave; and the pharmacologically active compound (A) is a psychotropically acting substance; and the content of the pharmacologically active compound (A) is at least 0.5 wt. %, based on the total weight of the dosage form; and polymer (C) is an polyalkylene oxide having a weight average molecular weight of at least 200,000 g/mol; and the content of polymer (C) is at least 15 wt.-%, based on the total weight of the dosage form; and the pharmacologically active compound (A) is embedded in the polymer (C); and the pharmaceutical dosage form is adapted for oral administration once daily or twice daily; and the pharmaceutical dosage form is thermoformed. ### Claim 75 (depends on 1) A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a pharmaceutical dosage form according to claim 1, wherein the pharmacologically active compound (A) is selected from the group consisting of analgesics. ### Claim 76 (depends on 2) A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a pharmaceutical dosage form according to claim 2, wherein the pharmacologically active compound (A) is selected from the group consisting of analgesics. ### Claim 77 (depends on 27) A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a pharmaceutical dosage form according to claim 27, wherein the pharmaceutically active ingredient with potential for abuse is selected from the group consisting of analgesics.