[go: up one dir, main page]

WO2022101247A1 - Formes posologiques à libération prolongée d'un sel de tapentadol avec de l'acide l-(+)-tartrique - Google Patents

Formes posologiques à libération prolongée d'un sel de tapentadol avec de l'acide l-(+)-tartrique Download PDF

Info

Publication number
WO2022101247A1
WO2022101247A1 PCT/EP2021/081197 EP2021081197W WO2022101247A1 WO 2022101247 A1 WO2022101247 A1 WO 2022101247A1 EP 2021081197 W EP2021081197 W EP 2021081197W WO 2022101247 A1 WO2022101247 A1 WO 2022101247A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
dosage form
tapentadol
pharmaceutical dosage
tartaric acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2021/081197
Other languages
German (de)
English (en)
Inventor
Ulrike Bertram
Ulrich Reinhold
Christian Grosse
Carmen HARTMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=78536235&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2022101247(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from EP20206800.3A external-priority patent/EP3995135B1/fr
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to PE2023001584A priority Critical patent/PE20240113A1/es
Priority to MX2023005472A priority patent/MX2023005472A/es
Publication of WO2022101247A1 publication Critical patent/WO2022101247A1/fr
Priority to CONC2023/0005962A priority patent/CO2023005962A2/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to a tablet providing a prolonged release of tapentadol, where tapentadol is in the form of a salt with tartaric acid, in particular L-(+)-tartaric acid.
  • the tablet has satisfactory mechanical properties, e.g. B. with regard to breaking strength and friability, and can be produced under greatly facilitated tabletting conditions, in particular with reduced compression force.
  • Tablets are made by subjecting a powder to a compressive force and consolidating the powder into a compacted form in the die of a press.
  • compaction is an increase in the mechanical strength of the powder under force due to the consolidation of the particles. Compaction is thus related to particle consolidation and binding, which has a direct impact on tablet crush strength.
  • Compression is defined as a reduction in the bulk volume of the powder under the action of force by displacement of air between the particles. Compression leads to a reduction in the void space between solid particles, which means a decrease in the porosity of a tablet (for details see e.g. Y. Qiu et al., Developing Solid Oral Dosage Forms, Pharmaceutical Theory & Practice, 2nd ed ., Elsevier, 2017, pp. 940-942).
  • Tablet manufacture is affected by a number of interdependent parameters including
  • the desired properties of the tablet e.g. mechanical strength, weight variability, disintegration time, size and shape
  • the conditions in the tableting machine e.g. compression force, tabletting speed, dwell time of the stamp in the die, stamp geometry, tool material, etc.
  • the dose of drug to be contained in a tablet is determined by the potency of the drug and the planned administration frequency determined.
  • the release characteristics determine the nature and amount of excipients as well as the overall distribution of excipients in the tablet.
  • Matrix retardation for example, requires significant amounts of extended-release matrix material in which the drug is embedded.
  • Sufficient mechanical strength is required to e.g. B. to allow ejection of the compacted forms from the die during the tableting process and the release of tablets from a suitable packaging such as a blister pack.
  • powder excipients are used as binders for cohesion, fillers for tablet tensile strength, lubricants for successful processing of a mixture or granules into a tablet, disintegrants to facilitate disintegration of the tablet in vivo, as controlled release materials for sustained dissolution and sometimes as lubricants for mixtures with poor flowability.
  • the excipients are each predominantly either elastic or plastic or brittle. Elastic particles deform to their elastic limit during compression and then break. Before this yield point is reached, the deformation of the elastic material is reversible. After removing the compression forces, elastic powders expand (relaxation).
  • Tablet punches are used to compress a mixture or granules into a compacted unit dose.
  • the lower punch is first lowered so that the feed device can deliver powder into an embossing mold. Excess powder is removed with a scraper so that the formulation is level with the top edge of the mold. The amount of powder in the embossing mold is the fill level. Then the upper stamp is lowered into the embossing mold.
  • the pre-compression rollers apply pressure which deflates the charge in the mold by forcing the particles closer together.
  • the main compression rollers then apply force that compacts the powder into a compacted form.
  • the upper punch is then pulled out of the die by the upper lifting cam.
  • the lower punch is then pushed up by the ejector cam, ejecting the compacted shape from the embossing mold for removal by a scraper. Compression allows particles to bond to particles for the purpose of producing a tablet with sufficient cohesive strength or hardness to maintain its shape and appearance.
  • Some of the deformation characteristics are time dependent and therefore machine characteristics can have a large impact on tableting performance. These characteristics determine the rate of force application, the dwell time (ie the time of maximum pressing force, which depends on the diameter of the face of the punch head and the tangential velocity), and the decompression rate. For materials undergoing plastic deformation, there is typically less time available for stress relaxation with increased machine speed. Tablets must be able to withstand the rigors of manufacture, packaging, shipping and distribution. According to the FDA's August 2018 Quality Attribute Considerations for Chewable Tablets, Guidance for Industry, chewable tablets should have a hardness of ⁇ 12 kp (-19.6 N), recognizing that tablet size and shape are important factors in determining acceptable tablet hardness are of importance.
  • a hardness value of 20 N could be quite high.
  • fast-disintegrating tablets with immediate release of the drug should have a hardness of about 70-100N
  • tablets with prolonged-release of the drug should have a hardness of about 100-200N.
  • the tablet hardness should therefore be at least 100N, preferably at least 150N.
  • tablet hardness is a function of compression force; the higher the pressing force, the higher the tablet hardness.
  • increased tablet hardness can often be achieved by increasing the compression force.
  • this may require a reduction in machine speed to properly adjust the residence time, thereby reducing the overall tablet hourly yield.
  • Dwell time refers to the amount of time a stamper compresses powder in the die. It is a function of machine speed, with faster tabletting allowing less time for the punch to compress the powder in the die.
  • Tablet attributes should be considered when trying to find a compromise between compression force and residence time (for more details see e.g. M.T. Ende et al., Chemical Engineering In The Pharmaceutical Industry, Drug Product Design, Development, and Modeling, 2nd ed ., Wiley, 2019, pp. 228-232, J. Swarbrick, M. Bogda, Encylopedia of Pharmaceutical Technology, 3rd ed., Informa Healthcare, 2007, Tablet Compression: Machine Theory, Design, and Process Troubleshooting, 3611-2629 ).
  • Tablet tooling strength is a function of tablet size, shape and fill weight. There are therefore several tablet shapes and sizes that allow maximum compression forces of less than 10 kN. As a result, tableting machines equipped with punches of this size and shape are already operated at compression forces close to their maximum tooling force, and under these conditions there is little maneuvering room to increase compression force to increase tablet hardness (for more see e.g.
  • WO 2003/035054 A1 relates to a pharmaceutical formulation which is characterized by a delayed release of tapentadol HCl in a matrix with delayed release of the active ingredient.
  • This matrix contains between 1 and 80% by weight of at least one hydrophilic or hydrophobic polymer as a pharmaceutically acceptable matrix forming agent.
  • the granules were pressed on an EKO eccentric press (Korsch) to give oblong tablets with a size of 6 ⁇ 15 mm and a score line.
  • EP 2 942 054 A1 relates to a slow-release pharmaceutical formulation containing tapentadol HCl in a slow-release matrix, the matrix containing between 15 and 50% by weight of mono-, di- and triglycerides of saturated fatty acids with a Chain length between 16 and 22 carbon atoms or a mixture thereof.
  • the influence of compression force and tablet dimensions on tablet hardness and dissolution behavior was investigated. With a constant force of 27 kN, a tablet hardness of only 53 to 79 N could be achieved, while lower forces produced an even worse tablet hardness.
  • WO 2008/051617 A2 relates to a method for producing a dry granulate composition, in which a pharmaceutical composition is compressed to form one or more blanks to a hardness of 800 to 900 kPa and the one or more blanks to form a granulate grinds in an oscillating granulator.
  • An exemplary pharmaceutical formulation contains tapentadol HCl, hypromellose, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate.
  • the influence of the pressing force on the tablet hardness is shown in FIGS. At compression forces of 2000 to 3000 lbs ( ⁇ 8.9 to -13.3 kN), tablets with a hardness of about 7 to 20 kp (-69 to -196 N) were obtained.
  • WO 2015/014980 A1 discloses a pharmaceutical composition which comprises (a) dissolved tapentadol HCl, (b) organic solvent with a boiling point of 110° to 350° C. and (c) solid carrier. If a rotary press is used to produce the tablets, the main compression force can be in the range from 1 to 50 kN, preferably from 3 to 40 kN.
  • the tablets obtained can have a hardness of from 30 to 400 N, particularly preferably from 50 to 250 N, especially preferably from 30 to 180 N and even more preferably from 40 to 150 N.
  • the oral dosage forms should preferably be provided in the form of tablets, preferably monolithic tablets, i. H. the production of a large number of particles should not be necessary.
  • the production of the oral dosage forms should be possible on standard equipment on a large industrial scale with high throughput, preferably by compression of powder mixtures, possibly with granulation (dry granulation or wet granulation), but preferably by direct compression of powder mixtures.
  • the object of the invention is to provide pharmaceutical dosage forms of tapentadol which offer advantages compared to the pharmaceutical dosage forms from the prior art.
  • salts of tapentadol with tartaric acid are of particular use for pharmaceutical dosage forms providing prolonged release of tapentadol.
  • the production of compressed tablets comprising salts of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, requires significantly reduced compression forces in order to achieve a desired target breaking strength of the tablets.
  • this effect does not depend on the particle size of the salts of tapentadol with tartaric acid, nor on the polymorphic form of the salt of tapentadol with tartaric acid.
  • this effect is also observed with various other excipients, i. H. it can be attributed to the properties of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, as such.
  • a crystalline product of tapentadol with tartaric acid is known from WO 2017/085734 A1.
  • the reduction in compression forces to achieve a desired target breaking strength of the tablets is not addressed in this reference.
  • tapentadol tablets contain Palexia® retard tapentadol as the hydrochloride salt, with the tablet core additionally containing hypromellose, microcrystalline cellulose, finely divided silicon dioxide and magnesium stearate. Palexia® retard tablets thus contain hypromellose as an extended-release matrix.
  • the tablet cores are coated with a composition fdmbe comprising hypromellose, lactose monohydrate, talc, macrogol 6000 and coloring agents. These tablets correspond to WO 03/035053 A1 and the comparative examples contained here in the experimental part.
  • FIG. 1 shows the XRPD diffractogram of the crystalline form of tapentadol and L-(+)-tartaric acid obtained according to WO 2017/085734 A1.
  • FIG. 2 shows the infrared spectrum of the crystalline form of tapentadol and L-(+)-tartaric acid obtained according to WO 2017/085734 A1.
  • FIG. 3 shows the XRPD diffractogram of the crystalline form of tapentadol tartrate according to example 1.
  • a first aspect of the invention relates to a pharmaceutical dosage form comprising tapentadol for twice-daily oral administration; wherein tapentadol is present as a salt with tartaric acid, especially L-(+)-tartaric acid; wherein the dosage form provides an extended release of tapentadol; and wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is in the range of 10 to 300 mg in terms of tapentadol free base.
  • Tapentadol i.e. H. (-)-(lR,2R)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)phenol, is a synthetic centrally acting analgesic useful in the management of moderate to severe acute or chronic pain.
  • the synthesis of the free base of tapentadol is z. B. from EP-A 693 475 known.
  • the pharmaceutical dosage form according to the invention contains tapentadol as a salt with tartaric acid, in particular L-(+)-tartaric acid. It is contemplated that the pharmaceutical dosage form of the invention may contain mixtures of different salts of tapentadol or mixtures of salt(s) of tapentadol free base (e.g. the non-salt form of tapentadol), however, preferably the total amount of tapentadol contained in the pharmaceutical dosage form is present as a salt with tartaric acid, in particular L-(+)-tartaric acid.
  • Salts of tapentadol with tartaric acid include in principle the salts with L-(+)-tartaric acid, D-(-)-tartaric acid, DL-( ⁇ )-tartaric acid and meso-tartaric acid.
  • L-(+)-tartaric acid is also referred to as (2R,3R)-tartaric acid
  • D-(-)-tartaric acid is also referred to as (2S,3S)-tartaric acid
  • DL-( ⁇ )-tartaric acid as (2RS,3SR )-tartaric acid.
  • the corresponding salts are referred to as L-(+)-tartrates, D-(-)-tartrates and DL-( ⁇ )-tartrates.
  • the salt of tapentadol with tartaric acid is the salt of tapentadol with L-(+)-tartaric acid, which may optionally be solvated (e.g. hydrated) or ansolvated (e.g. anhydrated).
  • the salt of tapentadol may be in the form of a single polymorph or a mixture of different polymorphs in any mixing ratio.
  • the salt of tapentadol with tartaric acid is the salt with L-(+)-tartaric acid which is in the essentially pure crystalline form of tapentadol-L-(+)-tartrate.
  • Salts having an essentially 2:1 stoichiometry of tapentadol to tartaric acid, especially L-(+)-tartaric acid, are also referred to as hemi-salts and are also included.
  • the salt of tapentadol with tartaric acid is a crystalline L-(+)-tartaric acid salt, i.e. tapentadol L-(+)-tartrate, with characteristic X-ray powder diffraction peaks at 14.1, 20.0 , 21.1 and 23.7 degrees 20 ( ⁇ 0.2 degrees 20); preferably characterized by one or more further X-ray powder diffraction peaks at 12.7, 18.6, 21.6, 22.1, 25.6 and/or 28.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • the crystalline tapentadol L-(+)-tartrate may be characterized by the following X-ray powder diffraction peaks at degree 20 ⁇ 0.2 degree 20: 12.7, 14.1, 18.6, 20.0, 21.1 , 21.6, 22.1, 23.7, 25.6 and/or 28.5.
  • X-ray powder diffraction measurements are carried out with Cu K a radiation at room temperature.
  • a suitable device is eg D8 ADVANCE Eco, Bruker.
  • DSC measurements are performed according to ASTM D3418.
  • IR spectra are performed on an FTIR spectrometer.
  • the crystalline tapentadol L-(+)-tartrate can be characterized in that differential scanning calorimetry shows an endothermic transition at 132°C ⁇ 3°C.
  • the crystalline tapentadol L-(+)-tartrate can be characterized by absorption bands in the infrared spectrum at 3319, 3237, 2960, 1731, 1597, 1305, 1263, 1213, 791, 679 and 485 cm 1 .
  • tapentadol is intended to include the salt of tapentadol with tartaric acid.
  • the salt of tapentadol with tartaric acid in particular L-(+)-tartaric acid, can be in the form of any solvate, e.g. hydrates, ansolvates, e.g. B. anhydrate, and any polymorphic form, z. B. crystalline form and / or amorphous form.
  • the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form according to the invention is in the range of 10 to 300 mg, based on the free base of tapentadol, e.g. 25mg, 50mg, 100mg, 150mg, 200mg or 250mg.
  • Tapentadol free base i.e. the free molecule
  • 10 mg of tapentadol free base corresponds to 0.0452 mmol
  • 300 mg of tapentadol free base corresponds to 1.3556 mmol.
  • the pharmaceutical dosage form contains a molar equivalent dose of tapentadol in the range of 0.0452 to 1.3556 mmol.
  • the hydrochloride salt of tapentadol (anhydrate) has a molecular weight of 257.8 g/mol, while the tartaric acid salt of tapentadol (anhydrate) has a molecular weight of 371.4 g/mol.
  • the pharmaceutical dosage form according to the invention contains z. B. a weight equivalent dose of 100 mg in terms of tapentadol free base (0.4518 mmol), it actually contains 167.8 mg of the tartaric acid salt of tapentadol (0.4518 mmol).
  • the dose information for tapentadol is expressed as an equivalent weight based on the free base of tapentadol, ie the non-salt form, the non-solvate form, the non-co-crystal form and the non-aggregated form of tapentadol with any other molecules.
  • the form of tapentadol actually contained in the pharmaceutical dosage form ie the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, may be in the form of any polymorphic form and/or any solvate and/or any co-crystal and/or any other aggregate of such a salt with other molecules.
  • the pharmaceutical dosage form according to the invention can contain additional pharmacologically active ingredients in addition to tapentadol; however, tapentadol is preferably the sole pharmacologically active ingredient contained in the pharmaceutical dosage form.
  • Tapentadol is preferably distributed homogeneously over the pharmaceutical dosage form according to the invention.
  • the pharmaceutical dosage form according to the invention is intended for oral administration, preferably by swallowing the pharmaceutical dosage form whole.
  • the pharmaceutical dosage form according to the invention is therefore preferably not intended for buccal or sublingual administration, in which case the pharmaceutical dosage form would remain in the oral cavity.
  • the pharmaceutical dosage form according to the invention is intended for administration twice a day.
  • the pharmaceutical dosage form according to the invention thus contains 50% of the daily dose of tapentadol intended for administration to bring about the desired therapeutic effect.
  • Twice daily administration may be at intervals of about every 12 hours, although such a protocol need not be strictly followed.
  • twice daily is also intended to encompass an administration regimen in which the two pharmaceutical dosage forms of the invention are administered over a period of about 24 hours, with the two administrations being separated by at least 4 hours, preferably at least 8 hours.
  • the pharmaceutical dosage form of the present invention provides extended release of tapentadol.
  • prolonged release means non-immediate release.
  • Extended release includes controlled release, sustained release, sustained release, staged release, repeated release, the sustained release and the uniform sustained release.
  • Prolonged release preferably means release at a reduced release rate, to maintain a therapeutic effect, to reduce toxic effects, or for some other therapeutic purpose.
  • the extended release can be based on various techniques known to those skilled in the art. According to a preferred embodiment, the extended release is based on extended release coating materials with which the pharmaceutical dosage form as such or with which a multiplicity of particles can be coated. According to another preferred embodiment, the extended release is based on an extended release matrix in which tapentadol is preferably embedded. According to the invention, it is further considered that a prolonged release can be achieved by alternative concepts such as ion exchange resins, osmotic dosage forms and the like.
  • the pharmaceutical dosage form according to the invention preferably provides plasma levels of tapentadol which provide pain relief (analgesia) over a period of at least 6 hours, preferably at least 8 hours, more preferably at least 10 hours, most preferably at least 12 hours.
  • the pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37°C,
  • the pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of aqueous phosphate buffer at a pH of 6.8 at 37°C,
  • the pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at pH 4.5 at 37°C,
  • the pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at pH 4.5 at 37°C,
  • the pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of 0.1 N HCl at a pH of 1.0 and 37 °C,
  • the pharmaceutical dosage form according to the invention preferably provides an in vitro dissolution profile in which, measured by the USP paddle method at 50 rpm in 900 ml of 0.1N HCl at a pH of 1.0 and 37 °C,
  • the pharmaceutical dosage form according to the invention preferably provides resistance to ethanol-induced dose dumping.
  • the pharmaceutical dosage form according to the invention preferably provides a slower in vitro dissolution of tapentadol in aqueous ethanol-containing medium than in non-ethanol-containing medium.
  • the pharmaceutical dosage form according to the invention preferably provides a slower dissolution of tapentadol in 0.1N HCl with 5.0% by volume ethanol (pH 1.0) than in 0.1N HCl without 5.0% by volume.
  • Ethanol (pH 1.0) prepared, each measured by the USP paddle method at 50 rpm in 900 mL at 37°C.
  • the pharmaceutical dosage form according to the invention preferably provides a slower dissolution of tapentadol in 0.1N HCl with 20% by volume ethanol (pH 1.0) than in 0.1N HCl without 20% by volume ethanol (pH 1 ,0) ready, each measured according to the USP paddle method at 50 rpm in 900 ml at 37°C.
  • the pharmaceutical dosage form according to the invention preferably provides a slower dissolution of tapentadol in 0.1N HCl with 40% by volume ethanol (pH 1.0) than in 0.1N HCl without 40% by volume ethanol (pH 1 ,0) ready, each measured according to the USP paddle method at 50 rpm in 900 ml at 37°C.
  • the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 25 mg, 50 mg or 100 mg, based in each case on the free base of tapentadol.
  • the pharmaceutical dosage form according to the invention preferably has a total weight in the range from 150 to 750 mg.
  • the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg, 200 mg or 250 mg, based in each case on the free base of tapentadol.
  • the pharmaceutical dosage form according to the invention preferably has a total weight in the range from 300 to 1200 mg.
  • the pharmaceutical dosage form according to the invention preferably comprises one, two or more physiologically acceptable excipients.
  • a "pharmaceutical excipient” is preferably considered to be any pharmacologically inactive substance typically used as a carrier for the active ingredients of a medicament.
  • the pharmaceutical excipient may have a physiological effect, e.g. B. like a vitamin, but no pharmacological effect like a drug.
  • Typical examples of pharmaceutical excipients include antiblocking agents, binders, coating materials, disintegrants, fillers, diluents, flavoring agents, colorants, glidants, lubricants, preservatives, sorbents, surfactants, sweeteners, colorants, pigments, and the like.
  • excipients can each be divided into subgroups.
  • preservatives can be divided into antioxidants, buffers, antimicrobials, and the like
  • binders can be divided into solution binders and dry binders.
  • excipients exhibit different properties at the same time, so they can serve different purposes.
  • polyethylene glycol can be used as a binder, plasticizer, and the like.
  • the pharmaceutical dosage form according to the invention preferably the extended-release matrix, preferably comprises a binder.
  • the binder is preferably made from cellulose, magnesium aluminum silicates (e.g. bentonite), mono-, oligo- and polysaccharides (e.g. dextrose, lactose, mannose), sugar alcohols (e.g. lactitol, mannitol) , starches (eg, pregelatinized starch, hydrolyzed starch, modified starch), calcium phosphate, polyvinylpyrrolidone, and vinylpyrrolidone-vinyl acetate copolymers; preferably microcrystalline cellulose; particularly preferably silicified microcrystalline cellulose, selected from the existing group.
  • magnesium aluminum silicates e.g. bentonite
  • mono-, oligo- and polysaccharides e.g. dextrose, lactose, mannose
  • sugar alcohols e.g. lactitol, manni
  • the content of binder by weight is preferably at least 5.0% by weight, more preferably at least 10% by weight, even more preferably at least 15% by weight, even more preferably at least 20% by weight more preferably at least 25% by weight, most preferably at least 30% by weight and in particular at least 35% by weight, based in each case on the total weight of the pharmaceutical dosage form.
  • the content of binder by weight is preferably at most 85% by weight, more preferably at most 82.5% by weight, even more preferably at most 80% by weight, even more preferably at most 77.5% by weight , even more preferably at most 75% by weight, most preferably at most 72.5% by weight and in particular at most 70% by weight, based in each case on the total weight of the pharmaceutical dosage form.
  • the content of binder by weight is in the range of 52 ⁇ 30% by weight, more preferably 52 ⁇ 27.5% by weight, even more preferably 52 ⁇ 25% by weight, even more preferably 52 ⁇ 22.5% by weight, more preferably 52 ⁇ 20% by weight, most preferably 52 ⁇ 17.5% by weight and in particular 52 ⁇ 15% by weight, each based on the Total weight of the pharmaceutical dosage form.
  • the above percentages relate to the total content of all binders contained in the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention preferably comprises a lubricant.
  • the lubricant is preferably composed of salts of fatty acids (e.g. magnesium stearate, calcium stearate, zinc stearate), fatty acids (e.g. stearic acid, palmitic acid), glyceryl fatty acid esters (e.g. glyceryl monostearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate) , sorbitan monostearate, sucrose monopaimitate, sodium stearyl fumarate, hydrated magnesium silicate and talc and is preferably magnesium stearate.
  • fatty acids e.g. magnesium stearate, calcium stearate, zinc stearate
  • fatty acids e.g. stearic acid, palmitic acid
  • glyceryl fatty acid esters e.g. glyceryl monostearate, glyceryl monobehenate, glyceryl dibehenate, g
  • the content of lubricant by weight is at least 0.20% by weight, more preferably at least 0.25% by weight, even more preferably at least 0.30% by weight, even more preferably at least 0.35% by weight %, even more preferably at least 0.40% by weight, most preferably at least 0.45% by weight and in particular at least 0.50% by weight, based in each case on the total weight of the pharmaceutical dosage form.
  • the content of the lubricant by weight is at most 3.0% by weight, more preferably at most 2.8% by weight, even more preferably at most 2.6% by weight, even more preferably at most 2.40% by weight %, even more preferably at most 2.20% by weight, most preferably at most 2.00% by weight and in particular at most 1.80% by weight, based in each case on the total weight of the pharmaceutical dosage form.
  • the content of lubricant by weight is preferably in the range of 0.1 ⁇ 1.0% by weight, more preferably 0.50 ⁇ 0.45% by weight, even more preferably 0.50 ⁇ 0 .40% by weight, more preferably from 0.50 ⁇ 0.35% by weight, even more preferably from 0.50 ⁇ 0.30% by weight, most preferably from 0.50 ⁇ 0.25 % by weight and in particular 0.50 ⁇ 0.20% by weight, in each case based on the total weight of the pharmaceutical dosage form.
  • the dosage form contains an extended-release coating which comprises an extended-release coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy products and mixtures thereof.
  • the dosage form will be a monolith comprising such an extended release coating.
  • the dosage form is multiparticulate, with the individual particles (granules, pellets and the like) comprising such a prolonged-release coating.
  • the number of particles contained in the dosage form is not particularly limited and can range from 1, 2, 3, 4 or 5 to 10, 20, 30, 40 to 100, 200 and more.
  • the particles are preferably of substantially the same weight, size and composition. According to a preferred embodiment, the particles contain a core comprising substantially all of the tapentadol, optionally together with one or more excipients, and a sustained-release coating encapsulating the core.
  • the particles contain an inert core not containing tapentadol (e.g. sugar spheres), a drug coating layer encapsulating the core and comprising substantially all of tapentadol, optionally together with one or more excipients, and an extended release coating encapsulating the core and the drug coating layer.
  • tapentadol e.g. sugar spheres
  • drug coating layer encapsulating the core and comprising substantially all of tapentadol, optionally together with one or more excipients
  • an extended release coating encapsulating the core and the drug coating layer.
  • the extended release coating material is preferably of the type selected from acrylic acid and methacrylic acid copolymers, aminoalkyl methacrylate copolymers, cyanoethyl methacrylates, ethoxyethyl methacrylates, ethyl cellulose, methacrylic acid alkylamide copolymers, methacrylic acid copolymers, methyl methacrylates, methyl methacrylate copolymers, poly(acrylic acid), poly (methacrylic acid) (anhydride), poly(methacrylic acid), glycidyl methacrylate copolymers, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide and polymethacrylate.
  • the acrylic polymer consists of one or more ammoniomethacrylate copolymers, i. H. Copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • ammoniomethacrylate copolymers i. H. Copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the coating is preferably made from an aqueous dispersion or from an organic dispersion or from an organic solution of a hydrophobic polymer.
  • the coating preferably includes an effective amount of a plasticizer that is also present in the aqueous dispersion of hydrophobic polymer.
  • the plasticizer further improves the physical properties of the film. For example, since ethyl cellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize the ethyl cellulose before using it as a coating material.
  • the amount of plasticizer added to a coating solution is based on the concentration of the film former, e.g. B. most often from about 1 to about 50 percent by weight of the film former.
  • plasticizers for ethyl cellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although it is possible to use other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.).
  • Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • plasticizers for the acrylic polymers of the present invention include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and optionally 1,2-propylene glycol.
  • Other plasticizers that have been found useful in improving the elasticity of films formed from acrylic films such as Eudragit® RL/RS varnish solutions include polyethylene glycols, propylene glycols, diethyl phthalate, castor oil and triacetin.
  • Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • talc reduces the tendency of the aqueous dispersion to stick during processing and acts as a polishing agent.
  • the dissolution profile of the final product can also be modified by, for example, increasing or decreasing the thickness of the retardant coating.
  • aqueous dispersion of the hydrophobic polymer is used to coat inert pharmaceutical beads, a plurality of the resulting stabilized solid, sustained-release beads can then be incorporated in an amount sufficient upon ingestion and contact with gastric juice to provide an effective sustained-release dose put in a gelatin capsule.
  • the extended release profile can be relatively controlled, for example, by varying the amount of coating with the aqueous dispersion of hydrophobic polymer, changing the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic polymer to the hydrophobic polymer, by incorporating additional ingredients or excipients, by changing the manufacturing process, etc.
  • the coating preferably contains a colorant in addition to the film former, plasticizer and solvent system (ie water) to provide elegance and product differentiation.
  • Suitable ingredients for providing color to the formulation when using an aqueous dispersion of an acrylic polymer include titanium dioxide and color pigments such as iron oxide pigments. However, the inclusion of pigments can increase the retarding effect of the coating.
  • the plasticized aqueous dispersion or organic dispersion or organic solution of the hydrophobic polymer can be applied to the substrate comprising tapentadol by spraying using any suitable spraying device known in the art.
  • a preferred method uses a Wurster fluidized bed system in which a jet of air introduced from below fluidizes the core material and causes drying as the acrylic polymer coating is sprayed on. It is preferred to bring about a predetermined controlled release of tapentadol upon exposure of the coated substrate to aqueous solutions, e.g. gastric juice, sufficient amount of the aqueous dispersion of the hydrophobic polymer, taking into account the manner in which the plasticizer has been incorporated, etc.
  • a film-forming agent such as Opadry®
  • the release of tapentadol from the extended-release formulation can be further influenced by the addition of one or more release-modifying agents or by providing one or more passages through the coating, e.g. H. set to a desired rate.
  • the ratio of hydrophobic polymer to water-soluble material is determined by the release rate required and the solubility characteristics of the materials chosen, among other factors.
  • the release-modifying agents acting as pore formers can be organic or inorganic and can include materials that can be leached, extracted or leached from the coating in the environment of use.
  • the pore formers may comprise one or more hydrophilic polymers such as hydroxypropyl methyl cellulose.
  • the controlled release coatings can also include erosion promoting agents such as starches and gums.
  • the controlled release coatings of the present invention can also include materials suitable for forming microporous laminae in the environment of use, such as polycarbonates made from straight chain carbonic polyesters in which the carbonate groups recur in the polymer chain.
  • the dosage form is multiparticulate, wherein the individual particles (granules, pellets and the like) with a prolonged release coating are contained in a capsule, optionally together with additional excipients, which are present in the capsule in powder form or else in the form of particles (granules, pellets and the like) can be included.
  • the capsules contain at least two different types of particles, namely particles containing tapentadol and particles not containing tapentadol.
  • the dosage form is multiparticulate, wherein the individual particles (granules, pellets and the like) are contained with a coating for prolonged release in a tablet containing an extraparticulate material (Multiple Unit Pellet System, MUPS) .
  • the extraparticulate material preferably contains at least one excipient selected from binders, disintegrants and lubricants.
  • the tapentadol is embedded in a matrix with prolonged release.
  • the pharmaceutical dosage form according to the invention preferably the matrix with prolonged release, preferably contains at least one physiologically harmless polymer which serves to delay the release of the pharmacologically active substance from the pharmaceutical dosage form.
  • the at least one physiologically harmless polymer is thus part of the matrix for the prolonged release of the pharmaceutical dosage form according to the invention.
  • the extended release matrix preferably comprises or consists essentially of at least one extended release matrix material selected from the group consisting of hydrophilic or hydrophobic polymers and hydrocarbons.
  • the extended-release matrix comprises at least one polymer selected from the group consisting of or the extended-release matrix essentially consists of at least one polymer selected from the group consisting of
  • polysaccharides or gums e.g. xanthan gum, guar gum, karaya gum, locust bean gum, sodium alginate, carob gum, chitosan, polysaccharides of mannose and galactose, pectin, tragacanth, agar
  • xanthan gum guar gum
  • karaya gum locust bean gum
  • sodium alginate carob gum
  • chitosan polysaccharides of mannose and galactose
  • pectin pectin
  • tragacanth agar
  • - cellulose ethers e.g. HPMC, HPC, HEC, MC, EC
  • cellulose esters e.g. cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate
  • cellulose esters e.g. cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate
  • PVA Polyvinyl alcohol
  • PVA crosslinked polyvinyl alcohol
  • PVP polyvinylpyrrolidone
  • PVP crosslinked polyvinylpyrrolidone
  • PVC polyvinyl chloride
  • PVAc polyethylene vinyl acetate
  • PDS polydimethylsiloxane
  • PEU polyetherurethane
  • PLA polylactic acid
  • PLA polyglycolic acid
  • PCL polycaprolactone
  • acrylic resins e.g. crosslinked homopolymers and copolymers of acrylic acids, acrylic acid and methacrylic acid copolymers, aminoalkyl methacrylate copolymer, cyanoethyl methacrylate, ethoxyethyl methacrylates, methacrylic acid alkylamide copolymer, methacrylic acid copolymers, methyl methacrylates, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), poly(methacrylic anhydride), glycidyl methacrylate copolymers, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide, polyhydroxyethyl methacrylate (PHEMA) and polymethacrylate); and
  • the extended release matrix comprises or consists essentially of at least one hydrocarbon selected from the group consisting of long chain (Cs-Cso, especially C12-C40) fatty acids, long chain fatty alcohols, glyceryl esters of long chain fatty acids, mineral oils, vegetable oils and waxes .
  • Cs-Cso especially C12-C40
  • glyceryl esters of long chain fatty acids mineral oils, vegetable oils and waxes .
  • the extended release matrix preferably comprises an extended release matrix material selected from the group consisting of (i) hydroxypropyl methyl cellulose (HPMC); (ii) hydroxypropyl cellulose (HPC); (iii) hydroxyethyl cellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethyl cellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinyl acetate copolymer (PVP/PVAc); (ix) poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride); (x) poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate); (xi) poly(methyl methacrylate-co-methacrylic acid
  • the content of extended-release matrix material is preferably in the range of 15 ⁇ 10% by weight, or 20 ⁇ 10% by weight, or 25 ⁇ 10% by weight, or 30 ⁇ 10% by weight, or 35 ⁇ 10% by weight. % or 40 ⁇ 10% by weight or 45 ⁇ 10% by weight or 50 ⁇ 10% by weight or 55 ⁇ 10% by weight or 60 ⁇ 10 % by weight or 65 ⁇ 10% by weight or 70 ⁇ 10% by weight or 75 ⁇ 10% by weight or 80 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • the pharmaceutical dosage forms according to the invention preferably do not comprise any poly(alkylene oxide), e.g. B. poly (ethylene oxide), nor ethylene-vinyl acetate copolymers (EVA).
  • poly(alkylene oxide) differs from poly(alkylene glycol) by its molecular weight; Polymers with a weight average molecular weight Mw of less than 100,000 g/mol are considered poly(alkylene glycol), while polymers with a weight average molecular weight Mw of 100,000 g/mol or more are considered poly(alkylene oxide).
  • the extended release matrix preferably comprises a cellulose derivative selected from cellulose ethers and cellulose esters or a poly(meth)acrylate or copolymer thereof.
  • the cellulose derivative is preferably a cellulose ether selected from the group consisting of methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose; preferably hydroxypropylmethyl cellulose.
  • the cellulose derivative is preferably hydroxypropylmethylcellulose.
  • the hydroxypropylmethylcellulose is preferably selected from USP hypromellose types 1828, 2208, 2906 and 2910 with the following methoxyl content and hydroxypropoxyl content:
  • the viscosity of the physiologically acceptable polymer is preferably in the range of 100,000 ⁇ 80,000 mPa s, particularly preferably 100,000 ⁇ 60,000 mPa s, even more preferably 100,000 ⁇ 40,000 mPa s, even more preferably 100,000 ⁇ 20000mPas.
  • the number-average molecular weight M n of the physiologically acceptable polymer is preferably no more than 220,000 g/mol, particularly preferably no more than 180,000 g/mol, even more preferably no more than 140,000 g/mol , more preferably no more than 120,000 g/mol, nor more preferably no more than 110,000 g/mol, most preferably no more than 86,000 g/mol and especially no more than 63,000 g/mol.
  • the content of physiologically acceptable polymer, preferably cellulose ether, by weight is preferably at least 2.0% by weight, particularly preferably at least 3.0% by weight, even more preferably at least 4.0% by weight more preferably at least 5.0% by weight, even more preferably at least 6.0% by weight, most preferably at least 7.0% by weight and in particular at least 8.0% by weight, based in each case on the total weight the pharmaceutical dosage form.
  • the content of physiologically acceptable polymer, preferably cellulose ether, by weight is preferably at most 62.5% by weight, particularly preferably at most 60% by weight, even more preferably at most 57.5% by weight, even more preferably at most 55% by weight, more preferably at most 52.5% by weight, most preferably at most 50% by weight and in particular at most 47.5% by weight, based in each case on the total weight of the pharmaceutical dosage form.
  • the content of physiologically acceptable polymer, preferably cellulose ether, by weight is preferably in the range of 30 ⁇ 28% by weight, particularly preferably 30 ⁇ 26% by weight, even more preferably 30 ⁇ 24% by weight , even more preferably from 30 ⁇ 22% by weight, even more preferably from 30 ⁇ 20% by weight, most preferably from 30 ⁇ 18% by weight and in particular from 30 ⁇ 16% by weight, in each case based on the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form contains more than one physiologically acceptable polymer, which serves the purpose of significantly retarding the release of the pharmacologically active substance from the pharmaceutical dosage form, preferably cellulose ethers, the above percentages relate to the total content of all such physiologically acceptable polymers, preferably Cellulose ethers contained in the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix comprises as extended-release matrix material hydroxypropylmethylcellulose (HPMC), preferably in an amount of 5.0 to 60% by weight, e.g. B.
  • HPMC hydroxypropylmethylcellulose
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material hydroxypropyl cellulose (HPC), preferably in an amount of 10 to 50% by weight, e.g. B. 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight or 40 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • HPC hydroxypropyl cellulose
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material hydroxyethyl cellulose (HEC), preferably in an amount of 5.0 to 50% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight or 40 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • HEC hydroxyethyl cellulose
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix comprises as extended-release matrix material microcrystalline cellulose (MCC), preferably in an amount of 10 to 70% by weight, e.g. B.
  • MMC microcrystalline cellulose
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range of 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material ethyl cellulose (EC), preferably in an amount of 5.0 to 30% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • EC extended-release matrix material
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material polyvinyl acetate (PVAc), preferably in an amount of 25 to 70% by weight, e.g. B.
  • PVAc polyvinyl acetate
  • the polyvinyl acetate is preferably used in the form of a mixture with polyvinylpyrrolidone (povidone).
  • a preferred mixture is commercially available, e.g. B. as Kollidon® SR (80% by weight polyvinyl acetate, 19% by weight povidone, 0.8% by weight sodium lauryl sulfate and 0.2% by weight silica).
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and a sustained release matrix in which the of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material polyvinylpyrrolidone (PVP), preferably in an amount of from 2.0 to 21% by weight, e.g. B. 10 ⁇ 5.0% by weight or 15 ⁇ 5.0% by weight, in each case based on the total weight of the dosage form.
  • PVP polyvinylpyrrolidone
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix comprises as extended-release matrix material polyvinylpyrrolidone-vinyl acetate copolymer (PVP/PVAc), preferably in an amount of 1.0 to 30% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • PVP/PVAc polyvinylpyrrolidone-vinyl acetate copolymer
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix comprises as extended-release matrix material poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), preferably in an amount of 5.0 to 45% by weight.
  • % e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) is commercially available e.g. B. available as Eudragit® RS and Eudragit®RL.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix comprises as extended-release matrix material poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), preferably in an amount of 5.0 up to 45% by weight, e.g.
  • B 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) is commercially available e.g. B. available as Eudragit® E.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material poly(methyl methacrylate-co-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. B.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B.
  • the extended-release matrix comprising as extended-release matrix material poly(ethyl acrylate-co-methacrylic acid), preferably in an amount of from 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Poly(ethyl acrylate-co-methacrylic acid) is commercially available e.g. B. available as Eudragit® S.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix comprises as extended-release matrix material poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), preferably in an amount of 5.0 to 45% by weight. %, e.g. B.
  • Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) is commercially available e.g. B. available as Eudragit® FS.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material poly(ethyl acrylate-co-methyl methacrylate), preferably in an amount of from 5.0 to 45% by weight, e.g. B.
  • Poly(ethyl acrylate-co-methyl methacrylate) is commercially available e.g. B. available as Eudragit® NE.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on the free base of tapentadol, and an extended-release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, is embedded, the extended-release matrix as extended-release matrix material poly( ethylene oxide) (PEO), preferably in an amount of 25 to 65% by weight, e.g. B. 35 ⁇ 10% by weight or 40 ⁇ 10% by weight or 45 ⁇ 10% by weight or 50 ⁇ 10% by weight or 55 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • PEO extended-release matrix material
  • PEO poly( ethylene oxide)
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material polyethylene glycol (PEG), preferably in an amount of from 5.0 to 35% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • PEG polyethylene glycol
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix comprises as extended-release matrix material a long-chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated and straight-chain or branched , preferably in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • the extended-release matrix comprises as extended-release matrix material a long-chain fatty alcohol having 8 to 50 carbon atoms,
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material cetostearyl alcohol, preferably in an amount of from 15 to 40% by weight, e.g. B.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material stearyl alcohol, preferably in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material cetyl alcohol, preferably in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid, wherein the extended-release matrix contains as extended-release matrix material a hydrocarbon selected from the group of long-chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, saturated or unsaturated and straight-chain or branched, glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes, each preferably in an amount of from 5.0 to 70% by weight, e.g.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, z. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol with L-(+)-tartaric acid embedded, wherein the Extended release matrix comprises xanthan as the extended release matrix material, preferably in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the prolonged-release matrix comprising as prolonged-release matrix material sodium alginate, preferably in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material guar gum, preferably in an amount of from 5.0 to 35% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • the pharmaceutical dosage form according to the invention comprises a weight-equivalent dose of tapentadol in the range from 10 to 300 mg, e.g. B. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, each based on tapentadol free base, and a sustained release matrix in which the salt of tapentadol with tartaric acid, preferably the salt of tapentadol embedded with L-(+)-tartaric acid, the extended-release matrix comprising as extended-release matrix material locust bean gum, preferably in an amount of from 5.0 to 35% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • an extended release matrix can also contain appropriate amounts of other materials, e.g. B. diluents, lubricants, binders, granulation auxiliaries, dyes, flavorings and accompanying agents customary in pharmacy.
  • Pharmaceutical dosage forms containing extended release matrices in which tapentadol is embedded can be prepared by conventional methods known to those skilled in the art such as mixing and direct compression, dry granulation, wet granulation, extrusion and the like.
  • the pharmaceutical dosage form according to the invention is a capsule which preferably contains a multiplicity of particles containing a prolonged-release coating.
  • the pharmaceutical dosage form according to the invention is a tablet.
  • the tablet is preferably monolithic.
  • monolithic tablets are optionally film-coated tablets in which the tablet cores contain a compressed powder and/or a mixture of granules.
  • tablets produced by direct compression of powder mixtures are all to be considered as monolithic tablets according to the invention.
  • MUPS Multiple Unit Pellet Systems
  • MUPS Multiple Unit Pellet Systems
  • capsules that are precipitated with a large number of loose particles are also not to be regarded as monolithic.
  • the tablet preferably has a breaking strength of at least 100 N, preferably at least 150 N, particularly preferably at least 200 N.
  • the breaking strength is preferably determined according to Ph. Eur. 10, Chapter 2.9.8. "Resistance to Crushing of Tablets'".
  • Another aspect of the invention relates to a method for producing a pharmaceutical dosage form according to the invention as described above.
  • the production method according to the invention comprises the following steps according to a preferred embodiment: (A) the provision of inner starting pellets, e.g. B. Sugar spheres containing one or more excipients but no tapentadol;
  • (B) providing a solution or dispersion of tapentadol (including the salt with tartaric acid, especially L-(+)-tartaric acid) in water or an organic solvent or a mixture thereof, optionally with the one or more excipients, the organic solvent is preferably selected from ethanol and acetone;
  • step (C) coating the inner starting pellets provided in step (A) with the solution or dispersion of tapentadol provided in step (B), preferably in a fluidized bed, to obtain intermediate product particles which have an inner core not containing tapentadol and an inner core encapsulating the core drug coating layer comprising substantially all of the amount of tapentadol to be contained in the dosage form, optionally together with the one or more excipients;
  • step (D) optionally drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles;
  • step (F) coating the intermediate product particles obtained in step (C) or the dried intermediate product particles obtained in step (D) with the solution or dispersion of the prolonged-release coating material provided in step (E), preferably in a fluidized bed, to obtain particles with extended release formulations comprising an inner core not containing tapentadol, a core encapsulating drug coating layer comprising substantially the entire amount of tapentadol optionally together with the one or more excipients, and a core and drug coating layer encapsulating sustained release coating layer ;
  • step (G) optionally drying the prolonged-release particles obtained in step (F) to obtain dried prolonged-release particles;
  • step (H) either filling the prolonged-release particles obtained in step (F) or the dried prolonged-release particles obtained in step (G) into capsules; or mixing the extended release particles obtained in step (F) or the dried extended release particles obtained in step (G) with extraparticulate excipients and compressing the mixture into tablets (Multiple Unit Pellet Systems, MUPS).
  • MUPS Multiple Unit Pellet Systems
  • Another aspect of the invention relates to a pharmaceutical dosage form obtainable by this preferred method according to the invention as described above. If the pharmaceutical dosage form contains particles comprising a coating with prolonged release, the production method according to the invention comprises the following steps according to a preferred embodiment:
  • step (B) preparing drug pellets from the mixture provided in step (A) by dry granulation, wet granulation or extrusion, preferably wet granulation comprising the use of a solvent selected from water, ethanol, acetone and any mixture thereof;
  • step (C) optionally drying and/or spheronizing the drug pellets produced in step (B) to obtain dried and/or spheronized drug pellets;
  • step (E) coating the drug pellets produced in step (B) or the dried and/or spheronized drug pellets obtained in step (C) with the solution or dispersion of the prolonged-release coating material provided in step (D), preferably in a fluidized bed obtaining extended-release particles containing a core comprising substantially the total amount of tapentadol, optionally together with one or more excipients, and an extended-release coating encapsulating the core;
  • step (F) optionally drying the prolonged-release particles obtained in step (E) to obtain dried prolonged-release particles;
  • step (G) either discharging the extended-release particles obtained in step (E) or the dried extended-release particles obtained in step (F) into capsules; or mixing the extended release particles obtained in step (E) or dried extended release particles obtained in step (F) with extraparticulate excipients and compressing the mixture into tablets (Multiple Unit Pellet Systems, MUPS).
  • MUPS Multiple Unit Pellet Systems
  • Another aspect of the invention relates to a pharmaceutical dosage form obtainable by this preferred method according to the invention as described above.
  • the pharmaceutical dosage form contains an extended-release matrix in which the tapentadol (including the salt with tartaric acid, in particular L-(+)-tartaric acid) is embedded is, the production method according to the invention comprises the following steps according to a preferred embodiment:
  • step (b) optionally granulating the mixture provided in step (a) to obtain granules, the granulating preferably comprising: (i) wet granulation using a solvent preferably selected from water, ethanol, acetone and any mixture thereof, optionally followed by Dry; (ii) dry granulation; or (iii) extrusion;
  • step (c) optionally mixing the granules obtained in step (b) with one or more excipients to obtain a granulate mixture;
  • step (d) compressing the mixture provided in step (a) or the granules obtained in step (b) or the mixture of granules obtained in step (c) into tablets;
  • step (e) optionally film-coating the tablets compressed in step (d).
  • the pressing in step (d) of the method according to the invention is preferably carried out with a pressing force of not more than 20 kN, particularly preferably not more than 15 kN, even more preferably not more than 10 kN, even more preferably not more than 9, 5 kN, more preferably no more than 9.0 kN, most preferably no more than 8.75 kN and especially no more than 8.5 kN.
  • step (d) of the method according to the invention is preferably carried out under conditions in which the compressed tablet has a breaking strength of at least 100N, more preferably at least 150N, even more preferably at least 200N.
  • the pharmaceutical dosage form according to the invention is preferably not produced by thermal molding such as melt extrusion.
  • the pharmaceutical dosage form according to the invention preferably does not contain a large number of particles or pellets with a specific design, specific shape and specific weight, which are optionally compressed into tablets, in which the particles or pellets form a discontinuous phase in a continuous phase of an outer matrix material .
  • Opioid antagonists are entities that modify the response of opioid receptors.
  • Opioid antagonists include naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, nalinefen, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.
  • Another aspect of the invention relates to the pharmaceutical dosage form according to the invention as described above for use in the treatment of pain, the dosage form being administered orally, preferably twice a day.
  • Another aspect of the invention relates to the use of a salt of tapentadol with tartaric acid, of tapentadol with L-(+)-tartaric acid for the production of a pharmaceutical dosage form according to the invention as described above for the treatment of pain, the dosage form being administered orally, preferably twice daily.
  • Another aspect of the invention relates to a method for the treatment of pain, which comprises the step of orally, preferably twice daily, administering a pharmaceutical dosage form according to the invention as described above to a subject in need thereof.
  • the pain is preferably chronic pain.
  • the pharmaceutical dosage form according to the invention provides in a patient population of at least 10 patients, preferably at least 50 patients, an average Tmax value within the range of 5.0 ⁇ 3.0 hours after oral administration.
  • the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 50 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients having an average value of
  • the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 100 mg, based on the free base of tapentadol, with the dosage form after oral administration in a patient population of at least 50 patients has an average value of
  • the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients having an average value of
  • the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 200 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients having an average value of
  • the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 250 mg, based on the free base of tapentadol, the dosage form after oral administration in a patient population of at least 50 patients having an average value of
  • Article 1 A pharmaceutical dosage form comprising tapentadol for twice daily administration; wherein tapentadol is present as a salt with tartaric acid; wherein the dosage form provides an extended release of tapentadol; and wherein the weight equivalent dose of tapentadol contained in the pharmaceutical dosage form is in the range of 10 to 300 mg in terms of tapentadol free base.
  • Paragraph 2 The pharmaceutical dosage form according to Paragraph 1, wherein the salt is the salt of tapentadol with L-(+)-tartaric acid, a solvate, an ansolvate and/or a polymorph thereof.
  • Paragraph 3 The pharmaceutical dosage form according to Paragraph 1 or 2, which comprises one, two or more physiologically acceptable excipients.
  • Paragraph 4 The pharmaceutical dosage form according to any one of the preceding paragraphs which, after oral administration, provides plasma levels of tapentadol sufficient to provide pain relief over a period of at least 6 hours.
  • the pharmaceutical dosage form according to any one of the preceding paragraphs which has an in vitro dissolution profile, measured by the USP paddle method at 50 rpm in 900 ml of aqueous phosphate buffer at pH 6.8 at 37°C, provides in which after 0.5 hours 20 ⁇ 20% by weight; preferably 20 ⁇ 15% by weight; particularly preferably 20 ⁇ 10% by weight; after 4 hours 60 ⁇ 20% by weight; preferably 60 ⁇ 15% by weight; particularly preferably 60 ⁇ 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form has been released.
  • Paragraph 6 The pharmaceutical dosage form according to any one of the preceding paragraphs, which has an in vitro dissolution profile, measured by the USP paddle method at 50 rpm in 900 ml of aqueous phosphate buffer at pH 6.8 at 37°C, in which - after 1 hour 25 ⁇ 15% by weight; - after 2 hours 35 ⁇ 20% by weight; - after 4 hours 50 ⁇ 20% by weight; - after 8 hours 80 ⁇ 20% by weight % of the tapentadol originally contained in the dosage form have been released.
  • Paragraph 7 The pharmaceutical dosage form according to any one of the preceding paragraphs, which has an in vitro dissolution rate measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at pH 4.5 at 37°C, provides in which after 0.5 hours 20 ⁇ 20% by weight; preferably 20 ⁇ 15% by weight; particularly preferably 20 ⁇ 10% by weight; after 4 hours 60 ⁇ 20% by weight; preferably 60 ⁇ 15% by weight; particularly preferably 60 ⁇ 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form has been released.
  • Paragraph 8 The pharmaceutical dosage form according to any one of the preceding paragraphs, which has an in vitro dissolution rate measured by the USP paddle method at 50 rpm in 900 ml of aqueous buffer at pH 4.5 at 37°C, provides at which - after 1 hour 25 ⁇ 15 % by weight; - after 2 hours 35 ⁇ 20% by weight; - after 4 hours 50 ⁇ 20% by weight; - after 8 hours 80 ⁇ 20% by weight of the tapentadol originally contained in the dosage form have been released .
  • Paragraph 9 The pharmaceutical dosage form of any preceding paragraph, which has an in vitro dissolution profd measured by the USP paddle method at 50 rpm in 900 mL of 0.1N HCl at pH 1.0 and 37 °C, at which after 0.5 hours 20 ⁇ 20% by weight; preferably 20 ⁇ 15% by weight; particularly preferably 20 ⁇ 10% by weight; after 4 hours 60 ⁇ 20% by weight; preferably 60 ⁇ 15% by weight; particularly preferably 60 ⁇ 10% by weight; and after 12 hours at least 60% by weight; preferably at least 70% by weight; particularly preferably at least 80% by weight of the tapentadol originally contained in the dosage form has been released.
  • Paragraph 10 The pharmaceutical dosage form of any preceding paragraph, which has an in vitro dissolution profd measured by the USP paddle method at 50 rpm in 900 mL of 0.1N HCl at pH 1.0 and 37 °C, at which - after 1 hour 25 ⁇ 10% by weight; - after 2 hours 40 ⁇ 30% by weight; - after 4 hours 60 ⁇ 20% by weight; - after 8 hours 80 ⁇ 20% % by weight of the tapentadol originally contained in the dosage form have been released.
  • Paragraph 11 The pharmaceutical dosage form of any preceding Paragraph which provides resistance to ethanol-induced dose dumping.
  • Paragraph 12 The pharmaceutical dosage form of Paragraph 11, which provides slower in vitro dissolution of tapentadol in aqueous ethanolic medium than in aqueous non-ethanolic medium.
  • Paragraph 13 The pharmaceutical dosage form according to Paragraph 11 or 12 which has a slower dissolution of tapentadol in 0.1N HCl with 40% v/v ethanol (pH 1.0) than in 0.1N HCl without 40% v/v ethanol (pH 1.0), each measured by the USP paddle method at 50 rpm in 900 mL at 37°C.
  • Paragraph 14 The pharmaceutical dosage form according to any one of the preceding paragraphs, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 25 mg, 50 mg or 100 mg, in each case based on tapentadol free base.
  • Paragraph 15 The pharmaceutical dosage form according to Paragraph 14, wherein the dosage form has a total weight in the range of 150 to 750 mg.
  • Paragraph 16 The pharmaceutical dosage form according to any one of Paragraphs 1 to 13, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg, 200 mg or 250 mg, each based on tapentadol free base.
  • Paragraph 17 The pharmaceutical dosage form according to Paragraph 16, wherein the dosage form has a total weight in the range of 300 to 1200 mg.
  • Paragraph 18 The pharmaceutical dosage form according to any one of the preceding Paragraphs, wherein the dosage form comprises an extended release coating which comprises an extended release coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy products and mixtures thereof.
  • an extended release coating which comprises an extended release coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy products and mixtures thereof.
  • Paragraph 19 The pharmaceutical dosage form according to Paragraph 18, wherein the extended-release coating material is preferably selected from the group consisting of acrylic acid and methacrylic acid copolymers, aminoalkyl methacrylate copolymers, cyanoethyl methacrylates, ethoxyethyl methacrylates, ethyl cellulose, methacrylic acid alkylamide copolymers, methacrylic acid copolymers, methyl methacrylates, methyl methacrylate copolymers , poly(acrylic acid), poly(methacrylic acid) (anhydride), poly(methacrylic acid), glycidyl methacrylate copolymers, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide and polymethacrylate.
  • acrylic acid and methacrylic acid copolymers aminoalkyl methacrylate copolymers, cyanoethyl methacrylates, ethoxyethyl meth
  • Paragraph 20 The pharmaceutical dosage form according to any one of the preceding paragraphs, wherein tapentadol is embedded in a sustained release matrix.
  • Paragraph 21 The pharmaceutical dosage form of Paragraph 20, wherein the extended release matrix comprises or consists essentially of at least one extended release matrix material selected from the group consisting of hydrophilic or hydrophobic polymers and hydrocarbons.
  • Paragraph 22 The pharmaceutical dosage form of Paragraph 21, wherein the extended release matrix comprises at least one polymer selected from the group consisting of polysaccharides or gums (e.g. xanthan gum, guar gum, karaya gum, locust bean gum, sodium alginate, carob gum, chitosan, polysaccharides of mannose and galactose, pectin, tragacanth, agar); cellulose ethers (e.g. HPMC, HPC, HEC, MC, EC); cellulose esters (e.g.
  • polysaccharides or gums e.g. xanthan gum, guar gum, karaya gum, locust bean gum, sodium alginate, carob gum, chitosan, polysaccharides of mannose and galactose, pectin, tragacanth, agar
  • cellulose ethers e.g. HPMC, HPC, HEC, MC, EC
  • PHEMA polyhydroxyethyl methacrylate
  • Paragraph 23 The pharmaceutical dosage form of Paragraph 21 or 22, wherein the extended release matrix comprises at least one hydrocarbon selected from the group consisting of comprises or consists essentially of long-chain (C8-C50, in particular C12-C40) fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral oils, vegetable oils and waxes.
  • C8-C50 long-chain fatty acids
  • fatty alcohols fatty alcohols
  • glyceryl esters of fatty acids mineral oils, vegetable oils and waxes.
  • Paragraph 24 The pharmaceutical dosage form of any one of Paragraphs 20 to 23, wherein the extended release matrix comprises an extended release matrix material selected from the group consisting of (i) hydroxypropylmethylcellulose (HPMC); (ii) hydroxypropyl cellulose (HPC); (iii) hydroxyethyl cellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethyl cellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinyl acetate copolymer (PVP/PVAc); (ix) poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride); (x) poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); (xi)
  • Paragraph 25 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, hydroxypropylmethylcellulose (HPMC) in an amount of 5.0 to 50% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight or 40 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • HPMC hydroxypropylmethylcellulose
  • Paragraph 26 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, hydroxypropylcellulose (HPC) in an amount of 10 to 50% by weight, e.g. B. 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight or 40 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • HPC hydroxypropylcellulose
  • Paragraph 27 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, hydroxyethyl cellulose (HEC) in an amount of 5.0 to 50% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight or 40 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • HEC hydroxyethyl cellulose
  • Paragraph 28 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, microcrystalline cellulose (MCC) in an amount of 10 to 70% by weight, e.g. B. 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight or 40 ⁇ 10% by weight or 45 ⁇ 10% by weight or 50 ⁇ 10% by weight or 55 ⁇ 10% by weight or 60 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • Paragraph 29 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, ethyl cellulose (EC) in an amount of 5.0 to 30% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • MCC microcrystalline cellulose
  • Paragraph 30 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, polyvinyl acetate (PVAc) in an amount of 25 to 70% by weight, e.g. B. 35 ⁇ 10% by weight or 40 ⁇ 10% by weight or 45 ⁇ 10% by weight or 50 ⁇ 10% by weight or 55 ⁇ 10% by weight or 60 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • PVAc polyvinyl acetate
  • Paragraph 31 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, polyvinylpyrrolidone (PVP) in an amount of from 2.0 to 21% by weight, e.g. B. 10 ⁇ 5.0% by weight or 15 ⁇ 5.0% by weight, in each case based on the total weight of the dosage form.
  • PVP polyvinylpyrrolidone
  • Paragraph 32 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, polyvinylpyrrolidone-vinyl acetate copolymer (PVP/PVAc) in an amount of 1.0 to 30% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • PVP/PVAc polyvinylpyrrolidone-vinyl acetate copolymer
  • Paragraph 33 The pharmaceutical dosage form according to Paragraph 24, wherein the extended release matrix comprises as extended release matrix material poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in an amount of 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • extended release matrix material poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in an amount of 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • Paragraph 34 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) in an amount of from 5.0 to 45% by weight %, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) in an amount of from 5.0 to 45% by weight %, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • Paragraph 35 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, poly(methyl methacrylate-co-methacrylic acid) in an amount of 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • poly(methyl methacrylate-co-methacrylic acid) in an amount of 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • Paragraph 36 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, poly(ethyl acrylate-co-methacrylic acid) in an amount of from 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • poly(ethyl acrylate-co-methacrylic acid) in an amount of from 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • Paragraph 37 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) in an amount of 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) in an amount of 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • Paragraph 38 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, poly(ethyl acrylate-co-methyl methacrylate) in an amount of from 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • poly(ethyl acrylate-co-methyl methacrylate) in an amount of from 5.0 to 45% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight or 30 ⁇ 10% by weight or 35 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • Paragraph 39 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, poly(ethylene oxide) (PEO) in an amount of 25 to 65% by weight, e.g. B. 35 ⁇ 10% by weight or 40 ⁇ 10% by weight or 45 ⁇ 10% by weight or 50 ⁇ 10% by weight or 55 ⁇ 10% by weight, in each case based on the total weight of the dosage form, includes.
  • PEO poly(ethylene oxide)
  • Paragraph 40 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, polyethylene glycol (PEG) in an amount of 5.0 to 35% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • PEG polyethylene glycol
  • Paragraph 41 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, a long-chain fatty alcohol having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated and straight-chain or branched, in an amount from 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • Paragraph 42 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix contains, as the extended-release matrix material, cetostearyl alcohol in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Paragraph 43 The pharmaceutical dosage form according to Paragraph 24, wherein the prolonged-release matrix comprises, as the prolonged-release matrix material, stearyl alcohol in an amount from 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, based in each case on the total weight of the dosage form.
  • Paragraph 44 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix contains, as the extended-release matrix material, cetyl alcohol in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • cetyl alcohol in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Paragraph 45 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix contains as extended-release matrix material a hydrocarbon selected from the group of long-chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, saturated or unsaturated and straight-chain or branched may be, glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes, each in an amount of from 5.0 to 70% by weight, e.g. B.
  • a hydrocarbon selected from the group of long-chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, saturated or unsaturated and straight-chain or branched
  • glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils and waxes each in an amount of from 5.0 to 70% by weight, e.g. B.
  • Paragraph 46 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix contains xanthan as the extended-release matrix material in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Paragraph 47 The pharmaceutical dosage form according to Paragraph 24, wherein the prolonged-release matrix comprises, as the prolonged-release matrix material, sodium alginate in an amount of 15 to 40% by weight, e.g. B. 25 ⁇ 10% by weight or 30 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Paragraph 48 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, guar gum in an amount of from 5.0 to 35% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Paragraph 49 The pharmaceutical dosage form according to Paragraph 24, wherein the extended-release matrix comprises, as the extended-release matrix material, locust bean gum in an amount of from 5.0 to 35% by weight, e.g. B. 15 ⁇ 10% by weight or 20 ⁇ 10% by weight or 25 ⁇ 10% by weight, in each case based on the total weight of the dosage form.
  • Paragraph 50 The pharmaceutical dosage form according to any one of the preceding Paragraphs, which is a capsule.
  • Paragraph 51 The pharmaceutical dosage form of any one of Paragraphs 1 to 49 which is a tablet.
  • Paragraph 52 The pharmaceutical dosage form of Paragraph 51, wherein the tablet is monolithic.
  • Paragraph 53 The pharmaceutical dosage form according to Paragraph 51 or 52, wherein the tablet has a crush strength of at least 100 N.
  • Paragraph 54 The dosage form of any preceding Paragraph for use in the treatment of pain, wherein the dosage form is administered orally twice daily.
  • Paragraph 55 The dosage form for use according to paragraph 54, wherein the pain is chronic pain.
  • Paragraph 56 The dosage form for use according to Paragraph 54 or 55, which provides a mean Tmax within the range of 5.0 ⁇ 3.0 hours after oral administration in a patient population of at least 10 patients.
  • Paragraph 57 The dosage form for use according to any one of Paragraphs 54 to 56, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 50 mg in terms of tapentadol free base, and wherein the dosage form after oral administration in a patient population of at least 10 patients had a mean Cmax in the range of 12 ⁇ 3 ng/mL; and/or AUClast in the range of 204 ⁇ 50 ng h/ml; and/or AUCoo in the range of 214 ⁇ 50 ng h/ml.
  • Paragraph 58 The dosage form for use according to any one of Paragraphs 54 to 56, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 100 mg in terms of tapentadol free base, and wherein the dosage form after oral administration in a patient population of at least 10 patients had a mean Cmax in the range of 29 ⁇ 6 ng/mL; and/or AUClast in the range of 440 ⁇ 100 ng h/ml; and/or AUCoo in the range of 447 ⁇ 100 ng h/ml.
  • Paragraph 59 The dosage form for use according to any one of Paragraphs 54 to 56, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 150 mg in terms of tapentadol free base, and wherein the dosage form after oral administration in a patient population of at least 10 patients had a mean Cmax in the range of 47 ⁇ 9 ng/mL; and/orAU Clast in the range of 662 ⁇ 150 ng h/ml; and/or AUCoo in the range of 665 ⁇ 150 ng h/ml.
  • Paragraph 60 The dosage form for use according to any one of Paragraphs 54 to 56, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 200 mg in terms of tapentadol free base, and wherein the dosage form after oral administration in a patient population of at least 10 patients had a mean Cmax in the range of 64 ⁇ 12 ng/mL; and/orAUClast in the range of 890 ⁇ 200 ng h/ml; and/or AUCoo in the range of 895 ⁇ 200 ng h/ml.
  • Paragraph 61 The dosage form for use according to any one of Paragraphs 54 to 56, wherein the weight-equivalent dose of tapentadol contained in the pharmaceutical dosage form is 200 mg in terms of tapentadol free base, and wherein the dosage form after oral administration in a patient population of at least 10 patients had a mean Cmax in the range of 64 ⁇ 12 ng/mL; and/orAUClast in the range of 890 ⁇ 200 ng
  • Paragraph 62 A process for the manufacture of a pharmaceutical dosage form comprising extended release coated particles according to any one of the preceding Paragraphs, the process comprising the steps of: (A) providing starting inner pellets containing one or more excipients but no tapentadol ; (B) providing a solution or dispersion of tapentadol in water or an organic solvent or a mixture thereof, optionally with the one or more excipients; (C) coating the inner starting pellets provided in step (A) with the solution or dispersion of tapentadol provided in step (B) to obtain intermediate product particles having an inner core not containing tapentadol and a drug coating layer encapsulating the core, which essentially the total amount of tapentadol to be contained in the dosage form, optionally together with the one or more excipients; (D) optionally drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles; (E) providing a solution or dispersion of an extended release coating material in water or an
  • Section 63 A pharmaceutical dosage form obtainable by the process of Section 62.
  • Paragraph 64 A process for the manufacture of a pharmaceutical dosage form comprising particles comprising an extended release coating according to any one of Paragraphs 1 to 61, the process comprising the steps of: (A) providing substantially all of the amount of tapentadol contained in the dosage form should contain, containing mixture, optionally together with one or more excipients; (B) the production of drug pellets from the mixture provided in step (A) by dry granulation, wet granulation or extrusion; (C) optionally drying and/or spheronizing the drug pellets produced in step (B) to obtain dried and/or spheronized drug pellets; (D) providing a solution or dispersion of an extended release coating material in water or an organic solvent or mixture thereof, optionally with one or more excipients; (E) coating the drug pellets produced in step (B) or the dried and/or spheronized drug pellets obtained in step (C) with the solution
  • Section 65 A pharmaceutical dosage form obtainable by the process of Section 64.
  • Paragraph 66 A process for the manufacture of a pharmaceutical dosage form comprising an extended release matrix embedding tapentadol according to any one of Paragraphs 1 to 61, the process comprising the steps of: (a) providing substantially the entire amount a mixture containing tapentadol to be contained in the dosage form and at least one matrix material with prolonged release, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a) to obtain granules, (c) optionally mixing the granules obtained in step (b) with one or more excipients to obtain a granulate mixture; (d) compressing the mixture provided in step (a) or the granules obtained in step (b) or the mixture of granules obtained in step (c) into tablets; (e) optionally film-coating the tablets compressed in step (d).
  • Paragraph 67 The method according to Paragraph 66, wherein the pressing in step (d) with a pressing force of not more than 20 kN, more preferably not more than 15 kN, even more preferably not more than 10 kN, even more preferably not more than 9.5 kN, even more preferably no more than 9.0 kN, most preferably no more than 8.75 kN and in particular no more than 8.5 kN.
  • a pharmaceutical dosage form comprising a plurality of coated particles; said coated particles comprising a salt of tapentadol with tartaric acid and having a tapentadol sustained release coating comprising ethyl cellulose; the dosage form releases tapentadol in a delayed manner; and wherein the weight equivalent dose of tapentadol contained in the dosage form is in the range of 10 to 300 mg, based on tapentadol free base.
  • Sentence 2 The pharmaceutical dosage form according to sentence 1, wherein the dosage form comprises only those coated particles which are essentially of the same nature.
  • Sentence 3 The pharmaceutical dosage form according to sentence 1, wherein the dosage form comprises at least two different types of coated particles which differ from one another in at least one property.
  • Clause 4 The pharmaceutical dosage form according to Clause 3, wherein the at least one property is selected from the group consisting of content of salt of tapentadol with tartaric acid, type of pharmaceutical excipient, content of pharmaceutical excipient, and content of coating for sustained release of tapentadol.
  • Clause 5 The pharmaceutical dosage form according to any one of the preceding clauses, wherein the salt of tapentadol with tartaric acid has a stoichiometric ratio of tapentadol: tartaric acid in the range of 2.0:1.0 to 1.0:2.0, preferably in the range of 1.5:1.0 to 1.0:1.5.
  • Clause 7 The pharmaceutical dosage form according to any one of clauses 1 to 5, wherein the salt of tapentadol with tartaric acid is crystalline.
  • Clause 8 The pharmaceutical dosage form according to any one of the preceding clauses, wherein the salt of tapentadol is a salt with L-(+)-tartaric acid, a solvate, an ansolvate and/or a polymorph thereof.
  • Clause 9 The pharmaceutical dosage form according to Clause 8, wherein the salt of tapentadol is a crystalline salt with L-(+)-tartaric acid having characteristic X-ray powder diffraction peaks at 14.1, 20.0, 21.1 and 23.7 degrees 20 ( ⁇ 0.2 grade 20).
  • Sentence 10 The pharmaceutical dosage form according to sentence 9, characterized in that it has one or more further X-ray powder diffraction peaks at 12.7, 18.6, 21.6, 22.1, 25.6 and/or 28.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Clause 11 The pharmaceutical dosage form according to any one of the preceding clauses, which is a capsule containing the coated particles, optionally together with additional pharmaceutical excipients, which are contained in the capsule in powder form or also in the form of particles .
  • Clause 12 The pharmaceutical dosage form of any one of clauses 1 to 10, which is a tablet incorporating the coated particles and containing an extraparticulate material.
  • Clause 13 The pharmaceutical dosage form according to Clause 12, wherein the extraparticulate material contains at least one pharmaceutical excipient selected from binders, disintegrants and lubricants.
  • Clause 14 The pharmaceutical dosage form according to any one of the preceding clauses, wherein the dosage form contains no other forms of tapentadol apart from the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid.
  • - a core comprising substantially all of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with one or more pharmaceutical excipients, and
  • Sentence 16 The pharmaceutical dosage form according to sentence 15, wherein the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, is distributed homogeneously in the core.
  • Sentence 17 The pharmaceutical dosage form according to sentence 15 or 16, wherein the content of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, in the core is in the range from 50 to 90% by weight, based on the total weight of the core
  • Clause 18 The pharmaceutical dosage form according to any one of clauses 15 to 17, wherein the core contains one or more binders.
  • Clause 19 The pharmaceutical dosage form according to Clause 18, wherein the binder or binders are independently selected from the group consisting of cellulose, cellulose derivatives, magnesium aluminum silicates, mono-, oligo- and polysaccharides, sugar alcohols, starches, calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone vinyl acetate copolymers; preferably microcrystalline cellulose, silicified microcrystalline cellulose and/or hydroxypropyl cellulose.
  • Clause 20 The pharmaceutical dosage form according to Clause 18 or 19, wherein the total content of all binders in the core is in the range from 5.0 to 50% by weight, based on the total weight of the core.
  • Clause 21 The pharmaceutical dosage form of any one of clauses 15 to 20, wherein the core contains one or more lubricants.
  • lubricant or lubricants are independently selected from the group consisting of salts of fatty acids, fatty acids, glyceryl fatty acid esters, sorbitan monostearate, sucrose monopaimitate, sodium stearyl fumarate, hydrated magnesium silicate, and talc; preferably magnesium stearate.
  • Clause 23 The pharmaceutical dosage form according to Clause 21 or 22, wherein the total content of all lubricants in the core is in the range of 0.1 to 5.0% by weight based on the total weight of the core.
  • Clause 24 The pharmaceutical dosage form of any one of clauses 15 to 23, wherein the core comprises extruded and optionally spheronized pellets.
  • Clause 25 The pharmaceutical dosage form of any one of clauses 15 to 23, wherein the core comprises microtablets.
  • Clause 26 The pharmaceutical dosage form according to any one of clauses 15 to 25, wherein the core comprises microcrystalline cellulose in a content ranging from 5.0 to 25% by weight based on the total weight of the core, and hydroxypropyl cellulose in a content ranging from 5.0 to 25% by weight based on the total weight of the core.
  • Clause 27 The pharmaceutical dosage form of any one of Clauses 15 to 25, wherein the core comprises silicified microcrystalline cellulose in the range of 5.0 to 50% by weight based on the total weight of the core and magnesium stearate in the range from 0.1 to 5.0% by weight based on the total weight of the core.
  • Clause 28 The pharmaceutical dosage form according to any one of clauses 15 to 27, wherein the pharmaceutical dosage form is obtainable by a process comprising the following steps:
  • step (B) production of drug pellets or microtablets from the mixture provided in step (A) by dry granulation, wet granulation, extrusion or direct compression;
  • step (C) optionally drying and/or spheronizing the drug pellets or microtablets produced in step (B) to obtain dried and/or spheronized drug pellets or microtablets;
  • step (E) coating the drug pellets or microtablets produced in step (B) or the dried and/or spheronized drug pellets or microtablets obtained in step (C) with the solution or dispersion of the coating material provided in step (D) to obtain coated particles with sustained release, which contain a core comprising essentially the total amount of salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with one or more pharmaceutical excipients, and a coating encapsulating the core for the sustained release of tapentadol ;
  • step (F) optionally drying the coated particles obtained in step (E) to obtain dried coated particles;
  • step (G) either scraps of the coated particles obtained in step (E) or the dried coated particles obtained in step (F) in capsules; or mixing the coated particles obtained in step (E) or the dried coated particles obtained in step (F) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets.
  • an inert core which does not contain a salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid,
  • Clause 30 The pharmaceutical dosage form of Clause 29, wherein the inert core is a sugar sphere, microcrystalline cellulose sphere or lactose crystal.
  • Sentence 31 The pharmaceutical dosage form according to sentence 29 or 30, wherein the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, is distributed homogeneously in the active substance layer.
  • Clause 32 The pharmaceutical dosage form according to any one of Clauses 29 to 31, wherein the content of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, in the active substance layer is in the range from 50 to 90% by weight, based on the total weight of the inert core and the drug layer.
  • Clause 33 The pharmaceutical dosage form according to any one of clauses 29 to 32, wherein the drug layer contains one or more glidants.
  • Clause 34 The pharmaceutical dosage form of Clause 33, wherein the or more flow modifiers are independently selected from the group consisting of silica gel, colloidal silica, precipitated silica, talc, kaolin, and glycerol monostearate; preferably colloidal anhydrous silicon dioxide.
  • Clause 35 The pharmaceutical dosage form according to Clause 33 or 34, wherein the total content of all flow control agents in the drug layer is in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the drug layer.
  • Clause 36 The pharmaceutical dosage form according to any one of clauses 29 to 35, wherein the active substance layer contains one or more film formers.
  • Clause 37 The pharmaceutical dosage form of Clause 36, wherein the or more film formers are independently selected from the group consisting of cellulose ethers and polyvinylpyrrolidone; preferably hydroxypropylmethyl cellulose or ethyl cellulose.
  • Clause 38 The pharmaceutical dosage form according to Clause 36 or 37, wherein the total content of all film formers in the active substance layer is in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • Clause 39 The pharmaceutical dosage form according to any one of clauses 29 to 38, wherein the inert core forms a build-up pellet with the drug layer encapsulating the inert core.
  • Clause 40 The pharmaceutical dosage form according to any one of clauses 29 to 39, wherein the active substance layer comprises colloidal anhydrous silicon dioxide with a content in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the active substance layer, and Ethyl cellulose in a content in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • the active substance layer comprises colloidal anhydrous silicon dioxide with a content in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the active substance layer, and Ethyl cellulose in a content in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • Sentence 41 The pharmaceutical dosage form according to any one of sentences 29 to 39, wherein the active substance layer comprises colloidal anhydrous silicon dioxide with a content in the range from 0.1 to 5.0% by weight, based on the total weight of the inert core and the active substance layer, and Hydroxypropylmethylcellulose in a content in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • Clause 42 The pharmaceutical dosage form according to any one of clauses 29 to 41, wherein the pharmaceutical dosage form is obtainable by a process comprising the following steps:
  • composition comprising the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with one or more pharmaceutical excipients;
  • step (C) Coating the inert cores provided in step (A) with the composition provided in step (B) to obtain intermediate product particles which contain an inert core containing no salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, and a the active ingredient layer encapsulating the inert core, which essentially comprises the entire amount of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, which is to be contained in the dosage form, optionally together with the one or more pharmaceutical excipients;
  • step (D) optionally drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles;
  • step (F) coating the intermediate product particles obtained in step (C) or the dried intermediate product particles obtained in step (D) with the solution or dispersion of the coating material provided in step (E) to obtain coated sustained-release particles which do not contain a salt of tapentadol with an inert core containing tartaric acid, in particular L-(+)-tartaric acid, an active substance layer encapsulating the inert core, which essentially comprises the entire amount of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with the one or more pharmaceutical excipients, and a coating encapsulating the inert core and the active substance layer for the delayed release of tapentadol;
  • step (G) optionally drying the coated particles obtained in step (F) to obtain dried coated particles; and (H) filling either the coated particles obtained in step (F) or the dried coated particles obtained in step (G) into capsules; or mixing the coated particles obtained in step (F) or the dried coated particles obtained in step (G) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets.
  • Clause 43 The pharmaceutical dosage form of Clause 42, wherein the composition provided in step (B) is a dispersion or solution in water or in an organic solvent or a mixture thereof.
  • Clause 44 The pharmaceutical dosage form of clause 42 or 43, wherein step (C) is performed by powder coating in a coating pan.
  • Clause 45 The pharmaceutical dosage form according to Clause 43 or 44, wherein step (C) is carried out by spraying the inert cores in a fluid bed coater.
  • Clause 46 The pharmaceutical dosage form according to any one of the preceding clauses, wherein the coating for the sustained release of tapentadol contains talc in addition to ethylcellulose.
  • Clause 47 The pharmaceutical dosage form of Clause 46, wherein the relative weight ratio of ethylcellulose:talc is in the range of 2:1 to 1:20; preferably 2:1 to 1:2, or 1:8 to 1:12.
  • Clause 48 The pharmaceutical dosage form according to any one of the preceding clauses, wherein the coating for the sustained release of tapentadol comprises, in addition to ethylcellulose, one or more plasticizers.
  • Clause 50 The pharmaceutical dosage form according to Clause 48 or 49, wherein the total content of all plasticizers in the controlled-release coating for tapentadol is in the range of 5.0 to 20% by weight, based on the total weight of the coating.
  • Clause 51 The pharmaceutical dosage form according to any one of the preceding clauses, wherein the content of the sustained-release coating for tapentadol is in the range of 5.0 to 20% by weight based on the total weight of the coated particles.
  • Clause 52 The pharmaceutical dosage form according to any one of Clauses 1 to 50, wherein the content of the sustained-release coating for tapentadol is in the range of 15 to 30% by weight based on the total weight of the coated particles.
  • Clause 53 The pharmaceutical dosage form according to any one of Clauses 1 to 50, wherein the content of the sustained-release coating for tapentadol is in the range of 25 to 40% by weight based on the total weight of the coated particles.
  • Clause 54 The pharmaceutical dosage form according to any one of clauses 1 to 50, wherein the content of the sustained-release coating for tapentadol is in the range of 35 to 50% by weight based on the total weight of the coated particles.
  • Clause 55 The pharmaceutical dosage form according to any one of Clauses 1 to 50, wherein the content of the sustained-release coating for tapentadol is in the range of 45 to 60% by weight based on the total weight of the coated particles.
  • Clause 56 The pharmaceutical dosage form according to any one of the preceding clauses, which provides an in vitro dissolution rate measured at 50 rpm in 900 ml aqueous phosphate buffer at pH 6.8 at 37°C, in which
  • Clause 58 The pharmaceutical dosage form according to any one of the preceding clauses, which provides an in vitro dissolution rate measured at 50 rpm in 900 ml aqueous buffer at pH 4.5 at 37°C, in which
  • Clause 59 The pharmaceutical dosage form according to any one of the preceding clauses, which provides an in vitro dissolution rate measured at 50 rpm in 900 ml aqueous buffer at pH 4.5 at 37°C, in which - after 1 hour 25 ⁇ 15% by weight;
  • Clause 60 The pharmaceutical dosage form according to any one of the preceding clauses, which provides an in vitro dissolution profd measured at 50 rpm in 900 ml of 0.1N HCl at pH 1.0 and 37°C, in which
  • Clause 62 The pharmaceutical dosage form according to any one of the preceding clauses, which is for twice-daily oral administration.
  • a pharmaceutical dosage form comprising a plurality of coated particles; said coated particles comprising a salt of tapentadol with tartaric acid and having a tapentadol sustained release coating comprising acrylic copolymer; the dosage form releases tapentadol in a delayed manner; and wherein the weight equivalent dose of tapentadol contained in the dosage form ranges from 10 to 300 mg, based on tapentadol free base.
  • Section 2 The pharmaceutical dosage form of Section 1, wherein the dosage form comprises only those coated particles which are essentially the same.
  • Section 3 The pharmaceutical dosage form according to Section 1, wherein the dosage form comprises at least two different types of coated particles which differ from one another in at least one property.
  • Section 4 The pharmaceutical dosage form of Section 3, wherein the at least one property is selected from the group consisting of content of salt of tapentadol with tartaric acid, type of pharmaceutical excipient, content of pharmaceutical excipient, and content of sustained-release coating of tapentadol.
  • Section 5 The pharmaceutical dosage form of any preceding Section, wherein the salt of tapentadol with tartaric acid has a stoichiometric ratio of tapentadol:tartaric acid in the range of 2.0:1.0 to 1.0:2.0, preferably in the range of 1.5:1.0 to 1.0:1.5.
  • Section 6 The pharmaceutical dosage form of any preceding section, wherein the salt of tapentadol with tartaric acid is amorphous.
  • Section 7 The pharmaceutical dosage form of any one of Sections 1 to 5, wherein the salt of tapentadol with tartaric acid is crystalline.
  • Section 8 The pharmaceutical dosage form according to any one of the preceding sections, wherein the salt of tapentadol is a salt with L-(+)-tartaric acid, a solvate, an ansolvate and/or a polymorph thereof.
  • Section 9 The pharmaceutical dosage form according to Section 8, wherein the salt of tapentadol is a crystalline salt with L-(+)-tartaric acid having characteristic X-ray powder diffraction peaks at 14.1, 20.0, 21.1 and 23.7 degrees 20 ( ⁇ 0.2 grade 20).
  • Section 10 The pharmaceutical dosage form according to Section 9, characterized in that it has one or more further X-ray powder diffraction peaks at 12.7, 18.6, 21.6, 22.1, 25.6 and/or 28.5 degrees 20 ( ⁇ 0.2 degrees 20).
  • Section 11 The pharmaceutical dosage form according to any one of the preceding sections, which is a capsule containing the coated particles, optionally together with additional pharmaceutical excipients, which are contained in the capsule in powder form or also in the form of particles .
  • Section 12 The pharmaceutical dosage form of any one of sections 1 to 10 which is a tablet incorporating the coated particles and which contains an extraparticulate material.
  • Section 13 The pharmaceutical dosage form of section 12, wherein the extraparticulate material contains at least one pharmaceutical excipient selected from binders, disintegrants and lubricants.
  • Section 14 The pharmaceutical dosage form according to any one of the preceding sections, wherein the dosage form contains no other forms of tapentadol apart from the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid.
  • Section 15 The pharmaceutical dosage form according to any one of the preceding sections, wherein the coated particles
  • - a core comprising substantially all of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with one or more pharmaceutical excipients, and
  • Section 16 The pharmaceutical dosage form according to Section 15, wherein the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, is distributed homogeneously in the core.
  • Section 17 The pharmaceutical dosage form according to Section 15 or 16, wherein the content of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, in the core is in the range from 50 to 90% by weight, based on the total weight of the core
  • Section 18 The pharmaceutical dosage form of any one of sections 15 to 17, wherein the core contains one or more binders.
  • Section 19 The pharmaceutical dosage form of Section 18, wherein the binder or binders are independently selected from the group consisting of cellulose, cellulose derivatives, magnesium aluminum silicates, mono-, oligo- and polysaccharides, sugar alcohols, starches, calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone vinyl acetate copolymers; preferably microcrystalline cellulose, silicified microcrystalline cellulose and/or hydroxypropyl cellulose.
  • the binder or binders are independently selected from the group consisting of cellulose, cellulose derivatives, magnesium aluminum silicates, mono-, oligo- and polysaccharides, sugar alcohols, starches, calcium phosphate, polyvinylpyrrolidone and vinylpyrrolidone vinyl acetate copolymers; preferably microcrystalline cellulose, silicified microcrystalline cellulose and/or hydroxypropyl cellulose.
  • Section 20 The pharmaceutical dosage form of section 18 or 19, wherein the total content of all binders in the core is in the range of 5.0 to 50% by weight based on the total weight of the core.
  • Section 21 The pharmaceutical dosage form of any one of sections 15 to 20, wherein the core contains one or more lubricants.
  • Section 22 The pharmaceutical dosage form of Section 21, wherein the lubricant or lubricants are independently selected from the group consisting of salts of fatty acids, fatty acids, glyceryl fatty acid esters, sorbitan monostearate, sucrose monopalmitate, sodium stearyl fumarate, hydrated magnesium silicate, and talc; preferably magnesium stearate.
  • the lubricant or lubricants are independently selected from the group consisting of salts of fatty acids, fatty acids, glyceryl fatty acid esters, sorbitan monostearate, sucrose monopalmitate, sodium stearyl fumarate, hydrated magnesium silicate, and talc; preferably magnesium stearate.
  • Section 23 The pharmaceutical dosage form of section 21 or 22, wherein the total content of all lubricants in the core is in the range of 0.1 to 5.0% by weight based on the total weight of the core.
  • Section 24 The pharmaceutical dosage form of any one of sections 15 to 23, wherein the core comprises extruded and optionally spheronized pellets.
  • Section 25 The pharmaceutical dosage form of any one of Sections 15 to 23, wherein the core comprises microtablets.
  • Section 26 The pharmaceutical dosage form of any one of Sections 15 to 25, wherein the core comprises microcrystalline cellulose in a content ranging from 5.0 to 25% by weight based on the total weight of the core, and hydroxypropyl cellulose in a content ranging from 5.0 to 25% by weight based on the total weight of the core.
  • Section 27 The pharmaceutical dosage form of any one of Sections 15 to 25, wherein the core comprises silicified microcrystalline cellulose in an amount in the range of 5.0 to 50% by weight based on the total weight of the core and magnesium stearate in an amount in the range from 0.1 to 5.0% by weight based on the total weight of the core.
  • Section 28 The pharmaceutical dosage form of any one of Sections 15 to 27, wherein the pharmaceutical dosage form is obtainable by a process comprising the steps of:
  • step (B) production of drug pellets or microtablets from the mixture provided in step (A) by dry granulation, wet granulation, extrusion or direct compression;
  • step (C) optionally drying and/or spheronizing the drug pellets or microtablets produced in step (B) to obtain dried and/or spheronized drug pellets or microtablets;
  • step (E) coating the drug pellets or microtablets produced in step (B) or the dried and/or spheronized drug pellets or microtablets obtained in step (C) with the solution or dispersion of the coating material provided in step (D) to obtain coated particles with sustained release, which contain a core comprising essentially the total amount of salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with one or more pharmaceutical excipients, and a core-encapsulating coating for the sustained release of tapentadol ; (F) optionally drying the coated particles obtained in step (E) to obtain dried coated particles; and
  • step (G) either scraps of the coated particles obtained in step (E) or the dried coated particles obtained in step (F) in capsules; or mixing the coated particles obtained in step (E) or the dried coated particles obtained in step (F) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets.
  • Section 29 The pharmaceutical dosage form of any one of Sections 1 to 14, wherein the coated particles
  • an inert core which does not contain a salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid,
  • Section 30 The pharmaceutical dosage form of Section 29, wherein the inert core is a sugar sphere, microcrystalline cellulose sphere, or lactose crystal.
  • Section 31 The pharmaceutical dosage form according to Section 29 or 30, wherein the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, is homogeneously distributed in the active substance layer.
  • Section 32 The pharmaceutical dosage form according to any one of Sections 29 to 31, wherein the content of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, in the active substance layer is in the range from 50 to 90% by weight, based on the total weight of the inert core and the drug layer.
  • Section 33 The pharmaceutical dosage form of any one of Sections 29 to 32, wherein the drug layer contains one or more flow modifiers.
  • Section 34 The pharmaceutical dosage form of Section 33, wherein the or more flow modifiers are independently selected from the group consisting of silica gel, colloidal silica, precipitated silica, talc, kaolin and glycerol monostearate; preferably colloidal anhydrous silicon dioxide.
  • Section 35 The pharmaceutical dosage form according to Section 33 or 34, wherein the total content of all flow control agents in the drug layer is in the range of 0.1 to 5.0% by weight based on the total weight of the inert core and the drug layer.
  • Section 36 The pharmaceutical dosage form of any one of Sections 29 to 35, wherein the drug layer contains one or more film formers.
  • Section 37 The pharmaceutical dosage form of Section 36, wherein the or more film formers are independently selected from the group consisting of cellulose ethers and polyvinylpyrrolidone; preferably hydroxypropylmethyl cellulose or ethyl cellulose.
  • Section 38 The pharmaceutical dosage form according to Section 36 or 37, wherein the total content of all film formers in the drug layer is in the range of 0.5 to 10% by weight, based on the total weight of the inert core and the drug layer.
  • Section 39 The pharmaceutical dosage form of any one of Sections 29 to 38, wherein the inert core forms a build pellet with the drug layer encapsulating the inert core.
  • Section 40 The pharmaceutical dosage form according to any one of Sections 29 to 39, wherein the drug layer comprises colloidal anhydrous silica in a content ranging from 0.1 to 5.0% by weight based on the total weight of the inert core and the drug layer, and Ethyl cellulose in a content in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • the drug layer comprises colloidal anhydrous silica in a content ranging from 0.1 to 5.0% by weight based on the total weight of the inert core and the drug layer, and Ethyl cellulose in a content in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • Section 41 The pharmaceutical dosage form according to any one of Sections 29 to 39, wherein the drug layer comprises colloidal anhydrous silicon dioxide in a content ranging from 0.1 to 5.0% by weight based on the total weight of the inert core and the drug layer, and Hydroxypropylmethylcellulose in a content in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • the drug layer comprises colloidal anhydrous silicon dioxide in a content ranging from 0.1 to 5.0% by weight based on the total weight of the inert core and the drug layer, and Hydroxypropylmethylcellulose in a content in the range from 0.5 to 10% by weight, based on the total weight of the inert core and the active substance layer.
  • Section 42 The pharmaceutical dosage form of any one of Sections 29 to 41, wherein the pharmaceutical dosage form is obtainable by a process comprising the steps of:
  • composition comprising the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with one or more pharmaceutical excipients;
  • step (C) Coating the inert cores provided in step (A) with the composition provided in step (B) to obtain intermediate product particles which contain an inert core containing no salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, and a active ingredient layer encapsulating the inert core, which essentially contains the entire amount of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, which is to be contained in the dosage form, optionally included together with the one or more pharmaceutical excipients;
  • step (D) optionally drying the intermediate product particles obtained in step (C) to obtain dried intermediate product particles;
  • step (F) coating the intermediate product particles obtained in step (C) or the dried intermediate product particles obtained in step (D) with the solution or dispersion of the coating material provided in step (E) to obtain coated sustained-release particles which do not contain a salt of tapentadol with an inert core containing tartaric acid, in particular L-(+)-tartaric acid, an active substance layer encapsulating the inert core, which essentially comprises the entire amount of the salt of tapentadol with tartaric acid, in particular L-(+)-tartaric acid, optionally together with the one or more pharmaceutical excipients, and a coating encapsulating the inert core and the active substance layer for the delayed release of tapentadol;
  • step (G) optionally drying the coated particles obtained in step (F) to obtain dried coated particles;
  • step (H) either scrapping the coated particles obtained in step (F) or the dried coated particles obtained in step (G) into capsules; or mixing the coated particles obtained in step (F) or the dried coated particles obtained in step (G) with extraparticulate pharmaceutical excipients and compressing the mixture into tablets.
  • Section 43 The pharmaceutical dosage form of Section 42, wherein the composition provided in step (B) is a dispersion or solution in water or in an organic solvent or a mixture thereof.
  • Section 44 The pharmaceutical dosage form of Section 42 or 43, wherein step (C) is performed by powder coating in a coating pan.
  • Section 45 The pharmaceutical dosage form of Section 42 or 43, wherein step (C) is performed by spraying the inert cores in a fluid bed coater.
  • Section 46 The pharmaceutical dosage form of any preceding section, wherein the acrylic copolymer is a copolymer based on at least two comonomers independently selected from acrylic acid, methacrylic acid, acrylate esters, and methacrylate esters.
  • Section 47 The pharmaceutical dosage form according to one of the preceding sections, wherein the acrylic copolymer is a copolymer based on the comonomers ethyl acrylate and methyl methacrylate, optionally additionally in combination with trimethylaminoethyl methacrylate chloride (TAMCI).
  • TAMCI trimethylaminoethyl methacrylate chloride
  • Section 48 The pharmaceutical dosage form of any preceding section, wherein the acrylic copolymer is poly(ethyl acrylate-co-methyl methacrylate) or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride); preferably poly(ethyl acrylate-co-methyl methacrylate).
  • the acrylic copolymer is poly(ethyl acrylate-co-methyl methacrylate) or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride); preferably poly(ethyl acrylate-co-methyl methacrylate).
  • Section 49 The pharmaceutical dosage form of section 47 or 48, wherein the relative ratio of ethyl acrylate to methyl methacrylate is about 2:1.
  • Section 50 The pharmaceutical dosage form of any preceding section, wherein the tapentadol sustained release coating comprises talc in addition to the acrylic copolymer.
  • Section 51 The pharmaceutical dosage form of Section 50, wherein the relative weight ratio of acrylic copolymer: talc is in the range of 3:1 to 1:3; preferably 2:1 to 1:2.
  • Section 52 The pharmaceutical dosage form according to any one of the preceding sections, wherein the coating for the sustained release of tapentadol comprises one or more plasticizers in addition to the acrylic copolymer.
  • Section 53 The pharmaceutical dosage form of Section 52, wherein the plasticizer or plasticizers are independently selected from the group consisting of dibutyl sebacate, phthalate esters, diethyl phthalate, dibutyl phthalate, acetylated monoglycerides, triethyl citrate, tributyl citrate, triacetin, propylene glycols, 1,2-propylene glycol , polyethylene glycols and castor oil; preferably triethyl citrate.
  • the plasticizer or plasticizers are independently selected from the group consisting of dibutyl sebacate, phthalate esters, diethyl phthalate, dibutyl phthalate, acetylated monoglycerides, triethyl citrate, tributyl citrate, triacetin, propylene glycols, 1,2-propylene glycol , polyethylene glycols and castor oil; preferably triethyl citrate.
  • Section 54 The pharmaceutical dosage form of section 52 or 53, wherein the total content of all plasticizers in the controlled release coating for tapentadol ranges from 5.0 to 20% by weight based on the total weight of the coating.
  • Section 55 The pharmaceutical dosage form according to any one of the preceding sections, wherein the coating for the sustained release of tapentadol comprises one or more surfactants in addition to the acrylic copolymer.
  • Section 56 The pharmaceutical dosage form of Section 55, wherein the surfactant or surfactants are nonionic surfactants; preferably ethoxylated sorbitan fatty acid esters.
  • Section 57 The pharmaceutical dosage form of section 56 or 56, wherein the total content of all surfactants in the controlled release coating for tapentadol is in the range of 0.1 to 5.0% by weight based on the total weight of the coating.
  • Section 58 The pharmaceutical dosage form according to any one of the preceding sections, wherein the content of the sustained-release coating for tapentadol is in the range from 5.0 to 20% by weight, based on the total weight of the coated particles.
  • Section 59 The pharmaceutical dosage form according to any one of Sections 1 to 57, wherein the content of the sustained-release coating for tapentadol is in the range of 15 to 30% by weight based on the total weight of the coated particles.
  • Section 60 The pharmaceutical dosage form of any one of Sections 1 to 57, wherein the content of the sustained release coating of tapentadol is in the range of 25 to 40% by weight based on the total weight of the coated particles.
  • Section 61 The pharmaceutical dosage form of any one of Sections 1 to 57, wherein the content of the sustained release coating of tapentadol is in the range of 35 to 50% by weight based on the total weight of the coated particles.
  • Section 62 The pharmaceutical dosage form of any one of Sections 1 to 57, wherein the content of the sustained release coating of tapentadol is in the range of 45 to 60% by weight based on the total weight of the coated particles.
  • Section 63 The pharmaceutical dosage form according to any one of the preceding sections, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml aqueous phosphate buffer at pH 6.8 at 37°C, wherein
  • Section 64 The pharmaceutical dosage form according to any one of the preceding sections, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml aqueous phosphate buffer at pH 6.8 at 37°C, wherein
  • Section 65 The pharmaceutical dosage form according to any one of the preceding sections, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml aqueous buffer at pH 4.5 at 37°C, wherein
  • Section 66 The pharmaceutical dosage form of any preceding section, which provides an in vitro dissolution rate measured at 50 rpm in 900 mL of aqueous buffer at pH 4.5 at 37°C, wherein
  • Section 67 The pharmaceutical dosage form according to any one of the preceding sections, which provides an in vitro dissolution profile measured at 50 rpm in 900 ml of 0.1N HCl at pH 1.0 and 37°C, in which
  • Section 68 The pharmaceutical dosage form of any preceding section, which provides an in vitro dissolution profile measured at 50 rpm in 900 mL of 0.1N HCl at pH 1.0 and 37°C, in which
  • Section 69 The pharmaceutical dosage form of any preceding section, which is for twice daily oral administration.
  • Palexia® retard contain tapentadol as the hydrochloride salt, with the tablet core additionally containing hypromellose, microcrystalline cellulose, finely divided silicon dioxide and magnesium stearate. Palexia® retard tablets thus contain hypromellose as an extended-release matrix. These tablets correspond to WO 03/035053 A1 and the comparative examples described below.
  • Tablets with the following composition were prepared by mixing all the ingredients and compressing the resulting mixtures:
  • Tablets with the following composition were prepared by mixing all the ingredients and compressing the resulting mixtures:
  • Tablets C-2 and 1-2 both have an average crush strength of about 237 and 271 N, respectively; the hydrochloride salt requires tabletting forces of 12.4 kN and 9.9 kN, respectively, while the salt of L-(+)-tartaric acid requires only 8.1 kN and 6.5 kN, respectively.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un comprimé qui assure une libération prolongée de tapentadol, le tapentadol étant contenu sous la forme d'un sel avec de l'acide tartrique, en particulier sous la forme d'un sel avec de l'acide L-(+)-tartrique. Le comprimé présente des propriétés mécaniques satisfaisantes, par exemple en termes de résistance à la rupture et de friabilité, et peut être produit dans des conditions de fabrication de comprimés considérablement simplifiées, en particulier à une force de pression réduite.
PCT/EP2021/081197 2020-11-10 2021-11-10 Formes posologiques à libération prolongée d'un sel de tapentadol avec de l'acide l-(+)-tartrique Ceased WO2022101247A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PE2023001584A PE20240113A1 (es) 2020-11-10 2021-11-10 Formas de dosificacion de liberacion sostenida de una sal de tapentadol con acido l-(+)-tartarico
MX2023005472A MX2023005472A (es) 2020-11-10 2021-11-10 Formas de dosificacion de liberacion sostenida de una sal de tapentadol con acido l-(+)-tartarico.
CONC2023/0005962A CO2023005962A2 (es) 2020-11-10 2023-05-09 Formas de dosificación de liberación sostenida de una sal de tapentadol con ácido l-(+)-tartárico

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP20206812 2020-11-10
EP20206800.3 2020-11-10
EP20206800.3A EP3995135B1 (fr) 2020-11-10 2020-11-10 Formes pharmaceutiques avec libération prolongée d'un sel de tapentadol avec l - (+) - acide tartrique
EP20206812.8 2020-11-10

Publications (1)

Publication Number Publication Date
WO2022101247A1 true WO2022101247A1 (fr) 2022-05-19

Family

ID=78536235

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/081197 Ceased WO2022101247A1 (fr) 2020-11-10 2021-11-10 Formes posologiques à libération prolongée d'un sel de tapentadol avec de l'acide l-(+)-tartrique

Country Status (4)

Country Link
CO (1) CO2023005962A2 (fr)
MX (1) MX2023005472A (fr)
PE (1) PE20240113A1 (fr)
WO (1) WO2022101247A1 (fr)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0693475A1 (fr) 1994-07-23 1996-01-24 Grünenthal GmbH Dérivés propane 1-phényl-3-diméthylamino à activité pharmocologique
WO2003035054A1 (fr) 2001-10-24 2003-05-01 Grünenthal GmbH Medicament contenant du 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, caracterise par une liberation differee du principe actif
WO2006002886A1 (fr) 2004-07-01 2006-01-12 Grünenthal GmbH Forme posologique anti-abus pour administration par voie orale contenant du (1r, 2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
WO2008051617A2 (fr) 2006-10-27 2008-05-02 Janssen Pharmaceutica N.V. Compositions pharmaceutiques granulaires sèches et leurs procédés de production
WO2009092601A1 (fr) 2008-01-25 2009-07-30 Grünenthal GmbH Forme posologique pharmaceutique
WO2015014980A1 (fr) 2013-08-02 2015-02-05 Ratiopharm Gmbh Composition comprenant du tapentadol sous forme dissoute
US20150283087A1 (en) * 2014-04-07 2015-10-08 Banner Life Sciences Llc Abuse-deterrent controlled release formulations
EP2942054A1 (fr) 2014-05-09 2015-11-11 G.L. Pharma GmbH Formulation pharmaceutique à libération lente
WO2017085734A1 (fr) 2015-11-17 2017-05-26 Msn Laboratories Private Limited Formes cristallines de sels de tapentadol et leur procédé de préparation

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0693475A1 (fr) 1994-07-23 1996-01-24 Grünenthal GmbH Dérivés propane 1-phényl-3-diméthylamino à activité pharmocologique
WO2003035054A1 (fr) 2001-10-24 2003-05-01 Grünenthal GmbH Medicament contenant du 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, caracterise par une liberation differee du principe actif
WO2003035053A1 (fr) 2001-10-24 2003-05-01 Grünenthal GmbH Medicament contenant du 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, caracterise par une liberation differee du principe actif
WO2006002886A1 (fr) 2004-07-01 2006-01-12 Grünenthal GmbH Forme posologique anti-abus pour administration par voie orale contenant du (1r, 2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
WO2008051617A2 (fr) 2006-10-27 2008-05-02 Janssen Pharmaceutica N.V. Compositions pharmaceutiques granulaires sèches et leurs procédés de production
WO2009092601A1 (fr) 2008-01-25 2009-07-30 Grünenthal GmbH Forme posologique pharmaceutique
WO2015014980A1 (fr) 2013-08-02 2015-02-05 Ratiopharm Gmbh Composition comprenant du tapentadol sous forme dissoute
US20150283087A1 (en) * 2014-04-07 2015-10-08 Banner Life Sciences Llc Abuse-deterrent controlled release formulations
EP2942054A1 (fr) 2014-05-09 2015-11-11 G.L. Pharma GmbH Formulation pharmaceutique à libération lente
WO2017085734A1 (fr) 2015-11-17 2017-05-26 Msn Laboratories Private Limited Formes cristallines de sels de tapentadol et leur procédé de préparation

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
C. ROWE ET AL.: "Handbook of Pharmaceutical Excipients", PHARMACEUTICAL PRESS, article "20090806"
D.V. REDDY ET AL., JOURNAL OF PHARMACY RESEARCH, vol. 8, no. 10, 2014, pages 1368 - 1374
E.-M. HOEPFHER ET AL., FIEDLER—ENCYCLOPEDIA OF EXCIPIENTS, 6 August 2008 (2008-08-06)
J. SWARBRICKM. BOGDA: "Encylopedia of Pharmaceutical Technology", vol. 3, 2007, INFORMA HEALTHCARE, article "Tablet Compression: Machine Theory, Design, and Process Troubleshooting", pages: 3611 - 2629
J. ZHENG: "Formulation and Analytical Development for Low-Dose Oral Drug Products", 2009, WILEY, pages: 150 - 155
L.L. AUGSBURGER ET AL.: "Pharmaceutical Dosage Forms", 2008, INFORMA HEALTHCARE, pages: 26 - 30
M.T. ENDE ET AL.: "The Pharmaceutical Industry, Drug Product Design, Development, and Modeling", 2019, WILEY, article "Chemical Engineering", pages: 228 - 232
S.K. PARAMASIVAN ET AL., GSC BIOLOGICAL AND PHARMACEUTICAL SCIENCES, vol. 04, no. 03, 2018, pages 042 - 048
S.M. AFZAL ET AL., INT J A PS BMS, vol. 6, no. 1, 2017, pages 1 - 21
Y. QIU ET AL.: "Pharmaceutical Theory & Practice", 2017, ELSEVIER, article "Developing Solid Oral Dosage Forms", pages: 940 - 942

Also Published As

Publication number Publication date
MX2023005472A (es) 2023-05-22
CO2023005962A2 (es) 2023-05-19
PE20240113A1 (es) 2024-01-22

Similar Documents

Publication Publication Date Title
EP1830855B1 (fr) Produits pharmaceutiques solides, administres par voie orale et contenant du rivaroxaban, a liberation modifiee
US20070224281A1 (en) Sustained-Release Preparations Containing Topiramate and the Producing Method Thereof
EP2355802A1 (fr) Produits intermédiaires et formes galéniques orales contenant de la lénalidomide
EP2413910A1 (fr) Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation
EP2595607A2 (fr) Médicament d'administration orale contenant un mélange de silodosine et d'un copolymère basique
EP2309995A1 (fr) Formulation pharmaceutique pour la réduction de la pression artérielle pulmonaire
EP2309996A2 (fr) Ambrisentan amorphe
EP2490674A2 (fr) Cinacalcet granulé par fusion
EP2416761B1 (fr) Desfésotérodine sous forme d'un sel d'acide tartrique
EP3995135B1 (fr) Formes pharmaceutiques avec libération prolongée d'un sel de tapentadol avec l - (+) - acide tartrique
DE202021003994U1 (de) Dosierungsform mit verlängerter Freisetzung von Tapentadol-Phosphorsäuresalz
WO2022101247A1 (fr) Formes posologiques à libération prolongée d'un sel de tapentadol avec de l'acide l-(+)-tartrique
AU2020202056B2 (en) Dosage form providing prolonged release of tapentadol phosphoric acid salt
DE202020005470U1 (de) Darreichungsformen mit verlängerter Freisetzung eines Salzes von Tapentadol mit L-(+)-Weinsäure
AU2020100442A4 (en) Dosage form providing prolonged release of tapentadol phosphoric acid salt
DE102021119130A1 (de) Ethylcellulose-beschichtete Partikel enthaltend ein Salz aus Tapentadol und Phosphorsäure
EP2445484A1 (fr) Aprépitant sous forme de solution solide
EP1928441A2 (fr) Formulation a effet retard de 3-(2-dimethylaminomethyle-cyclohexyle)-phenol
BR112023008880B1 (pt) Formas de dosagem de liberação sustentada de um sal de tapentadol com ácido l-(+)-tartárico
DE202020106805U1 (de) Dosierungsformen mit verlängerter Freisetzung von Tapentadol-Phosphorsäuresalz
DE202020103814U1 (de) Dosierungsformen mit verlängerter Freisetzung von Tapentadol-Phosphorsäuresalz
EP2382967A1 (fr) Aliskiren sous forme d'une dispersion solide
DE102008057335A1 (de) Amorphes Lenalidomid

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21805539

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: NC2023/0005962

Country of ref document: CO

Ref document number: 001584-2023

Country of ref document: PE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023008880

Country of ref document: BR

WWP Wipo information: published in national office

Ref document number: NC2023/0005962

Country of ref document: CO

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 112023008880

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20230509

122 Ep: pct application non-entry in european phase

Ref document number: 21805539

Country of ref document: EP

Kind code of ref document: A1