Classifications

• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
  • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
• • 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
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the invention relates to a pharmaceutical dosage form providing prolonged release of Tapentadol, wherein Tapentadol is present in form of a salt with phosphoric acid (orthophosphoric acid), preferably as dihy- drogenphosphate salt.
• the dosage form according to the invention provides improved prolonged release properties, is particularly resistant against ethanol induced dose dumping, and beyond such resistance provides additional safety features with regard to concomitant use of ethanol, e.g. alcoholic beverages.
• ethanol induced dose dumping also referred to as alcohol induced dose dumping, alcoholic dose dumping, ethanolic dose dumping, and the like
• unintended rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified-release dosage form has been defined as the “ unintended rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified-release dosage form ”.
• Tapentadol (Nucynta ® , Palexia ® ) is an oral opioid analgesic in the benzenoid class with a dual mechanism of action that is similar to tramadol; it is a m-opioid receptor agonist and also inhibits the reuptake of norepineph- rine. Tapentadol is currently available as oral dosage form containing Tapentadol hydrochloride salt and providing immediate release or prolonged release.
• the mean Tapentadol AUC last and AUC mf were increased by 17%; the T max and t 1/2 were relatively unchanged.
• the mean C max value increased by 28% compared to control with a range of 0.90-fold up to 2.67-fold.
• the individual C max value for 2 of these subjects (10%) were at least 2.6 times that of the control mean C max value.
• the mean Tapentadol AUC last and AUC inf were increased by 16%; the T max and t 1/2 were relatively unchanged.
• Nucynta ® Extended-Release is expected to have additive effects when used in conjunction with alcohol (see PRODUCT MONOGRAPH, Nucynta ® Ex- tended-Release Tapentadol, October 28, 2013, Date of Revision: March 01, 2018).
• Nucynta ® and Palexia ® prescription information contain instructions not to consume alcohol or any products containing al- cohol while taking the medication.
• WO 2015/004245 A1 relates to a tamper-resistant, oral pharmaceutical dosage form comprising a phar- macologically active ingredient having psychotropic action and an ethylene-vinyl acetate (EVA) polymer which provides resistance against solvent extraction, resistance against grinding, and resistance against dose-dumping in aqueous ethanol.
• the pharmacologically active ingredient is preferably selected from the group consisting of Ox- ycodone, Oxymorphone, Hydrocodone, Hydromorphone, Tramadol, Tapentadol, Morphine, Buprenorphine and the physiologically acceptable salts thereof.
• the dosage forms are preferably multiparticulate and preparation re- quires the application of heat and pressure.
• the particles are extruded pellets, i.e. are produced by ther- moforming with the assistance of an extruder. All examples relate to multiparticulate dosage forms where the particles are prepared by hot-melt extrusion.
• WO 2018/219897 A1 relates to an oral pharmaceutical dosage form comprising a plurality of coated particles, wherein said coated particles comprise a core which comprises a Tapentadol component and which is coated with a controlled release coating material, wherein the controlled release coating material comprises a lub- ricant component and a polymer component, wherein the polymer component comprises one or more cellulose ethers and/or one or more acrylates, and wherein the pharmaceutical dosage form provides controlled release of the Tapentadol component.
• the controlled release coating material serves the purpose of controlling release of the Tapentadol component from the coated particles.
• Said controlled release coat of the controlled release coating material may form the outer surface of the particles or may be further overcoated with one or more layers of different or identical coating materials, e.g. in order to render the particles resistant against ethanol induced dose dumping.
• the particles When the particles are prepared from nonpareils, they are coated with a drug coat comprising Tapen- tadol. These particles are additionally coated with a controlled release coat comprising controlled release coating material.
• the coated particles provide resistance against ethanol induced dose dumping, they contain at least another two coating layers, namely an inner layer comprising an alginate salt, and an outer layer comprising an anionic acrylate polymer.
• oral dosage forms of Tapentadol that are easy to manufacture and do not require e.g. thermoforming or multiple coating steps.
• the oral dosage forms should preferably be provided in form of tablets, preferably monolithic tablets, i.e. should not require prep- aration of a multitude of particles.
• the preparation of the oral dosage forms should be possible on standard equip- ment on industrial high throughput scale, preferably by compression of powder mixtures possibly involving gran- ulation (dry granulation or wet granulation), preferably, however, by direct compression of powder mixtures.
• the invention relates to a tablet providing prolonged release of Tapentadol, wherein Tapen- tadol is present in form of a salt with phosphoric acid (orthophosphoric acid), preferably as dihydrogenphosphate salt.
• the tablet has satisfactory mechanical properties, e.g. in terms of resistance to crashing and friability, and can be prepared under greatly facilitated tableting conditions, especially at reduced compressing force.
• Tablets are formed by applying a compression force to a powder and consolidating that powder into a compact within a die of a press.
• compaction is the increase in mechanical strength of powder under force due to the consolidation of particles.
• compaction is related to particle consolidation and bonding, which has a direct effect on the tablet hardness and friability.
• Compression is defined as a reduction in bulk volume of the powder under force due to displacement of air between particles. Compression results in a reduction of void space between solid particles, which means a decrease in porosity of a tablet (for details see e.g. Y. Qiu et ak, Developing Solid Oral Dosage Forms, Pharmaceutical Theory & Practice, 2nd ed., Elsevier, 2017, pp. 940-942).
• Tablet manufacture is influenced 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, tableting speed, punch dwell time in the die, punch geometry, tooling material, etc.
• powder excipients are used as binders for cohe- siveness, as fillers for tablet tensile strength, as lubricants for successful processing of a blend or granulation into a tablet, as disintegrants to facilitate the disintegration of the tablet in vivo, as controlled release materials for retarding dissolution, and sometimes as glidants to aid poorly flowing mixtures.
• Each excipient is predominantly either elastic, or plastic, or brittle. Elastic particles deform during compression up to their elastic limit after which they will fracture. Prior to reaching that stretch limit, the deformation of elastic materials is reversible. Elastic powders expand after compression forces are removed (relaxation).
• Plastic deformation maintains shape after compressive forces are removed, and therefore deforms without recovery to provide good particulate binding.
• a brittle component will fracture under compression stress when the force goes beyond its deformation limit. While more surface area forms after brittle fracture, it also results in more friction and resistance to movement within the die during compression. Plastic and brittle excipients form physical shapes and add stability to the shape after compression.
• Tablet punches are used to compress a blend or granulation into a compacted unit dose.
• roller compaction tableting machines rotary tablet presses
• the bottom punch is lowered so that the feeder can dispense powder into a die.
• a scraper removes excess powder so that the formulation is level with the top of the die.
• the amount of powder in the die is the fill.
• the upper punch is then lowered into the die.
• the pre-compression rolls apply pressure to deaerate the fill in the die by forcing the particles closer together. This is followed by the main compression rollers applying force to compress the powder into a compact.
• the upper punch is then lifted from the die by the upper-lifting cam.
• Some of the deformation characteristics are time-dependent and therefore, machine characteristics can have a major effect on the tableting performance. These characteristics determine the rate of force application, dwell time (i.e. the time of maximum compression force, which depends on the punch head flat diameter and the tangential velocity), and the rate of decompression. Typically for materials that undergo plastic deformation, as machine speed is increased there is less time for stress relaxation.
• Tablets need to withstand the rigors of manufacturing, packaging, shipping, and distribution. According to FDA's Quality Attribute Considerations for Chewable Tablets, Guidance for Industry, August 2018, chewable tablets should have a hardness of ⁇ 12 kp (-19.6 N), whereas it is recognized that tablet size and shape are im- portant in determining acceptable tablet hardness. For example, for a very small tablet, a hardness value of 20 N may be quite high. Further, it has been recommended that fast disintegrating tablets providing immediate dmg release should have a hardness of from about 70 to 100 N, whereas tablets providing prolonged dmg release should have a hardness of from about 100 to 200 N. The larger the tablets, the harder they need to be in order to withstand the attrition during manufacture, packaging, shipping, and distribution. Therefore, with regard to prolonged release tablets, tablet hardness should be at least 100 N, preferably at least 150 N.
• tablet hardness is a function of the compression force; the higher the compression force, the higher the tablet hardness.
• increased tablet hardness can often be achieved by increasing the compression force.
• this may simultaneously require a reduction of machine speed in order to properly adjust the dwell time thereby reducing the overall tablet yield per hour.
• Dwell time refers to the length of time that a punch is compressing powder in the die.
• ft is a function of machine speed, whereby faster tableting leaves less time for the punch to compress the powder in the die.
• Lengthening the dwell time provides more time for particle defor- mation, fragmentation for increased surface area, and for interparticulate bonds to form.
• compres- sion force it should be also borne in mind that this not only affects tablet hardness. Harder tablets may have longer disintegration times and dissolution rates.
• tablet attributes must be considered (for details see e.g. M.T. Ende et al., Chemical Engineering In The Pharma- ceutical 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.
• Several tablet shapes and sizes therefore allow for maximum compression forces of less than 10 kN.
• tableting machines that are equipped with punches of such size and shape already operate at compression forces close to their maximum tooling force and under these conditions, there is little room for increasing compression force in order to increase tablet hardness (for details see e.g. L.L. Augsburger et al., Pharmaceutical Dosage Forms: Tablets, 3rd ed., informa healthcare, 2008, pp. 26-30; pp. J. Zheng, Formulation and Analytical Development for Low-Dose Oral Drug Products, Wiley 2009, 150-155).
• WO 2003/035054 A1 relates to a pharmaceutical formulation which is characterized by delayed release of Tapentadol HC1 in a matrix with delayed release of the active ingredient.
• Said matrix contains between 1 and 80 wt. % of at least one hydrophilic or hydrophobic polymer as a pharmaceutically acceptable matrix forming agent.
• the granules were pressed on a EKO eccentric press (Korsch) to 6 x 15 mm size oblong tablets with a breaking notch.
• EP 2 942 054 A1 relates to a slow-release pharmaceutical formulation containing Tapentadol HC1 in a slow release matrix, wherein the matrix contains between 15 and 50 wt.-% 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. At a con- stant force of 27 kN a tablet hardness of only 53 to 79 N could be achieved, while lower forces provided even poorer tablet hardness.
• WO 2008/051617 A2 relates to a method for producing a dry granule composition
• a method for producing a dry granule composition comprising compress- ing a pharmaceutical composition to 800 to 900 kPa hardness to produce one or more slugs, and milling the one or more slugs with an oscillating granulator to form granules.
• An exemplary pharmaceutical formulation contains Tapentadol HC1, hypromellose, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate.
• Fig- ure 7 to 9 show the influence of compression force on tablet hardness. At compression forces of 2000 to 3000 lbs ( ⁇ 8.9 to -13.3 kN), tablets having a hardness of about 7 to 20 kp (-69 to -196 N) were obtained.
• WO 2015/014980 A1 discloses a pharmaceutical composition
• a pharmaceutical composition comprising (a) dissolved Tapentadol HC1, (b) organic solvent with a boiling point of 110° to 350° C, and (c) solid carrier. If a rotary press is applied for manufacture of the tablets, the main compression force can range from 1 to 50 kN, preferably 3 to 40 kN.
• the resulting tablets can have a hardness of 30 to 400 N, more preferred of 50 to 250 N, particularly preferably of 30 to 180 N, more preferably 40 to 150 N.
• S.K. Paramasivan et ah, GSC Biological and Pharmaceutical Sciences, 2018, 04(03), 042-048 relates to tablets comprising Tapentadol manufactured by direct compression in a rotary tablet compression machine.
• the known tablets containing Tapentadol are not satisfactory in every respect, especially as compression of tablets from the starting materials requires considerable compression forces in order to achieve satisfactory mechanical strength, e.g. hardness.
• the pharmaceutical dosage forms should be safe and easy to manufacture in an economic manner, should provide advantageous patient compliance and resistance against ethanol induced dose dumping, should provide additional safety features with regard to co-ingestion of ethanol, particularly a more retarded dissolution in aqueous ethanol compared to non-ethanolic medium such that alterations of the pharmacological profile due to co-ingestion of ethanol are less likely to occur.
• salts of Tapentadol with phosphoric acid are particularly use- ful for pharmaceutical dosage forms providing prolonged release of Tapentadol. It has been surprisingly found that dosage forms containing salts of Tapentadol with phosphoric acid in vitro provide slower release of Tapentadol in ethanolic medium than in non-ethanolic medium. These dosage forms are therefore expected to further prolong drag release in vivo when co-ingested with ethanol. This effect neither depends upon the particle size of the salts of Tapentadol with phosphoric acid, nor on the polymorphic form of the salts of Tapentadol with phosphoric acid.
• prolonged release matrices comprising different prolonged release matrix materials (e.g. hypromellose or Kollidon ® SR) as well as from pellets comprising different prolonged release coat- ing materials (e.g. ethylcellulose containing different pore formers), i.e. is attributable to the properties of the salt of Tapentadol with phosphoric acid as such.
• different prolonged release matrix materials e.g. hypromellose or Kollidon ® SR
• pellets comprising different prolonged release coat- ing materials (e.g. ethylcellulose containing different pore formers), i.e. is attributable to the properties of the salt of Tapentadol with phosphoric acid as such.
• salts of Tapentadol with phosphoric acid are particularly useful for pharmaceutical dosage forms that provide prolonged release of Tapentadol. It has been surprisingly found that compared to conventional Tapentadol hydrochloride, the preparation of compressed tablets comprising salts of Tapentadol with phosphoric acid requires significantly reduced compression forces in order to achieve a desired target breaking strength of the tablets. This effect neither depends upon the particle size of the salt of Tapentadol with phosphoric acid, nor upon the polymorphic form of the salt of Tapentadol with phosphoric acid. Further, this effect is also observed with various different excipients, i.e. is attributable to the properties of the salt of Tapentadol with phosphoric acid as such.
• Salts of Tapentadol with phosphoric acid are known, e.g. from WO 2010/096045, WO 2012/010316 Al, WO 2012/051246 Al and WO 2017/182438 Al.
• WO 2010/096045 WO 2012/010316 Al
• WO 2012/051246 Al WO 2017/182438 Al.
• none of these references addresses the use of the salts for avoidance of ethanol induced dose dumping.
• none of these references addresses reduction of com- pressing forces in order to achieve a desired target breaking strength of the tablets.
• the commercial Tapentadol tablets Palexia ® retard contain Tapen- tadol as hydrochloride salt, whereas the tablet core additionally contains hypromellose, microcrystalline cellulose, highly disperse silicon dioxide, and magnesium stearate.
• Palexia ® retard tablets contain a prolonged release matrix of hypromellose.
• the tablet cores are film coated with a composition comprising hypromellose, lactose monohydrate, talcum, macrogol 6000 and colorants. These tablets are in accordance with WO 03/035053 Al and with the comparative examples contained herein in the experimental section.
• Figure 1 shows the XRPD spectrum of Tapentadol dihydrogenphosphate (mixed form) as obtained ac- cording to Example 1.1.
• Figure 2 shows the XRPD spectrum of Tapentadol dihydrogenphosphate hemihydrate as obtained accord- ing to Example 1.4.
• Figure 3 shows the DSC plot of Tapentadol dihydrogenphosphate hemihydrate as obtained according to Example 1.4.
• Figure 4 shows the XRPD spectrum of Tapentadol dihydrogenphosphate anhydrate as obtained according to Example 1.6.
• Figure 5 shows the DSC plot of Tapentadol dihydrogenphosphate anhydrate as obtained according to Example 1.6.
• Figure 6 shows three photographs of different particles size of the salt of Tapentadol with phosphoric acid (Figure 6A shows relatively fine particles, Figure 6B relatively coarse particles) and of the salt of Tapentadol with hydrochloric acid ( Figure 6C).
• Figure 7 compares the in vitro dissolution profiles of a conventional tablet containing Tapentadol hydro- chloride and an inventive tablet containing salt of Tapentadol with phosphoric acid at in 0.1 N HC1 (pH 1.0) and in 0.1 N HC1 (pH 1.0) with 40 vol.-% ethanol.
• Figure 8 compares the in vitro dissolution profdes of a conventional tablet containing Tapentadol hydro- chloride and an inventive tablet containing salt of Tapentadol with phosphoric acid at pH 4.5 in aqueous buffer (without ethanol).
• Figure 9 compares the in vitro dissolution profdes of a conventional tablet containing Tapentadol hydro- chloride at pH 1.0, pH 4.5, pH 6.8 in each case in aqueous buffer without ethanol and at pH 1.0 in 40 vol.-% ethanol.
• Figure 10 compares the in vitro dissolution profiles of an inventive tablet containing salt of Tapentadol with phosphoric acid at pH 1.0, pH 4.5, pH 6.8 in each case without ethanol and at pH 1.0 in 40 vol.-% ethanol.
• Figure 11 compares the in vitro dissolution profiles of an inventive tablet containing salt of Tapentadol with phosphoric acid in 0. 1 N HCL (pH 1.0) without ethanol and in 0. 1 N HCL (pH 1.0) with 40 vol.-% ethanol.
• Figure 12 compares the in vitro dissolution profiles in in 0. 1 N HC (LpH 1.0) of inventive pellet formulations containing Tapentadol dihydrogenphosphate in pellets that are coated with various amounts of a coating formula- tion comprising ethylcellulose, polyvinylpyrrolidone and dibutyl sebacate with the corresponding comparative pellet formulations containing Tapentadol hydrochloride.
• Figure 13 compares the in vitro dissolution profiles in 0. 1 N HCL (pH 1.0) of inventive pellet formulations containing Tapentadol dihydrogenphosphate in pellets that are coated with various amounts of a coating formula- tion comprising ethylcellulose, hydroxypropylmethylcellulose and magnesium stearate with the corresponding comparative pellet formulations containing Tapentadol hydrochloride.
• Figure 14 compares the in vitro dissolution profiles of an inventive pellet formulation containing Tapen- tadol dihydrogenphosphate and a corresponding comparative pellet formulation containing Tapentadol hydrochlo- ride in each case in 0.1N HCL (pH 1.0) without ethanol and in 0.1N HCL (pH 1.0) with 40 vol.-% ethanol.
• Figure 15 compares the in vitro dissolution profiles of another inventive pellet formulation containing Tapentadol dihydrogenphosphate and a corresponding comparative pellet formulation containing Tapentadol hy- drochloride in each case in 0.1N HCL (pH 1.0) without ethanol and in 0.1N HCL (pH 1.0) with 40 vol.-% ethanol.
• Figure 16 compares the in vitro dissolution profiles in acetate buffer (pH 4.5) and in phosphate buffer (pH 6.8) of inventive pellet formulations containing Tapentadol dihydrogenphosphate in pellets that are coated with 25 wt.-% of a coating formulation comprising ethylcellulose, polyvinylpyrrolidone and dibutyl sebacate with the cor- responding comparative pellet formulations containing Tapentadol hydrochloride.
• Figure 17 compares the in vitro dissolution profiles in acetate buffer (pH 4.5) and in phosphate buffer (pH 6.8) of inventive pellet formulations containing Tapentadol dihydrogenphosphate in pellets that are coated with 20 wt.-% of a coating formulation comprising ethylcellulose, hydroxypropylmethylcellulose and magnesium stearate with the corresponding comparative pellet formulations containing Tapentadol hydrochloride.
• a first aspect of the invention relates to a pharmaceutical dosage form comprising Tapentadol for oral administration twice daily; wherein Tapentadol is present as a salt with phosphoric acid; wherein the dosage form provides prolonged release of Tapentadol; and wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form is within the range of from 10 to 300 mg based on the free base of Tapentadol.
• Tapentadol i.e. (-)-(lR,2R)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenol
• Tapentadol is a synthetic, cen- trally acting analgesic which is effective in the treatment of moderate to severe, acute or chronic pain.
• the synthesis of the free base of Tapentadol is known e.g. from EP-A 693 475.
• the pharmaceutical dosage form according to the invention contains Tapentadol as a salt with phosphoric acid. While it is contemplated that the pharmaceutical dosage form according to the invention may contain mix- tures of different salts of Tapentadol or mixtures of salt(s) with the free base of Tapentadol (e.g. the non-salt form of Tapentadol), preferably the total amount of Tapentadol that is contained in the pharmaceutical dosage form is present as a salt with phosphoric acid.
• Salts of Tapentadol with phosphoric acid principally include the orthophos- phate salts (PO 4 3 ), the monohydrogenphosphate salts (HPO 4 2 ), and the dihydrogenphosphate (H 2 PO 4 ). Conden- sation products of phosphoric acid such as metaphosphate salts or pyrophosphate salts are also contemplated, but less preferred.
• the Tapentadol dihydrogenphosphate salts are particularly preferred.
• the salt of Tapentadol with phosphoric acid is the dihydrogenphosphate salt of Tapentadol, which may optionally be solvated (e.g. hydrated) or ansolvated (e.g. anhydrated).
• the dihydrogenphos- phate salt of Tapentadol is selected from the group consisting of ansolvated dihydrogenphosphate salt of Tapen- tadol, anhydrated dihydrogenphosphate salt of Tapentadol, solvated dihydrogenphosphate salt of Tapentadol, hy- drated dihydrogenphosphate salt of Tapentadol, and any mixtures of the foregoing.
• the salt of Tapentadol may be present in form of a single polymorph or as a mixture of different polymorphs in any mixing ratio.
• the salt of Tapentadol with phosphoric acid is the dihydrogenphosphate salt which is present in essentially pure crystalline form of Tapentadol dihydrogenphosphate hemihydrate salt.
• the salt of Tapentadol with phosphoric acid is the dihydrogenphosphate salt which is present in essentially pure crystalline form of Tapentadol dihydrogenphosphate anhydrate salt.
• the salt of Tapentadol with phosphoric acid is a crystalline dihydrogenphos- phate salt having characteristic X-ray powder diffraction peaks at 5.1 , 14.4, 17.7, 18.3 and 21.0 degrees 2Q ( ⁇ 0.2 degrees 2Q); preferably being characterized by one or more further XRPD diffraction peak(s) at 8.7, 17.6, 20.3,
• the crystalline dihydrogenphosphate salt can be characterized by the XRPD diffraction peak(s) at degrees 2Q ⁇ 0.2 degrees 2Q (intensity %): 5.1 (100), 8.7 (10),
• the crystalline dihydrogenphosphate salt can be characterized by the XRPD diffraction peak(s) at degrees 2Q ⁇ 0.2 degrees 2Q: 5.1 , 8.7, 10.1 , 12.5, 13.4, 14.4, 15.3, 17.6, 17.7, 18.3, 19.1 , 20.3, 21.0, 21.6, 22.1 , 23.4, 24.8, 25.0 and 25.3.
• the salt of Tapentadol with phosphoric acid is a crystalline dihy- drogenphosphate salt having characteristic X-ray powder diffraction peaks at 5.1 , 14.3, 17.6, 18.5 and 21.1 degrees 2Q ( ⁇ 0.2 degrees 2Q); preferably being characterized by one or more further XRPD diffraction peak(s) at 8.9, 20.5, 22.4, 23.5 and/or 24.3 degrees 2Q ( ⁇ 0.2 degrees 2Q).
• the crystalline dihydrogenphosphate salt can be characterized by the XRPD diffraction peak(s) at degrees 2Q ⁇ 0.2 degrees 2Q (intensity %): 5.1 (100), 8.9 (3), 12.4 (5), 13.5 (4), 14.3 (42), 15.2 (4), 17.6 (21), 18.5 (18), 19.1 (7), 20.5 (14), 21.1 (28), 21.7 (9), 22.4 (14), 23.5 (15), 24.3 (6), 24.9 (19), 25.1 (16), 25.8 (3), 26.2 (12), 26.4 (13), 26.7 (5), 27.3 (2), 28.2 (5), 28.8 (8), 29.1 (1 1), 29.4 (5), and 29.6 (5).
• the crystalline dihydrogenphosphate salt can be characterized by the XRPD diffraction peak(s) at degrees 2Q ⁇ 0.2 degrees 2Q: 5.1 , 8.9, 12.4, 13.5, 14.3, 15.2, 17.6, 18.5, 19.1 , 20.5, 21.1 , 21.7, 22.4, 23.5, 24.3, 24.9, and 25.1.
• the salt of Tapentadol with phosphoric acid has an average particle size, expressed as surface mean D [3 ,2] (Sauter Mean Diameter) and determined by laser diffraction in the dry mode in accordance with ISO 13320:2020, within the range of 5.0 to 500 pm, preferably 50 ⁇ 40 pm, or 75 ⁇ 40 pm, or 100 ⁇ 40 pm, or 125 ⁇ 40 pm, or 150 ⁇ 40 pm, or 175 ⁇ 40 pm, or 200 ⁇ 40 pm, or 225 ⁇ 40 pm, or 250 ⁇ 40 pm, or 275 ⁇ 40 pm, or 300 ⁇ 40 pm, or 325 ⁇ 40 pm, or 350 ⁇ 40 pm, or 375 ⁇ 40 pm, or 400 ⁇ 40 pm, or 425 ⁇ 40 pm, or 450 ⁇ 40 pm.
• surface mean D [3 ,2] Human Mean Diameter
• the salt of Tapentadol with phosphoric acid is present in crystalline form. In another preferred embodiment, the salt of Tapentadol with phosphoric acid is present in amorphous form. It is further contemplated that the pharmaceutical dosage form may contain mixtures of crystalline salt of Tapentadol with phosphoric acid with amorphous salt of Tapentadol with phosphoric acid in any mixing ratio. Preferably, essentially the total amount of the salt of Tapentadol with phosphoric acid that is present in the pharmaceutical dosage form is crystalline.
• the dihydrogenphosphate salt of Tapentadol is to be regarded as the acid addition salt of 1 mole orthophosphoric acid to 1 mole of Tapentadol. It is believed that one proton of ortho- phosphoric acid (H 3 PO 4 ) protonates the amino group of Tapentadol thereby forming an ammonium ion, whereas the remainder of orthophosphoric acid, i.e. the dihydrogenphosphate anion (H 2 PO 4 ), forms the counterion:
• Tapentadol shall include the salt of Tapentadol with phosphoric acid.
• the salt of Tapentadol with phosphoric acid may be present in form of any solvate, e.g. hydrate, ansolvate, e.g. anhydrate, and polymorphic form, e.g. any crystalline form and/or amorphous form.
• any solvate e.g. hydrate
• ansolvate e.g. anhydrate
• polymorphic form e.g. any crystalline form and/or amorphous form.
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form according to the invention is within the range of from 10 to 300 mg based on the free base of Tapentadol, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg.
• the free base of Tapentadol i.e. the free molecule
• 10 mg of the free base of Tapentadol correspond to 0.0452 mmol
• 300 mg of the free base of Tapentadol correspond to 1.3556 mmol.
• the pharmaceutical dosage form con- tains a mole equivalent dose of Tapentadol within the range of from 0.0452 to 1.3556 mmol.
• the hydrochloride salt of Tapentadol (anhydrate) has a molecular weight of 257.8 g/mol
• the dihydrogenphosphate salt of Tapentadol (anhydrate) has a molecular weight of 319.3 g/mol.
• the phar- maceutical dosage form according to the invention contains e.g. a weight equivalent dose of 100 mg based on the free base of Tapentadol (0.4518 mmol), it actually contains 144.3 mg dihydrogenphosphate salt of Tapentadol (0.4518 mmol).
• dose information for Tapentadol is thus expressed as equivalent weight relative to the free base of Tapentadol, i.e. the non-salt form, the non-solvate form, the non-cocrystal form, and the non-aggregate form of Tapentadol with any other molecules.
• the form of Tapentadol that is actually contained in the pharmaceutical dosage form i.e. the salt of Tapentadol with phosphoric acid, may be present in form of any polymorph and/or solvate and/or cocrystal and/or any other aggregate of such salt with other molecules.
• Tapentadol is preferably the sole pharmacolog- ically active ingredient that is contained in the pharmaceutical dosage form.
• Tapentadol is homogeneously distributed over the pharmaceutical dosage form according to the invention.
• the pharmaceutical dosage form according to the invention is devoted for oral administration, preferably by swallowing the pharmaceutical dosage form as a whole.
• the pharmaceutical dosage form according to the invention is preferably not devoted for buccal or sublingual administration where the pharmaceutical dosage form would be devoted to remain within the oral cavity.
• the pharmaceutical dosage form according to the invention is devoted for administration twice daily.
• the pharmaceutical dosage form according to the invention contains 50% of the daily dose of Tapentadol that is intended for administration in order to bring about the desired therapeutic effect.
• twice daily may proceed at intervals of about every 12 hours, although such regimen is not to be strictly followed.
• twice daily shall also encompass any administration regimen where two pharmaceutical dosage forms according to the invention are administered during a period of about 24 hours, where the two administrations must be separated from one another by at least 4 hours, preferably at least 8 hours.
• the pharmaceutical dosage form according to the invention provides prolonged release of Tapentadol.
• prolonged release means not immediate release.
• Prolonged release includes controlled release, delayed release, extended release, staggered release, repeat action release, sustained release and evenly sustained release.
• Prolonged release preferably means a release with a reduced release rate, to obtain a therapeutic effect upright, to reduce toxic effects or for some other therapeutic purpose.
• Prolonged release may be based upon different technologies that are known to the skilled person.
• prolonged release is based upon prolonged release coating materials with which the phar- maceutical dosage form as such or with which a multitude of particles may be coated.
• prolonged release is based upon a prolonged release matrix in which Tapentadol is preferably embedded. It is further contemplated in accordance with the invention that prolonged release may be achieved by alternative concepts such as ion exchange resins, osmotic dosage forms, and the like.
• the pharmaceutical dosage form according to the invention after oral administration provides plasma levels of Tapentadol providing pain relief (analgesia) for a duration 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 provides an in vitro dissolution profile, when measured by the USP Paddle Method at 50 rpm in 900 ml aqueous phosphate buffer at pH 6.8 at 37° C, wherein
• the pharmaceutical dosage form according to the invention provides an in vitro dissolution profile, when measured by the USP Paddle Method at 50 rpm in 900 ml aqueous phosphate buffer at pH 6.8 at 37° C, wherein
• the pharmaceutical dosage form according to the invention provides an in vitro dissolution profde, when measured by the USP Paddle Method at 50 rpm in 900 ml aqueous buffer at pH 4.5 at 37° C, wherein
• the pharmaceutical dosage form according to the invention provides an in vitro dissolution profde, when measured by the USP Paddle Method at 50 rpm in 900 ml aqueous buffer at pH 4.5 at 37° C, wherein
• the pharmaceutical dosage form according to the invention provides an in vitro dissolution profile, when measured by the USP Paddle Method at 50 rpm in 900 ml 0.1 N HC1 at pH 1.0 and 37 °C, wherein - after 0.5 hour 20 ⁇ 20 wt.-%; preferably 20 ⁇ 15 wt.-%; more preferably 20 ⁇ 10 wt.-%;
• the pharmaceutical dosage form according to the invention provides an in vitro dissolution profile, when measured by the USP Paddle Method at 50 rpm in 900 ml 0.1 N HC1 at pH 1.0 and 37 °C, wherein
• the pharmaceutical dosage form according to the invention provides resistance against ethanol induced dose dumping.
• the pharmaceutical dosage form according to the invention provides slower in vitro dissolution of Tapentadol in aqueous medium containing ethanol than in aqueous medium not containing ethanol.
• the pharmaceutical dosage form according to the invention provides slower dissolution of Tapentadol in 0.1 N HC1 containing 5.0 vol.-% of ethanol (pH 1.0) than in 0.1 N HC1 not containing 5.0 vol.-% of ethanol (pH 1.0), in each case when measured by the USP Paddle Method at 50 rpm in 900 ml at 37° C.
• the pharmaceutical dosage form according to the invention provides slower dissolution of Tapentadol in 0.1 N HC1 containing 20 vol.-% of ethanol (pH 1.0) than in 0.1 N HC1 not containing 20 vol.-% of ethanol (pH 1.0), in each case when measured by the USP Paddle Method at 50 rpm in 900 ml at 37° C.
• the pharmaceutical dosage form according to the invention provides slower dissolution of Tapentadol in 0.1 N HC1 containing 40 vol.-% of ethanol (pH 1.0) than in 0.1 N HCL not containing 40 vol.-% of ethanol (pH 1.0), in each case when measured by the USP Paddle Method at 50 rpm in 900 ml at 37° C.
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 25 mg, 50 mg, or 100 mg, in each case based on the free base of Tapentadol.
• the pharmaceutical dosage form according to the invention has a total weight within the range of from 150 to 750 mg.
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 150 mg, 200 mg or 250 mg, in each case based on the free base of Tapentadol.
• the pharmaceutical dosage form according to the invention has a total weight within the range of from 300 to 1200 mg.
• the pharmaceutical dosage form according to the invention comprises one, two or more phys- iologically acceptable excipients.
• a “pharmaceutical excipient” is preferably to be regarded as any pharmacologically inactive substance typically used as a carrier for the active ingredients of a medication.
• the pharmaceutical excipient may have a physiological effect, e.g. like a vitamin, but not a pharmacological effect, like a drug.
• Typical examples of pharmaceutical excipients include antiadherents, binders, coating materials, disintegrants, fillers, diluents, flavors, colorants, glidants, lubricants, preservatives, sorbents, surfactants, sweeteners, dyes, pigments, and the like.
• excipients can be divided into sub-groups.
• preservatives can be divided into antioxidants, buffers, antimicrobial substances and the like; whereas binders can be divided into solution binders and dry binders.
• binders can be divided into solution binders and dry binders.
• excipients simultaneously exhibit different properties so that they can serve dif- ferent purposes.
• polyethylene glycol can be used as binder, plasticizer and the like.
• the pharmaceutical dosage form according to the invention preferably the prolonged release matrix, comprises a binder.
• the binder is selected from the group consisting of cellulose, magnesium-aluminum silicates (e.g. bentonite), mono-, oligo- and polysaccharides (e.g. dextrose, lactose, mannose), sugar alcohols (e.g. lactitol, mannitol), starches (e.g. pregelatinized starch, hydrolyzed starch, modified starch), calcium phosphate, polyvi- nylpyrrolidone, and vinylpyrrolidone/vinyl acetate copolymers; preferably micro crystalline cellulose; more pref- erably silicified microcrystalline cellulose.
• magnesium-aluminum silicates e.g. bentonite
• mono-, oligo- and polysaccharides e.g. dextrose, lactose, mannose
• sugar alcohols e.g. lactitol, mannitol
• starches e.g. pregelatin
• the weight content of the binder is at least 5.0 wt.-%, more preferably at least 10 wt.-%, still more preferably at least 15 wt.-%, yet more preferably at least 20 wt.-%, even more preferably at least 25 wt.-%, most preferably at least 30 wt.-%, and in particular at least 35 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
• the weight content of the binder is at most 85 wt.-%, more preferably at most 82.5 wt.-%, still more preferably at most 80 wt.-%, yet more preferably at most 77.5 wt.-%, even more preferably at most 75 wt- %, most preferably at most 72.5 wt.-%, and in particular at most 70 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
• the weight content of the binder is within the range of from 52 ⁇ 30 wt.-%, more preferably 52 ⁇ 27.5 wt.-%, still more preferably 52 ⁇ 25 wt.-%, yet more preferably 52 ⁇ 22.5 wt.-%, even more preferably 52 ⁇ 20 wt.-%, most preferably 52 ⁇ 17.5 wt.-%, and in particular 52 ⁇ 15 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
• the pharmaceutical dosage form contains more than one binder, the above percentages refer to the total content of all binders that are contained in the pharmaceutical dosage form.
• the pharmaceutical dosage form according to the invention comprises a lubricant.
• the lubricant is selected from the group consisting 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 monopalmitate, sodium stearyl fumarate, hydrated magnesium silicate, and talc; 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,
• the weight content of the lubricant is at least 0.20 wt.-%, more preferably at least 0.25 wt.-%, still more preferably at least 0.30 wt.-%, yet more preferably at least 0.35 wt.-%, even more preferably at least 0.40 wt.-%, most preferably at least 0.45 wt.-%, and in particular at least 0.50 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
• the weight content of the lubricant is at most 3.0 wt.-%, more preferably at most 2.8 wt.-%, still more preferably at most 2.6 wt.-%, yet more preferably at most 2.40 wt.-%, even more preferably at most 2.20 wt. -%, most preferably at most 2.00 wt.-%, and in particular at most 1.80 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
• the weight content of the lubricant is within the range of from 0.1 to 1.0 wt.-%, more prefer- ably 0.50 ⁇ 0.45 wt. -%, still more preferably 0.50 ⁇ 0.40 wt.-%, yet more preferably 0.50 ⁇ 0.35 wt.-%, even more preferably 0.50 ⁇ 0.30 wt.-%, most preferably 0.50 ⁇ 0.25 wt.-%, and in particular 0.50 ⁇ 0.20 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
• the dosage form contains a prolonged release coating which comprises a prolonged release coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy-type products, and mixtures thereof.
• a prolonged release coating material selected from the group consisting of hydrophobic cellulose ethers, acrylic polymers, shellac, zein, hydrophobic waxy-type products, and mixtures thereof.
• the dosage form is a monolith comprising such a prolonged release coating.
• the dosage form is multiparticulate wherein the individual particles (granules, pellets and the like) comprising such a prolonged release coating.
• the number of particles that are contained in the dosage form is not particularly limited any may range from 1, 2, 3, 4 or 5 to 10, 20, 30, 40 to 100, 200, and more.
• the particles are essentially of the same weight, size and composition.
• the particles contain a core comprising essentially the total amount of Tapen- tadol, optionally together with one or more excipients, and a prolonged release coating encapsulating said core.
• the particles contain an inert core not containing any Tapentadol (e.g. nonpareils), a drug coating layer encapsulating said core and comprising essentially the total amount of Tapen- tadol, optionally together with one or more excipients, and a prolonged release coating encapsulating said core and said drag coating layer.
• Tapentadol e.g. nonpareils
• drug coating layer encapsulating said core and comprising essentially the total amount of Tapen- tadol, optionally together with one or more excipients, and a prolonged release coating encapsulating said core and said drag coating layer.
• the prolonged release coating material is selected from the group consisting of ethylcellulose, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copoly- mers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, meth- acrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly (methacrylic acid, methacrylic acid alkylamide copolymer, poly(methyl meth- acrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate,
• the acrylic polymer is comprised of one or more ammonio methacrylate co- polymers, i.e. copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
• ammonio methacrylate co- polymers i.e. copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
• two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acrylic esters.
• the coating is made from an aqueous dispersion or from an organic dispersion or from an organic solution of a hydrophobic polymer, preferably ethylcellulose.
• the coating comprises an effec- tive 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, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize the ethylcellulose before using the same as a coating material.
• the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former.
• plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water- insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
• Triethyl citrate is an especially 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 possibly 1,2- propylene glycol.
• Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
• Triethyl citrate is an especially preferred plasticizer for the aque- ous 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 ultimate product may also be modified, for example, by increasing or de- creasing the thickness of the retardant coating.
• aqueous dispersion of hydrophobic polymer is used to coat inert pharmaceutical beads, a plurality of the resultant stabilized solid prolonged-release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective prolonged-release dose when ingested and contacted by gastric fluid.
• the prolonged-release profile can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic polymer, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic polymer, by varying the amount of plasticizer relative to hydrophobic polymer, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
• the coating preferably contains, in addition to the film-former, plasticizer, and solvent system (i.e., wa- ter), a colorant to provide elegance and product distinction.
• Suitable ingredients for providing color to the formu- lation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating.
• the plasticized aqueous dispersion or organic dispersion or organic solution of hydrophobic polymer may be applied onto the substrate comprising Tapentadol by spraying using any suitable spray equipment known in the art.
• a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on.
• a further overcoat of a film-former such as Opadry® is optionally applied to the beads.
• This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
• the release of Tapentadol from the prolonged-release formulation can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passage- ways through the coating.
• the ratio of hydrophobic polymer to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.
• the release- modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
• the pore-formers may comprise one or more hydrophilic polymers such as hydroxypropylmethylcellulose.
• the controlled-release coatings can also include erosion-promoting agents such as starch and gums.
• the controlled-release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the poly
• the dosage form is multiparticulate wherein the individual particles (granules, pellets and the like) comprising a prolonged release coating are contained in a capsule, optionally together with additional excipients which may be contained in the capsule in powder form or also in form of particles (granules, pellets and the like).
• the capsules contain at least two different types of particles, namely particles that contain Tapentadol and particles that do not contain Tapentadol.
• the dosage form is multiparticulate wherein the individual particles (granules, pellets and the like) comprising a prolonged release coating are contained in a tablet containing an extra- particulate material (multiple unit pellet system).
• the extra-particulate material preferably contains at least one excipient selected from binders, disintegrants and lubricants.
• Tapentadol is embedded in a prolonged release matrix.
• the pharmaceutical dosage form according to the invention preferably the prolonged release matrix, contains at least one physiologically acceptable polymer that serves the purpose of retarding release of the pharmacologically active ingredient from the pharmaceutical dosage form.
• said at least one physiologically acceptable polymer is part of the prolonged release matrix of the pharmaceutical dosage form according to the invention.
• the prolonged release matrix comprises or essentially consists of at least one prolonged release matrix material selected from the group consisting of hydrophilic or hydrophobic polymers and hydrocarbons.
• the prolonged release matrix comprises or 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-agar
• xanthan gum guar gum
• karaya gum locust bean gum
• sodium alginate sodium alginate
• carob gum chitosan
• polysaccharides of mannose and galactose pectin
• pectin pectin
• tragacanth agar-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
• polyvinylalcohol PVA
• cross-linked polyvinylalcohol PVA
• polyvinylpyrrolidone PVP
• cross-linked pol- yvinylpyrrolidone PVP
• polyvinylpyrrolidone-vinylacetate copolymers polyvinylchloride (PVC), polyeth- ylene vinyl acetate (PVAc), polydimethylsiloxane (PDS), polyether methane (PEU), polylactic acid (PL A), polyglycolic acid (PGA), polycaprolactone (PCL), polyanhydrides, polyorthoesters; - acrylic resins (e.g.
• the prolonged release matrix comprises or essentially consists of at least one hydrocarbon selected from the group consisting of long chain (C 8 -C 50 , especially C 12 -C 40 ) fatty acids, long chain fatty alcohols, glyceryl esters of long chain fatty acids, mineral oils, vegetable oils, and waxes.
• hydrocarbon selected from the group consisting of long chain (C 8 -C 50 , especially C 12 -C 40 ) fatty acids, long chain fatty alcohols, glyceryl esters of long chain fatty acids, mineral oils, vegetable oils, and waxes.
• the prolonged release matrix comprises or essentially consists of a prolonged release matrix material selected from the group consisting of (i) hydroxypropylmethylcellulose (HPMC); (ii) hydroxypropyl- cellulose (HPC); (iii) hydroxyethylcellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinylacetate copolymer (PVP/PVAc); (ix) poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacry- late chloride); (x) poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); (xi) poly(methyl methyl),
• the content of the prolonged release matrix material is within the range of 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, or 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, or 35 ⁇ 10 wt.-%, or 40 ⁇ 10 wt.-%, or 45 ⁇ 10 wt.-%, or 50 ⁇ 10 wt. -%, or 55 ⁇ 10 wt. -%, or 60 ⁇ 10 wt.-%, or 65 ⁇ 10 wt.-%, or 70 ⁇ 10 wt.-%, or 75 ⁇ 10 wt.-%, or 80 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• the pharmaceutical dosage forms according to the invention comprise neither poly (alky lene oxide), e.g. polyethylene oxide), nor ethylene vinylacetate copolymers (EVA).
• poly(alkylene oxide) is distinguished from poly(alkylene glycol) by its molecular weight; polymers having a weight average molecular weight M w of less than 100,000 g/mol are to be regarded as poly(alkylene glycol), whereas polymers having a weight average molecular weight M w of 100,000 g/mol or more are to be regarded as poly(alkylene oxide).
• the prolonged release matrix comprises a cellulose derivative selected from cellulose ethers and cellulose esters or a poly(meth)acrylate or copolymer thereof.
• the cellulose derivative is a cellulose ether selected from the group consisting of methylcellu- lose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethyl- cellulose; preferably hydroxypropylmethylcellulose.
• the cellulose derivative is hydroxypropylmethylcellulose.
• the hydro xypropylme- thylcellulose is selected from hypromellose type 1828, 2208, 2906 and 2910 according to USP having the follow- ing methoxyl content hydroxypropoxyl content:
• the viscosity of the physiologically acceptable polymer is within the range of 100,000 ⁇ 80,000 mPa s, more preferably 100,000 ⁇ 60,000 mPa s, still more preferably 100,000 ⁇ 40,000 mPa s, yet more preferably 100,000 ⁇ 20,000 mPa s.
• the number average molecular weight M n of the physiologically acceptable polymer is not more than 220,000 g/mol, more preferably not more than 180,000 g/mol, still more preferably not more than 140,000 g/mol, yet more preferably not more than 120,000 g/mol, even more preferably not more than 110,000 g/mol, most preferably not more than 86,000 g/mol, and in particular not more than 63,000 g/mol.
• the weight content of the physiologically acceptable polymer is at least 2.0 wt.-%, more preferably at least 3.0 wt.-%, still more preferably at least 4.0 wt.-%, yet more preferably at least 5.0 wt.-%, even more preferably at least 6.0 wt.-%, most preferably at least 7.0 wt.-%, and in particular at least 8.0 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
• the weight content of the physiologically acceptable polymer is at most 62.5 wt. -%, more preferably at most 60 wt.-%, still more preferably at most 57.5 wt.-%, yet more preferably at most 55 wt.-%, even more preferably at most 52.5 wt.-%, most preferably at most 50 wt.-%, and in particular at most 47.5 wt. -%, in each case relative to the total weight of the pharmaceutical dosage form.
• the weight content of the physiologically acceptable polymer is within the range of from 30 ⁇ 28 wt.-%, more preferably 30 ⁇ 26 wt.-%, still more preferably 30 ⁇ 24 wt.-%, yet more preferably 30 ⁇ 22 wt.-%, even more preferably 30 ⁇ 20 wt.-%, most preferably 30 ⁇ 18 wt.-%, and in particular 30 ⁇ 16 wt. -%, in each case relative to the total weight of the pharmaceutical dosage form.
• the pharmaceutical dosage form contains more than one physiologically acceptable polymer serv- ing the purpose of significantly retarding release of the pharmacologically active ingredient from the pharmaceu- tical dosage form, preferably cellulose ether
• the above percentages refer to the total content of all such physiolog- ically acceptable polymers, preferably cellulose ethers, that are contained in the pharmaceutical dosage form.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material hydro xypropylme- thylcellulose (HPMC) preferably in an amount of from 5.0 to 60 wt.-%, e.g.
• HPMC hydro xypropylme- thylcellulose
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material hydroxypropylcellu- lose (HPC) preferably in an amount of from 10 to 50 wt.-%, e.g.
• HPC hydroxypropylcellu- lose
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material hydro xyethylcellu- lose (HEC) preferably in an amount of from 5.0 to 50 wt.-%, e.g.
• HEC hydro xyethylcellu- lose
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material microcrystalline cellulose (MCC) preferably in an amount of from 10 to 70 wt.-%, e.g.
• MMC microcrystalline cellulose
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material ethylcellulose (EC) preferably in an amount of from 5.0 to 30 wt.-%, e.g. 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• EC prolonged release matrix material
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material polyvinyl acetate (PVAc) preferably in an amount of from 25 to 70 wt.-%, e.g.
• PVAc polyvinyl acetate
• the polyvinyl acetate is employed in form of a blend with polyvinylpyrrolidone (povidone).
• a pre- ferred blend is commercially available e.g.
• Kollidon ® SR 80 wt.-% polyvinyl acetate, 19 wt.-% povidone, 0.8 wt.-% sodium lauryl sulfate, and 0.2 wt.-% silicic acid.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material polyvinylpyrroli- done (PVP) preferably in an amount of from 2.0 to 21 wt.-%, e.g. 10 ⁇ 5.0 wt.-%, or 15 ⁇ 5.0 wt.-%, in each case relative to the total weight of the dosage form.
• PVP polyvinylpyrroli- done
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material polyvinylpyrroli- done-vinylacetate copolymer (PVP/PVAc) preferably in an amount of from 1.0 to 30 wt.-%, e.g. 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• PVP/PVAc polyvinylpyrroli- done-vinylacetate copolymer
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material poly(ethyl acrylate- co-methyl methacrylate-co-trimethyl-ammonioethyl methacrylate chloride) preferably in an amount of from 5.0 to 45 wt.
• Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammoni- oethyl methacrylate chloride) is commercially available e.g. as Eudragit ® RS and Eudragit ® RL.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the tree base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material poly(butyl methac- rylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) preferably in an amount of from 5.0 to 45 wt.
• poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate- co-methyl methacrylate) is commercially available e.g. as Eudragit ® E.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material poly(methyl meth- acrylate-co-methacrylic acid) preferably in an amount of from 5.0 to 45 wt.-%, e.g.
• Poly(methyl methacrylate-co-methacrylic acid) is commercially available e.g. as Eudragit ® L.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material poly(ethyl acrylate- co-methacrylic acid) preferably in an amount of from 5.0 to 45 wt.-%, e.g.
• Poly(ethyl acrylate-co-methacrylic acid) is commercially available e.g. as Eudragit ® S.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the tree base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material poly(methyl acry- late-co-methyl methacrylate-co-methacrylic acid) preferably in an amount of from 5.0 to 45 wt.-%, e.g.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g.
• the prolonged release matrix comprises as prolonged release matrix material poly(ethyl acrylate- co-methyl methacrylate) preferably in an amount of from 5.0 to 45 wt.-%, e.g.
• Poly(ethyl acrylate-co-methyl methacrylate) is commercially available e.g. as Eudragit ® NE.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material poly/ethylene oxide) (PEO) preferably in an amount of from 25 to 65 wt.-%, e.g.
• PEO poly/ethylene oxide
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material polyethylene glycol (PEG) preferably in an amount of from 5.0 to 35 wt.-%, e.g. 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, or 25 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• PEG polyethylene glycol
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged 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, linear or branched, preferably in an amount of from 15 to 40 wt.-%, e.g. 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• the prolonged release matrix comprises as prolonged release matrix material a long chain fatty alcohol having 8
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material cetostearyl alcohol preferably in an amount of from 15 to 40 wt.-%, e.g.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g.
• the prolonged release matrix comprises as prolonged release matrix material stearyl alcohol pref- erably in an amount of from 15 to 40 wt.-%, e.g. 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material cetyl alcohol pref- erably in an amount of from 15 to 40 wt.-%, e.g. 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material a hydrocarbon se- lected from the group consisting of long chain fatty acids having 8 to 50 carbon atoms, preferably 12 to 40 carbon atoms, which may be saturated or unsaturated, linear or branched; glyceryl esters of such long chain fatty acids, mineral oils, vegetable oils, and waxes; in each case preferably in an amount of from 5.0 to 70 wt.-%, e.g.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material xanthan gum pref- erably in an amount of from 15 to 40 wt.-%, e.g. 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material sodium alginate preferably in an amount of from 15 to 40 wt.-%, e.g. 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the tree base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material guar gum preferably in an amount of from 5.0 to 35 wt.-%, e.g. 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, or 25 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• the pharmaceutical dosage form according to the invention com- prises a weight equivalent dose of Tapentadol within the range of from 10 to 300 mg, e.g. 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg, in each case based on the free base of Tapentadol, and a prolonged release matrix in which the salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, is em- bedded; wherein the prolonged release matrix comprises as prolonged release matrix material locust bean gum preferably in an amount of from 5.0 to 35 wt.-%, e.g. 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, or 25 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• a prolonged release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavors and glidants that are conven- tional in the pharmaceutical art.
• compositions containing prolonged release matrices in which Tapentadol is embedded may be prepared by conventional techniques that are known to the skilled person such as blending and direct compression, dry granulation, wet granulation, extrusion, and the like.
• the pharmaceutical dosage form according to the invention is a capsule, pref- erably containing a plurality of particles containing a prolonged release coating.
• the pharmaceutical dosage form according to the invention is a tablet.
• the tablet is monolithic.
• Monolithic tablets according to the invention mean tablets that are optionally film coated, wherein the core of the tablets contains a compressed powder and/or granulate mixture.
• tablets prepared by direct compression of powder mixtures are all to be regarded as monolithic tablets in accordance with the invention.
• multiple unit pellet systems or other dosage forms where a multitude of particles of specific design, weight and shape is mixed with an outer matrix material and subsequently compressed into tablets where the outer matrix material forms a continuous phase in which the pellets or particles are embedded, are preferably not to be regarded as monolithic tablets.
• capsules filled with a multitude of loose particles are not to be regarded as monolithic either.
• the tablet has abreaking strength of at least 100 N, preferably at least 150 N, more preferably at least 200 N.
• the breaking strength is preferably determined in accordance with Ph. Eur. 10, chapter 2.9.8. " Resistance to Crushing of Tablets" .
• the method for the preparation according to the invention comprises the steps of
• step (C) coahng the inert starter pellets provided in step (A) with the soluhon or dispersion of Tapentadol provided in step (B), preferably in a fluidized bed, thereby obtaining intermediate particles containing an inert core not containing any Tapentadol and a drug coating layer encapsulating said core and comprising essentially the total amount of Tapentadol to be contained in the dosage form, optionally together with the one or more excipients;
• step (D) optionally, drying the intermediate particles obtained in step (C) thereby obtaining dried intermediate parti- cles;
• step (F) coahng the intermediate particles obtained in step (C) or the dried intermediate particles obtained in step (D) with the soluhon or dispersion of prolonged release coahng material provided in step (E), preferably in a fluidized bed, thereby obtaining prolonged release particles containing an inert core not containing any Tapentadol, a drug coating layer encapsulating said core and comprising essentially the total amount of Tapentadol, optionally together with the one or more excipients, and a prolonged release coating encapsulat- ing said core and said drag coating layer;
• step (G) optionally, drying the prolonged release particles obtained in step (F) thereby obtained dried prolonged re- lease particles
• step (H) either filling the prolonged release particles obtained in step (F) or the dried prolonged release particles ob- tained in step (G) into capsules; or mixing the prolonged release particles obtained in step (F) or the dried prolonged release particles obtained in step (G) with extra-particle excipients and compressing the mixture into tablets (mulhple unit pellet systems).
• Another aspect of the invention relates to a pharmaceutical dosage form that is obtainable by this preferred method according to the invention as described above.
• the method for the preparation according to the invention comprises the steps of
• step (B) preparing drag pellets from the mixture provided in step (A) by dry granulation, wet granulation or extrusion, wherein wet granulation preferably involved use of a solvent selected from water, ethanol, acetone, and any mixture thereof;
• step (C) optionally, drying and/or spheronizing the drug pellets prepared in step (B) thereby obtaining dried and/or spheronized drag pellets;
• step (E) coating the drug pellets prepared in step (B) or the dried and/or spheronized drag pellets obtained in step (C) with the solution or dispersion of prolonged release coating material provided in step (D), preferably in a fluidized bed, thereby obtaining prolonged release particles containing a core comprising essentially the total amount of Tapentadol, optionally together with one or more excipients, and a prolonged release coating en- capsulating said core;
• step (F) optionally, drying the prolonged release particles obtained in step (E) thereby obtained dried prolonged re- lease particles
• step (G) either filling the prolonged release particles obtained in step (E) or the dried prolonged release particles ob- tained in step (F) into capsules; or mixing the prolonged release particles obtained in step (E) or the dried prolonged release particles obtained in step (F) with extra-particle excipients and compressing the mixture into tablets (multiple unit pellet systems).
• Another aspect of the invention relates to a pharmaceutical dosage form that is obtainable by this preferred method according to the invention as described above.
• the method for the preparation according to the invention comprises the steps of
• step (b) optionally granulating the mixture provided in step (a) thereby obtaining a granulate, wherein granulating preferably involves: (i) wet granulating by means of a solvent, preferably selected from water, ethanol, ace- tone, and any mixture thereof, optionally followed by drying; (ii) dry granulation; or (iii) extrusion;
• step (c) optionally mixing the granulate obtained in step (b) with one or more excipients thereby obtaining a granulate mixture
• step (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the granulate mixture obtained in step (c) into tablets; (e) optionally, film coating the tablets compressed in step (d).
• compressing in step (d) of the process according to the invention is performed at a compres- sion force of not more than 20 kN, more preferably not more than 15 kN, still more preferably not more than 10 kN, yet more preferably not more than 9.5 kN, even more preferably not more than 9.0 kN, most preferably not more than 8.75 kN, and in particular not more than 8.5 kN.
• step (d) of the process according to the invention is performed under condi- tions such that the compressed tablet has a breaking strength of at least 100 N, more preferably at least 150 N, still more preferably at least 200 N.
• the pharmaceutical dosage form according to the invention is not prepared by thermoforming such as hot-melt extmsion.
• the pharmaceutical dosage form according to the invention does not contain a multitude of particles or pellets of specific design, shape and weight that are optionally compressed into tablets wherein said particles or pellets form a discontinuous phase within a continuous phase of an outer matrix material.
• the pharmaceutical dosage form according to the invention does not contain an opioid antag- onist.
• Opioid antagonists are entities that modify the response of opioid receptors.
• Opioid antagonists include Naloxone, Naltrexone, Diprenorphine, Etorphine, Dihydroetorphine, Nalinefene, 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, wherein the dosage form is orally administered, preferably twice daily.
• Another aspect of the invention relates to the use of a salt of Tapentadol with phosphoric acid, preferably the dihydrogenphosphate salt of Tapentadol, for the manufacture of a pharmaceutical dosage form according to the invention as described above for the treatment of pain, wherein the dosage form is orally administered, prefer- ably twice daily.
• Another aspect of the invention relates to a method of treating pain comprising the step of administering to a subject in need thereof orally, preferably twice daily, a pharmaceutical dosage form according to the invention as described above.
• the pain is chronic pain.
• the pharmaceutical dosage form according to the invention provides in a pa- tient population of at least 10 patients, preferably at least 50 patients, an average value of T max within the range of 5.0 ⁇ 3.0 hours after oral administration.
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 50 mg based on the free base of Tapentadol and wherein the dosage form after oral administration in a patient population of at least 50 patients provides an average value of
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 100 mg based on the free base of Tapentadol and wherein the dosage form after oral administration in a patient population of at least 50 patients provides an average value of
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 150 mg based on the free base of Tapentadol and wherein the dosage form after oral administration in a patient population of at least 50 patients provides an average value of
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 200 mg based on the free base of Tapentadol and wherein the dosage form after oral administration in a patient population of at least 50 patients provides an average value of
• the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 250 mg based on the free base of Tapentadol and wherein the dosage form after oral administration in a patient population of at least 50 patients provides an average value of
• Clause 2 The pharmaceutical dosage form according to clause 1, wherein the salt of Tapentadol with phosphoric acid is the dihydrogenphosphate salt of Tapentadol, a solvate, an ansolvate, and/or a polymorph thereof, a crystal- line form and/or amorphous form thereof.
• Clause 3 The pharmaceutical dosage form according to clause 1 or 2, which is a tablet.
• Clause 4 The pharmaceutical dosage form according to clause 3, wherein the tablet is monolithic.
• Clause 5 The pharmaceutical dosage form according to clause 3 or 4, wherein the tablet has a breaking strength of at least 100 N, determined according to Ph. Eur. 2.9.8.
• Clause 6 The pharmaceutical dosage form according to any of the preceding clauses, which provides slower dis- solution of Tapentadol in 0.1 N HC1 containing 40 vol.-% of ethanol (pH 1.0) than in 0.1 N HC1 not containing 40 vol.-% of ethanol (pH 1.0), in each case when measured by the USP Paddle Method at 50 rpm in 900 ml at 37° C.
• Clause 7 The pharmaceutical dosage form according to any of the preceding clauses, wherein the dosage form provides an in vitro dissolution profile, when measured by the USP Paddle Method at 50 rpm in 900 ml (i) aqueous phosphate buffer at pH 6.8, (ii) aqueous buffer at pH 4.5, and/or (iii) 0.1 N HC1 at pH 1.0, in each case at 37° C, wherein - after 0.5 hour 20 ⁇ 15 wt.-%; - after 4 hours 60 ⁇ 15 wt.-%; and - after 12 hours at least 70 wt.-%; of the Tapentadol that was originally contained in the dosage form have been released.
• the prolonged re- lease matrix comprises or essentially consists of a prolonged release matrix material selected from the group con- sisting of (i) hydroxypropylmethylcellulose (HPMC); (ii) hydroxypropylcellulose (HPC); (iii) hydroxyethylcellu- lose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) polyvinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinylacetate copolymer (PVP/PVAc); (ix) poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride); (x) poly(butyl methacrylate- co-(2-dimethylaminoethyl) methacrylate-co-
• Clause 9 The pharmaceutical dosage form according to clause 8, wherein the content of the prolonged release matrix material is within the range of 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, or 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, or 35 ⁇ 10 wt.-%, or 40 ⁇ 10 wt.-%, or 45 ⁇ 10 wt.-%, or 50 ⁇ 10 wt.-%, or 55 ⁇ 10 wt.-%, or 60 ⁇ 10 wt.-%, or 65 ⁇ 10 wt.-%, or 70 ⁇ 10 wt.-%, or 75 ⁇ 10 wt.-%, or 80 ⁇ 10 wt.-%, in each case relative to the total weight of the dosage form.
• Clause 10 The pharmaceutical dosage form according to any of the preceding clauses for use in the treatment of pain.
• Clause 11 The pharmaceutical dosage form for use according to clause 10, wherein the dosage form is orally administered.
• Clause 12 The pharmaceutical dosage form for use according to clause 10 or 11, wherein the dosage form is administered twice daily.
• Clause 13 The pharmaceutical dosage form for use according to any of clauses 10 to 12, which after oral admin- istration provides plasma levels of Tapentadol providing pain relief for a duration of at least 6 hours.
• Clause 14 The pharmaceutical dosage form for use according to any of clauses 10 to 13, wherein the pain is chronic pain.
• Clause 15 A method for the preparation of a pharmaceutical dosage form according to any of clauses 1 to 14, the method comprising the steps of (a) providing a mixture containing essentially the total amount of Tapentadol to be contained in the dosage form and at least one prolonged release matrix material, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a) thereby obtaining a granulate; (c) optionally mixing the granulate obtained in step (b) with one or more excipients thereby obtaining a granulate mixture; (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the granulate mixture obtained in step (c) into tablets; (e) optionally, film coating the tablets compressed in step (d).
• a pharmaceutical dosage form comprising Tapentadol for oral administration twice daily; wherein Tapentadol is present as a salt with phosphoric acid; wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form is within the range of from 10 to 300 mg based on the free base of Tapentadol; wherein the dosage form is a tablet; wherein the dosage form provides prolonged release of Tapen- tadol; and wherein Tapentadol is embedded in a prolonged release matrix.
• Clause 17 The pharmaceutical dosage form according to clause 16, wherein the salt is the dihydrogenphosphate salt of Tapentadol, a solvate, an ansolvate, and/or a polymorph thereof, a crystalline form and/or amorphous form thereof.
• Clause 18 The pharmaceutical dosage form according to clause 16 or 17, wherein the tablet is monolithic.
• Clause 19 The pharmaceutical dosage form according to any of the preceding clauses, wherein the tablet has a breaking strength of at least 100 N, determined according to Ph. Eur. 2.9.8.
• Clause 20 The pharmaceutical dosage form according to any of clauses 16 to 19, wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 25 mg, 50 mg, or 100 mg, in each case based on the free base of Tapentadol; and wherein the dosage form has a total weight within the range of from 150 to 750 mg.
• Clause 21 The pharmaceutical dosage form according to any of clauses 16 to 19, wherein the weight equivalent dose of Tapentadol that is contained in the pharmaceutical dosage form amounts to 150 mg, 200 mg or 250 mg, in each case based on the free base of Tapentadol; and wherein the dosage form has a total weight within the range of from 300 to 1200 mg.
• Clause 22 The pharmaceutical dosage form according to any of clauses 16 to 21, wherein the prolonged release matrix comprises or essentially consists of a prolonged release matrix material selected from the group consisting of (i) hydroxypropylmethylcellulose (HPMC); (ii) hydroxypropylcellulose (HPC); (iii) hydroxyethylcellulose (HEC); (iv) microcrystalline cellulose (MCC); (v) ethylcellulose (EC); (vi) polyvinyl acetate (PVAc); (vii) poly- vinylpyrrolidone (PVP); (viii) polyvinylpyrrolidone-vinylacetate copolymer (PVP/PVAc); (ix) poly(ethyl acry- late-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride); (x) poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate); (
• Clause 23 The pharmaceutical dosage form according to clause 22, wherein the content of the prolonged release matrix material is within the range of 15 ⁇ 10 wt.-%, or 20 ⁇ 10 wt.-%, or 25 ⁇ 10 wt.-%, or 30 ⁇ 10 wt.-%, or 35 ⁇ 10 wt. -%, or 40 ⁇ 10 wt.
• Clause 24 The pharmaceutical dosage form according to any of clauses 16 to 23 for use in the treatment of pain.
• Clause 25 The pharmaceutical dosage form for use according to clause 24, wherein the dosage form is orally administered.
• Clause 26 The pharmaceutical dosage form for use according to clause 24 or 26, wherein the dosage form is administered twice daily.
• Clause 27 The pharmaceutical dosage form for use according to any of clauses 24 to 26, which after oral admin- istration provides plasma levels of Tapentadol providing pain relief for a duration of at least 6 hours.
• Clause 28 The pharmaceutical dosage form for use according to any of clauses 24 to 27, wherein the pain is chronic pain.
• Clause 29 A method for the preparation of a pharmaceutical dosage form according to any of clauses 16 to 28, the method comprising the steps of (a) providing a mixture containing essentially the total amount of Tapentadol to be contained in the dosage form and at least one prolonged release matrix material, optionally together with one or more excipients; (b) optionally granulating the mixture provided in step (a) thereby obtaining a granulate; (c) optionally mixing the granulate obtained in step (b) with one or more excipients thereby obtaining a granulate mixture; (d) compressing the mixture provided in step (a) or the granulate obtained in step (b) or the granulate mixture obtained in step (c) into tablets; (e) optionally, film coating the tablets compressed in step (d).
• Clause 30 The method according to clause 29, wherein compressing in step (d) is performed at a compression force of not more than 20 kN, more preferably not more than 15 kN, still more preferably not more than 10 kN, yet more preferably not more than 9.5 kN, even more preferably not more than 9.0 kN, most preferably not more than 8.75 kN, and in particular not more than 8.5 kN.
• Palexia ® retard contain Tapentadol as hydrochloride salt, whereas the tablet core additionally contains hypromellose, microcrystalline cellulose, highly disperse silicon dioxide, and magnesium stearate.
• Palexia ® retard tablets contain a prolonged release matrix of hypromellose.
• Example 1.4 Tapentadol dihydrogenphosphate hemihydrate: [0220] Tapentadol base (497 mg) was dissolved at 20 °C to 25 °C in a mixture of acetone (2.72 g, 3.44 ml) and water (50 mg, 50 m ⁇ ) to give a clear solution. Phosphoric acid (259 mg, 153 m ⁇ , 85 wt.-%) was added and after a short time the clear solution became a suspension. The suspension was mixed for 30 min at 20 °C to 25 °C, after that cooled to 5 °C and further mixed at 5 °C for 30 min. The resulting solid was isolated by vacuum filtration and dried (20 °C to 25 °C, vacuum, 30 min).
• the obtained product (404 mg, white crystalline powder) was analyzed by XRPD ( Figure 2) and DSC ( Figure 3).
• the first DSC peak had a normalized integral of 149.2 J g 1 , with an onset temperature of 56.7 °C and a peak temperature of 89.2 °C.
• the second DSC peak had a normalized integral of 22.0 J g -1 , with an onset temperature of 130.1 °C and a peak temperature of 133.4 °C. At about 200 °C, decom- position occurred. A weight loss of 3.7% up to 119 °C was detected by TGA.
• the resulting solid was isolated by vacuum fdtration and dried (20 °C to 25 °C, vacuum, 2 h).
• the obtained product (84.6 g, white crystalline solid) was analyzed by XRPD. A weight loss of 4.5% up to 113 °C was detected by TGA.
• the resulting solid was isolated by vacuum filtration and dried (20 °C to 25 °C, vacuum, 30 min).
• the obtained product (157 mg, white crystalline powder) was analyzed by XRPD ( Figure 4) and DSC ( Figure 5).
• the DSC peak had a normalized integral of 72.1 J g 1 , with an onset temperature of 146.5 °C and a peak temperature of 149.1 °C. At about 200 °C, decomposition occurred. A weight loss of 0.9% up to 134 °C was detected by TGA.
• Figure 6A shows relatively fine particles of the mixed form of Tapentadol dihydrogenphosphate (average particle size upon visual inspection about 10-20 pm).
• Figure 6B shows relatively coarse particles of the pure hem- ihydrate of Tapentadol dihydrogenphosphate according to Example 1.5 (needle like crystals, average particle size upon visual inspection about 100-200 pm).
• Figure 6C shows relatively coarse particles of Tapentadol hydrochlo- ride (average particle size upon visual inspection about 100-150 pm).
• thermodynamic solubility of Tapentadol hydrochloride and of Tapentadol dihydrogenphosphate was determined as saturation solubility in various media at various pH values.
• the solutions were stirred for 24 hours at 25 °C and the pH values of the solutions at the start and at the end of the experiments were measured.
• the dissolved amount of Tapentadol was quantified by HPLC (free base of Tapentadol). The experimental results are compiled in the table here below:
• Example 4 in vitro dissolution profdes of pharmaceutical dosage forms:
• Tablets having the following composition were prepared by mixing all ingredients and compressing the resultant mixtures: 4 relatively coarse particle size (average diameter about 100-200 pm upon visual inspection)
• Figure 9 compares the in vitro dissolution profdes of a conventional tablet containing Tapentadol hydro- chloride at pH 1.0, pH 4.5, pH 6.8 in each case in aqueous buffer without ethanol and in 0.1 N HC1 with 40 vol.- % ethanol (pH 1.0).
• Figure 10 compares the in vitro dissolution profiles of the inventive tablet containing salt of Tapentadol with phosphoric acid at pH 1.0, pH 4.5, pH 6.8 in each case in aqueous buffer without ethanol and in 0.1 N HC1 with 40 vol.-% ethanol (pH 1.0).
• Example 5 in vitro dissolution profdes of pharmaceutical dosage forms: [0242] Tablets having the following composition were prepared by mixing all ingredients and compressing the resultant mixtures:
• Figure 11 compares the in vitro dissolution profiles of an inventive tablet containing salt of Tapentadol with phosphoric acid in 0.1 N HC1 (pH 1.0) without ethanol and in 0.1 N HC1 (pH 1.0) in 40 vol.-% ethanol.
• Example 6 in vitro dissolution profiles of pharmaceutical dosage forms:
• Coated pellets having the following composition were prepared by spraying an aqueous spraying liquid containing Tapentadol onto inert spheres:
• a coating formulation comprising ethylcellulose, polyvinylpyrrolidone and dibutyl sebacate (EC/PVP/DBS)
• EC/PVP/DBS polyvinylpyrrolidone and dibutyl sebacate

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