[go: up one dir, main page]

WO2024200335A1 - Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32 h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide - Google Patents

Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32 h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide Download PDF

Info

Publication number
WO2024200335A1
WO2024200335A1 PCT/EP2024/057910 EP2024057910W WO2024200335A1 WO 2024200335 A1 WO2024200335 A1 WO 2024200335A1 EP 2024057910 W EP2024057910 W EP 2024057910W WO 2024200335 A1 WO2024200335 A1 WO 2024200335A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
chloro
aza
dioxo
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/057910
Other languages
French (fr)
Inventor
Susanne MERKEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Priority to AU2024248738A priority Critical patent/AU2024248738A1/en
Priority to KR1020257032237A priority patent/KR20250164210A/en
Priority to CN202480020029.8A priority patent/CN120936342A/en
Publication of WO2024200335A1 publication Critical patent/WO2024200335A1/en
Priority to MX2025011252A priority patent/MX2025011252A/en
Priority to CONC2025/0013103A priority patent/CO2025013103A2/en
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-7 4 -carboxamide (active ingredient (I)), characterized in that the active ingredient (I) is present in amorphous form and is immediately released from the solid pharmaceutical dosage forms for oral administration, and also methods for the preparation thereof, use thereof as medicaments, and also use thereof for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.
  • diseases in particular cardiovascular disorders, preferably thrombotic or thro
  • the active ingredient (I) acts as a factor Xia inhibitor and, owing to this specific mechanism of action, is, after oral administration, useful in the treatment and/or prophylaxis of disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, in particular cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non-cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
  • disorders preferably thrombotic or thrombo
  • active ingredient (I) (4S - 2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide, is used as amorphous form.
  • an oral solid pharmaceutical dosage form such as a tablet, should provide the release of substantially all of the active ingredient (I) immediately and provide sufficient dissolution properties.
  • the solid pharmaceutical dosage form should also have excellent properties which enable the manufacture of the solid pharmaceutical dosage form in industrial scale since it is needed in a large number of patients where at the same time using a sustainable manufacturing process.
  • the majority of solid drugs and dosage forms are prepared in the crystalline state, characterized by a regular ordered lattice structure. These physical structures are generally thermodynamically stable and are relatively simple to study using techniques such as differential scanning calorimetry and X- ray diffraction. Amorphous materials are thermodynamically unstable and will tend to revert to the crystalline form on storage. The mechanical properties and vapour sorption profiles of amorphous systems may be markedly different from the crystalline material, while the chemical reactivity of amorphous drugs may be greater. The amorphous state is, by definition, metastable with regard to the crystalline material, hence amorphous drugs will tend to revert to the crystalline form over a period of time.
  • amorphous solid dispersions Besides creating freeze dried systems in which the amorphous state of a drug (and excipients) is stabilized, creating of so-called amorphous solid dispersions (ASDs) is well known as stabilizing measure for originally amorphous materials as well as formerly crystalline materials and especially used for oral dosage forms.
  • ASDs amorphous solid dispersions
  • DE 10 2010 005 124 Al describes a solid oral dosage form manufactured via direct tableting/direct compression and comprising amorphous Lecanidipine and a hydrogelling agent, namely Hypromellose, incorporated as stabilizing excipient.
  • WO 2009/138224 discloses a pharmaceutical composition
  • a pharmaceutical composition comprising drosperinone substantially in amorphous form and a carrier selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC), and the drosperinone and carrier are present in co-milled state.
  • HPMC hydroxypropyl methyl cellulose
  • PVP polyvinylpyrrolidone
  • MCC microcrystalline cellulose
  • WO2022/189278 describes an amorphous solid dispersions (ASD) and solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena- heptaphane-7 4 -carboxamide.
  • Amorphous solid dispersions use specific carriers that amorphized the drug substance and stabilize it in the solid state. Incorporating additional stabilizing excipients results in increased tablet weight and tablet size which is known to be unfavorable for patient's compliance.
  • ASDs amorphous materials in ASDs eventually revert to their crystalline form, albeit at a slow rate.
  • pharmaceutical dosage forms comprising ASDs may require additional moisture -protective measures such as special coatings and/or application of specialized product packaging materials which act as moisture barriers or moisture adsorbers (desiccants).
  • Lopinavir und Ritonavir are provided as fixed dose combination tablets (KALETRA®) which are coated with polyvinylalcohol polymer which protects the active ingredients from moisture, oxygen and other environmental components, and Etravirin tablets (INTELENCE®) are needed to be marketed in bottles which contain three desiccant pouches per bottle to keep the tablets dry.
  • Solid pharmaceutical dosage forms which are manufactured via tabletting may optionally be roller compacted. As many materials are not suitable for direct compression often a granulation step takes place prior to tableting. Roller compaction and subsequently dry granulation of the compacted material is beside wet granulation one common way to produce granules, which gained in importance for the pharmaceutical industry. [Mosig in: Powder Technology 266 (2014) 156-166]
  • This method allows the granulation of materials sensitive to moisture and heat.
  • the process is environmental friendly, as no removing of solvents is necessary, and scale up is easily feasible.
  • a major advantage is the continuous production of granules leading to a reduction of costs.
  • the orally disintegrating tablet serves as a special type of tablets. They are attractive to many patient groups such as the elderly, children, and patients who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/diets have difficulties swallowing these dosage forms. Those who are traveling or have little access to water are similarly affected.
  • pharmaceutical technologists have developed a novel oral dosage form known as orally disintegrating tablets (ODTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take it water. Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms. [Hirani in: Tropical Journal of Pharmaceutical Research, April 2009, 8 (2), 161-172]
  • ODTs can be manufactured by different processes like lyophilisation, moulding and sublimation, using a sugar-floss system or direct compression.
  • the process of direct compression is convenient and cost-effective, but is highly influenced by the characteristics of the active pharmaceutical ingredient (API) as well as the used excipients, like flowability, compressibility and compactability. Therefore, excipients that offer excellent compaction properties should be preferably used.
  • Excipients for ODTs have to be selected based on material characteristics (plastic, elastic or brittle material) and desired functionalities like defined particle size distribution, good flowability, enhanced compactability or fast disintegration. Mannitol represents an often used excipient for fast-dissolving drug formulations.
  • Co-processing means the interacting of two or more excipients at the subparticle level, due to co-spray-drying, cospray-agglomerating or cogranulating, which led to an improved functionality.
  • Co-processed mannitol as used in the present invention is marketed under various tradenames such as Pharmaburst®.
  • mannitol is known to induce crystallization of an amorphous drug even when stabilized in an amorphous spray-dried dispersion.
  • Excipients such as fillers such as mannitol have been shown in the literature to have effects on polymorphic transformations during wet granulation so the potential for excipient-induced physical instability does exist. Therefore, it was to be expected that a mannitol comprising co-processed excipient system such as Pharmaburst® will induce crystallization of an amorphous drug in a pharmaceutical dosage form, especially when manufactured without any stabilizing measures.
  • the aim of the development was, therefore, to provide solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- l 4 -(trifluoro- methyl)-3 2 H-6-aza-3(4, l)-pyridina-l (l)-[ 1 ,2,3]triazola-2( 1 ,2),7(l)-dibenzenaheptaphane-7 4 - carboxamide (active ingredient (I)), where the active ingredient (I) is present in amorphous form and the oral solid pharmaceutical dosage forms show a superior dissolution behaviour and a good bioavailability.
  • the solid pharmaceutical dosage form should also have excellent properties which enable the manufacture of the solid pharmaceutical dosage form in industrial scale. Furthermore, the amorphous form of the active ingredient (I) shall be stable in the solid pharmaceutical dosage forms during long-term storage. Crystallization needs to be prevented in any case since, crystallization of the active ingredient (I) results in a lower dissolution rate and a lower bioavailability of the active ingredient (I).
  • a solid pharmaceutical dosage form is prepared without using water, organic solvents or heat in which the active ingredient (I) is present and stable in an amorphous form.
  • This solid pharmaceutical dosage form shows a superior dissolution behaviour and a good bioavailability and in addition, excellent tablet properties resulting from a manufacturing process that enables large industrial scale manufacturing, if needed also a continuous manufacturing process without individual batches, and sustainability at the same time.
  • the present invention describes a pharmaceutical dosage form manufactured by a process which is not based on solvent evaporation or melting and in which the comprised amorphous drug is chemically and physically long-term stable.
  • the present invention describes a pharmaceutical dosage form provided as orally disintegrating tablet (ODT) manufactured by compression and comprising mannitol in which the comprised amorphous drug is chemically and physically long-term stable.
  • ODT orally disintegrating tablet
  • Solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form characterized in that the dosage form is
  • Solid pharmaceutical dosage forms for oral administration comprising (45)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form characterized in that the dosage form is
  • Solid pharmaceutical dosage forms based on direct compression and manufacturing processes thereof as such are known.
  • the solid pharmaceutical dosage forms for oral administration comprising (45)-2 4 - chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoro-methyl)-3 2 H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in form of a roller compacted granulate or a tablet with good tablet hardness and low brittleness enabling manufacture of the tablets in large industrial scale.
  • the solid pharmaceutical dosage forms are robust against variations in the manufacturing process during operation and technical transfer such that the properties of the solid pharmaceutical dosage forms are not affected.
  • an immediate release tablet prepared without using water or organic solvents or heat comprising active ingredient (I) in amorphous form according to the present invention shows a superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent properties which enable the manufacture of the solid pharmaceutical dosage form in industrial scale and, if needed also a continuous manufacturing process without individual batches, since it is needed in a large number of patients where at the same time using a sustainable manufacturing process.
  • the present invention provides a process where the active ingredient (I) is used in its amorphous form and mixed together with other excipients. This mixture may than be roller compacted. Afterwards a disintegration promoter may be added and mixed again. Finally, the lubricant may be added and mixed again. This mixture is used as the granulate as such or it is used to manufacture tablets. The tablets may optionally be coated.
  • the methods and excipients chosen for the present invention are in some aspects in contrast to the methods and excipients known by the person skilled in the art and which are known as common to prepare immediate release tablets without using water or organic solvents or heat comprising active ingredient (I) in amorphous form.
  • the present invention provides solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, which are prepared without using water or organic solvents or heat.
  • the present invention provides also solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients, which are prepared without using water or organic solvents or heat.
  • the present invention provides also solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients such as sweeteners, flavoring agents and colorants, which are prepared without using water or organic solvents or heat.
  • the present invention provides solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, which are prepared without using water or organic solvents or heat, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
  • the present invention provides solid pharmaceutical dosage forms A) for oral administration comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one disintegration promoter, and c) at least one filler.
  • the present invention also provides solid pharmaceutical dosage forms A) for oral administration comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one disintegration promoter, and c) at least one filler, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
  • the present invention provides solid pharmaceutical dosage forms B) or C) for oral administration comprising d) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, e) at least one lubricant, f) at least one disintegration promoter, and g) at least one filler.
  • the present invention also provides solid pharmaceutical dosage forms B) or C) for oral administration comprising d) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, e) at least one lubricant, f) at least one disintegration promoter, and g) at least one filler, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
  • the present invention provides solid pharmaceutical dosage forms D) for oral administration comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, and c) at least one filler or disintegration promoter.
  • the present invention provides solid pharmaceutical dosage forms D) for oral administration comprising h) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, i) at least one lubricant, and j) at least one filler or disintegration promoter, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
  • the present invention provides solid pharmaceutical dosage forms D) for oral administration comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, and c) at least one filler or disintegration promoter, wherein the disintegration time is maximal 3 minutes according to disintegration method of the European Pharmacopoeia using the rigid basket-rack apparatus with disk.
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (45)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is a roller compacted granulate which is obtained by roller compacting and grinding a mixture of active ingredient (I) in amorphous form and excipients.
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is a roller compacted granulate which is obtained by roller compacting and grinding a mixture of active ingredient (I) in amorphous form and excipients, which is prepared without using water or organic solvents or heat.
  • the present invention provides solid pharmaceutical dosage forms for oral administration, which are a roller compacted granulate, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one disintegration promoter, and c) at least one filler.
  • a roller compacted granulate comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-
  • the present invention also provides solid pharmaceutical dosage forms for oral administration, which are a roller compacted granulate, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and c) at least one filler in an amount of 2 mg up to 150 mg.
  • active ingredient (I) active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg
  • b) at least one disintegration promoter in
  • the present invention also provides solid pharmaceutical dosage forms for oral administration, which are a roller compacted granulate, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) croscarmellose sodium as disintegration promoter, and c) microcrystalline cellulose and lactose as filler.
  • a roller compacted granulate comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4
  • the advantage of a roller compacted granulate is the improved flowability of the granulate compared to the initial powder mixture. It is known from literature that compression induces demixing which is of even greater importance when leading to amorphous phase separation and finally instability of drugs in amorphous form as described in Ayenew, see above.
  • the advantage of the present invention is that the mixture can be roller compacted without losing its superior dissolution behaviour and a good bioavailability of the active ingredient (I).
  • the compression of the mixture reduces the risk of inhomogeneous distribution of active ingredient (I) in amorphous form in the solid pharmaceutical dosage form.
  • the amorphous form of active ingredient (I) is long-term stable in the roller compacted granules comprising of well-known standard excipients without the means of any stabilizer (e.g. polymer in an ASD matrix or gelling agents as described above).
  • any stabilizer e.g. polymer in an ASD matrix or gelling agents as described above.
  • roller compaction force [kN/cm] and the gap [mm] has to be well controlled in the roller compaction process.
  • the roller compaction force is preferred between 0.1 and 5.0 kN/cm and the gap between 1.0 bis 6.0 mm. Preferred is that the roller compaction force is low when the gap is small, and that the roller compaction force is high when the gap is wide. Most preferred is a roller compaction force of 2 kN/cm and a gap of 3 mm.
  • Roller compaction is not known as a method to stabilize the amorphous form of an active ingredient. Therefore, it could be surprisingly proven, that the roller compaction process is suitable to manufacture a solid pharmaceutical dosage form where the amorphous form of active ingredient (I) is long-term stable.
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to an immediate release tablet.
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to an immediate release tablet, which is prepared without using water or organic solvents or heat.
  • the present invention provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet containing roller compacted granulate, comprising a) (45)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, c) at least one disintegration promoter, and d) at least one filler.
  • an immediate release tablet containing roller compacted granulate comprising a) (45)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dio
  • the present invention also provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet containing roller compacted granulate, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 0.5 mg up to 7 mg, c) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and d) at least one filler in an amount of 2 mg up to 150 mg.
  • an immediate release tablet containing roller compacted granulate comprising
  • the advantage of a roller compacted granulate is the improved flowability of the granulate compared to the initial powder mixture. It is known from literature that compression induces demixing which is of even greater importance when leading to amorphous phase separation and finally instability of drugs in amorphous form as described in Ayenew, see above.
  • roller compacted solid pharmaceutical dosage forms tend to suffer from final tablet hardness or slowed down dissolution behavior.
  • the advantage of the present invention is that the mixture can be roller compacted without losing its superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent tableting properties.
  • the resulting tablets show excellent tablet hardness.
  • the compression of the mixture reduces the risk of inhomogeneous distribution of active ingredient (I) in amorphous form in the solid pharmaceutical dosage form.
  • the amorphous form of active ingredient (I) is long-term stable in the tablet based on roller compacted granules.
  • the tablet comprises only well-known standard excipients without the means of any stabilizer (e.g. polymer in an ASD matrix or gelling agents as described above).
  • roller compaction force [kN/cm] and the gap [mm] has to be well controlled in the roller compaction process.
  • the roller compaction force is preferred between 0.1 and 5.0 kN/cm and the gap between 1.0 bis 6.0 mm. Preferred is that the roller compaction force is low when the gap is small, and that the roller compaction force is high when the gap is wide. Most preferred is a roller compaction force of 2 kN/cm and a gap of 3 mm.
  • Roller compaction itself is not known as a method to stabilize the amorphous form of an active ingredient. Therefore, it could be surprisingly proven, that tablets based on roller compacted granules can be manufactured, where the amorphous form of active ingredient (I) is long-term stable.
  • immediate release tablet which is based on direct compression (solid pharmaceutical dosage form C))
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet which is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients.
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet which is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients, which is prepared without using water or organic solvents or heat.
  • the present invention provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet which is based on direct compression, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, c) at least one disintegration promoter, and d) at least one filler.
  • an immediate release tablet which is based on direct compression, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-
  • the present invention also provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet which is based on direct compression, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 0.5 mg up to 7 mg, c) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and d) at least one filler in an amount of 2 mg up to 150 mg.
  • an immediate release tablet which is based on direct compression
  • the present invention also provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet which is based on direct compression, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) magnesium stearate as lubricant, c) croscarmellose sodium as disintegration promoter, and d) microcrystalline cellulose and lactose as filler.
  • an immediate release tablet which is based on direct compression, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5
  • the advantage of the present invention is that the amorphous form of active ingredient (I) is longterm stable in an immediate release tablet which is based on direct compression without any means of stabilization (e.g. polymer in an ASD matrix or gelling agents as described above) while at the same time showing a superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent tablet properties.
  • the resulting tablets show excellent tablet hardness.
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is an orally dispersible tablet containing active ingredient (I) in amorphous form and excipients.
  • the present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form which is an orally dispersible tablet containing active ingredient (I) in amorphous form and excipients, which is prepared without using water or organic solvents or heat.
  • the present invention provides solid pharmaceutical dosage forms for oral administration, which are an orally dispersible tablet, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, and c) at least one filler or disintegration promoter.
  • 4S 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina-
  • the present invention also provides solid pharmaceutical dosage forms for oral administration, which are an orally dispersible tablet, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 2 mg up to 30 mg, and c) at least one filler or disintegration promoter in an amount of 20 mg up to 700 mg.
  • active ingredient (I) active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg
  • the present invention also provides solid pharmaceutical dosage forms for oral administration, which are an orally dispersible tablet, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in amorphous form, b) magnesium stearate as lubricant, and c) a sugar alcohol mixture as filler or disintegration promoter.
  • solid pharmaceutical dosage forms for oral administration which are an orally dispersible tablet, comprising a) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-diox
  • the advantage of the present invention is that the amorphous form of active ingredient (I) can be formulated in an orally dispersible tablet by without any means of stabilization while at the same time showing a superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent disintegration behavior.
  • the roller compacted granulate comprising the active ingredient (I) in amorphous form can be formulated into solid or liquid preparations such as tablets, sachets, capsules, dragees, chewable tablets, effervescent tablets, dispersible tablets, troches, lozenges, melts, or suspensions, and may be prepared according to the methods known to the art of the manufacture of pharmaceutical compositions.
  • the pharmaceutical dosage form according to the present invention is a tablet.
  • the pharmaceutical dosage form according to the present invention is an immediate release tablet.
  • the pharmaceutical dosage form according to the present invention is a tablet, where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to a tablet, the tablet optionally is covered with a coating, preferably the tablet is covered with a coating.
  • the pharmaceutical dosage form according to the present invention is a tablet, where the tablet is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients, the tablet optionally is covered with a coating, preferably the tablet is covered with a coating.
  • the pharmaceutical dosage form according to the present invention is also an orally dispersible tablet, where the tablet is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients.
  • the solid pharmaceutical dosage form especially in form of a tablet, as well as the roller compacted granulate are expected to be storage stable for an extended period of time, preferably long-term stable.
  • the solid pharmaceutical dosage form especially in form of a tablet, as well as the roller compacted granulate are storage stable for at least 3 months, preferred for at least 6 months, also preferred for at least 12 months, also preferred for at least 24 months, also preferred for at least 30 months and more preferred for at least 48 months.
  • Long-term storage means storage for more than 24 months.
  • Storage stable means stable with a maximum of 10% degradation of the active ingredient (I), preferred with a maximum of 3% degradation of the active ingredient (I), and with preservation of the amorphous form of the active ingredient (I).
  • Storage conditions for evaluation of the stability are in example closed container 25°C/60% relative humidity or closed container 30°C/75% relative humidity or open container 25°C/60% relative humidity or open container 40°C/75% relative humidity (stress conditions).
  • the surprisingly excellent stability behavior of the solid pharmaceutical dosage form containing active ingredient (I), even at stress conditions (open storage at 40°C and 75% relative humidity for 6 months) allows for non-protective packaging (e.g blisters or High Density Polyethylene (HDPE) bottles without desiccant) of the pharmaceutical dosage form of active ingredient (I).
  • non-protective packaging e.g blisters or High Density Polyethylene (HDPE) bottles without desiccant
  • immediate release tablets are particularly those which have released at least 85% of active ingredient (I) into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
  • the rotation speed of the stirrer is 75 rpm (revolutions per minute) in 900 ml release medium.
  • the release medium is acetate buffer pH 4.5 + 0.15% SDS.
  • SDS is the abbreviation for sodium dodecyl sulfate also called sodium lauryl sulfate.
  • the pharmaceutical dosage form according to the present invention is also an orally dispersible tablet characterized by a disintegration of maximal 3 minutes according to disintegration method of the European Pharmacopoeia using the rigid basket-rack apparatus with disk.
  • the apparatus is operated by using water as a medium at 37 +/- 2°C and have released at least 85% of active ingredient (I) into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
  • the rotation speed of the stirrer is 75 rpm (revolutions per minute) in 900 ml release medium.
  • the release medium is acetate buffer pH 4.5 + 0.15% SDS.
  • SDS is the abbreviation for sodium dodecyl sulfate also called sodium lauryl sulfate.
  • the present invention further relates to the use of (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy- 3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( 1)- dibenzenaheptaphane-7 4 -carboxamide (I) in amorphous form for preparing a solid pharmaceutical dosage form for oral administration according to the invention.
  • the active ingredient (I) is present in the pharmaceutical dosage forms according to the invention in amorphous form.
  • excipients are fillers, lubricants, disintegration promoters, sweeteners, flavoring agents and colorants. It may therefore come to happen that a person skilled in the art assigns similar or even identical substances to be member of more than one of the above- mentioned groups of substances. Within the context of the present invention, the functional descriptions of the substances are however intentionally filled with specific substances to clarify their respective property assigned to them.
  • pharmaceutically acceptable refers to those excipients, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Fillers that can be used in the formulation according to the present invention are those selected from the list consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins or Pharmaburst®.
  • Preferred as filler is microcrystalline cellulose or lactose or a combination thereof or Pharmaburst®.
  • a filler can also be used as a binder.
  • Binders that can be used are cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins or hypromellose (e.g. hypromellose 3 cP).
  • Preferred as binder is hypromellose (e.g. hypromellose 3 cP).
  • Lubricants prevent ingredients from sticking, e.g. to production equipment.
  • Lubricants that can be used in the formulation according to the present invention are those selected from the list consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydogenated vegetable fat or oil, polyethylenglycol and talc.
  • Preferred lubricants according to the present invention are those selected from the list consisting of magnesium stearate, stearic acid and talc. Very preferred as lubricant is magnesium stearate.
  • Disintegration promoter expand and dissolve when wet. They can be used to break the dosage form apart in the digestive tract, releasing the active ingredients.
  • Disintegration promoters suitable in the context of the present invention are those selected from the list consisting of alginic acid, crosslinked polyvinylpyrrolidone, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium) or microcrystalline cellulose or a combination of croscarmellose sodium and microcrystalline cellulose.
  • Preferred as a disintegration promoter is croscarmellose sodium or cross-linked polyvinylpyrrolidone.
  • Very preferred as a disintegration promoter is croscarmellose sodium.
  • sweetener is a pharmaceutically acceptable excipients that has a similar taste to sugar.
  • Sweeteners suitable in the context of the present invention are those selected from the list consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol.
  • sweeteners are added in amounts known for persons skilled in the art.
  • flavoring agents are pharmaceutically acceptable excipients appropriate to improve or give an agreeable taste of a pharmaceutical dosage form to complement its effect and also to increase its elegance.
  • flavoring agents are natural flavoring substances obtained from plant or animal raw materials, nature-identical flavoring substances obtained by synthesis or isolated through chemical processes, which are chemically and organoleptically identical to flavoring substances naturally present in products intended for human consumption and artificial flavoring substances.
  • flavoring agents are added in amounts known for persons skilled in the art.
  • Flavoring agents suitable in the context of the present invention are those selected from the list consisting of synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart.
  • synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose
  • colorants are pharmaceutically acceptable excipients appropriate to color an uncolored pharmaceutical dosage form or to enhance its color, to minimize batch-to-batch variations or to replace a color already present to complement its effect and also to increase its elegance. It can be any dyes, lakes or pigment such as indigo carmine, riboflavine and titanium dioxide. In the context of the present invention colorants are added in amounts known for persons skilled in the art.
  • the optional coating is carried out with addition of customary coating and film-forming agents familiar to the person skilled in the art, such as hydroxy- propylcellulose, hydroxypropylmethylcellulose (Hypromellose), ethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (e.g.
  • polyethylene glycol 3350 polyethylene glycol 3350
  • glycerol triacetate or triethyl citrate and/or colorants/pigments such as, for example, titanium dioxide, iron oxide (e.g. red iron oxide, yellow iron oxide), indigotin or suitable colour lakes, and/or antitacking agents such as talc, and/or opacifiers such as titanium dioxide.
  • colorants/pigments such as, for example, titanium dioxide, iron oxide (e.g. red iron oxide, yellow iron oxide), indigotin or suitable colour lakes, and/or antitacking agents such as talc, and/or opacifiers such as titanium dioxide.
  • Hypromellose and polyethylene glycol are preferred, as colorant iron oxide red is preferred and as opacifier titanium dioxide is preferred.
  • a preferred mixture of coating substances may be about 60 wt.% hydroxypropylmethylcellulose, about 17.5 wt.% ferric oxide yellow, about 0.25 wt.% ferric oxide red and about 20 wt
  • a mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available under the trade name Opadry®.
  • Opadry 14F94373® is a mixture of about 60 wt.% hydroxypropylmethylcellulose, about 19.4 wt.% titanium dioxide, about 0.6 wt.% ferric oxide red and about 20 wt.% polyethylene glycol.
  • the ready-to-use coating system available under the trade name Opadry® is preferred.
  • the coating is about 0.5% to 10% by weight of the coated tablet formulation, preferably 0.5% to 4.5% by weight of the coated tablet formulation, more preferably about 1.5% to 4.5% by weight of the coated tablet formulation.
  • a ratio of active ingredient (I) to excipients of 1 to 0.5 up to 1 to 10 also preferred is a ratio of active ingredient (I) to excipients of 1 to 0.5 up to 1 to 5 and more preferred is a ratio of active ingredient (I) to excipients of 1 to 2 and very preferred is a ratio of active ingredient (I) to excipients of 1 to 1.6.
  • a ratio of active ingredient (I) to excipients of 1 to 1.6 enables high drug-load and small tablet sizes.
  • the present invention provides a process for preparing solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- 1 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)) in amorphous form, which are prepared without using water or organic solvents or heat.
  • the present invention provides also a process for preparing solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients, which are prepared without using water or organic solvents or heat.
  • the present invention provides also a process for preparing solid pharmaceutical dosage forms for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients such as sweeteners, flavoring agents and colorants, which are prepared without using water or organic solvents or heat.
  • the manufacturing process without any water, organic solvents or head allows clearly smaller tablet sizes, facilitating swallowing on the one hand and a higher number of tablets per batch for the industry on the other hand.
  • the present invention provides a process for preparing roller compacted granulate containing (4S)- 2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)), characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenahepta
  • the present invention provides also a process for preparing roller compacted granulate containing (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, 1)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)), characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane
  • Roller compacted granulate containing (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)) producible by one of the processes mentioned above.
  • roller compacted granulate may be converted into a pharmaceutical dosage form comprising, for example, tabletting, filling into capsules, preferably hard gelatine capsules, or filling as sachets, in each case according to customary methods familiar to the person skilled in the art, if appropriate with addition of further pharmaceutically suitable excipients. of an immediate release tablet roller form B))
  • the present invention provides a process for preparing solid pharmaceutical dosage forms containing roller compacted granulate for oral administration comprising (4 )-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,
  • the present invention provides also a process for preparing solid pharmaceutical dosage forms containing roller compacted granulate for oral administration comprising (4 )-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l
  • the present invention provides also a process for preparing solid pharmaceutical dosage forms containing roller compacted granulate for oral administration comprising (4 )-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l
  • Solid pharmaceutical dosage forms for oral administration comprising (4.S')-2 4 -chloro-4-cthyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l (l)-[ 1 ,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form producible by one of the processes mentioned above.
  • Solid pharmaceutical dosage forms for oral administration comprising (45)-2 4 -chloro-4-ethyl-7 3 - fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form produced by one of the processes mentioned above. of an immediate release tablet which is based on direct form C))
  • the present invention provides a process for preparing an immediate release tablet which is based on direct compression for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 - methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(
  • the present invention provides also a process for preparing an immediate release tablet which is based on direct compression for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 - methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola
  • the present invention provides also a process for preparing an immediate release tablet which is based on direct compression for oral administration comprising (45)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 - methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2
  • Immediate release tablet which is based on direct compression for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form producible by one of the processes mentioned above.
  • Immediate release tablet which is based on direct compression for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form produced by one of the processes mentioned above.
  • the present invention provides a process for preparing an orally dispersible tablet for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- 1 4 -
  • the present invention provides also a process for preparing an orally dispersible tablet for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- 1 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l
  • the present invention provides also a process for preparing an orally dispersible tablet for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- 1 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l
  • the present invention provides also a process for preparing an orally dispersible tablet for oral administration comprising (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- 1 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 -(trifluoromethyl)-3 2 //-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l
  • the sugar alcohol mixture is a mixture comprising mannitol.
  • the sugar alcohol mixture can additionally to mannitol contain sorbitol and a disintegrant, such as crospovidone.
  • Orally dispersible tablet for oral administration comprising (4 )-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 - methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form producible by one of the processes mentioned above.
  • Orally dispersible tablet for oral administration comprising (4 )-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 - methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)) in the amorphous form produced by one of the processes mentioned above.
  • the oral solid dosage form comprising amorphous active ingredient (I) and manufactured by a large industrial scale process which leads to high relative bioavailability in human ranging from 85% up to even 100%, preferred ranking from 88% up to even 100%.
  • the present invention further provides medicaments comprising a solid pharmaceutical dosage form for oral administration in accordance with the invention comprising the active ingredient (I).
  • the present invention further relates to the use of solid pharmaceutical dosage forms for oral administration in accordance with the invention comprising the active ingredient (I) and for preparing a medicament for the treatment and/or prophylaxis of disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, in particular cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non- cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
  • disorders preferably thrombotic or
  • the present invention further relates to the use of solid pharmaceutical dosage forms for oral administration in accordance with the invention comprising the active ingredient (I) for prophylaxis, secondary prophylaxis and/or treatment of disorders, particularly myocardial infarction, ischemic strokes including cardioembolic as well as non-cardioembolic strokes, acute limb ischemia, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
  • disorders particularly myocardial infarction, ischemic strokes including cardioembolic as well as non-cardioembolic strokes, acute limb ischemia, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
  • IR tablet immediate release tablet
  • SDS sodium dodecyl sulfate also called sodium lauryl sulfate rh: relative humidity
  • Active ingredient (I) crystalline means active ingredient (I) in crystalline modification I.
  • ASD matrix amorphous solid dispersion matrix
  • FaSSIV Fasted State Simulated Intestinal Fluid kN/cm: Kilonewton per centimeter dry granulation is used synonym to roller compaction
  • Active ingredient (I) is (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide, also named as 4-( ⁇ (2S)-2-[4- ⁇ 5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l- yl]phenyl ⁇ -5-methoxy-2-oxopyridin-l(2H)-yl]butanoyl ⁇ amino)-2-fluorobenzamide, which can be prepared according to WO 2017/005725 Example 234 and Example 235 in the amorphous form.
  • the oral solid dosage form is tested with apparatus 2 (paddle).
  • the rotation speed of the stirrer is 75 rpm (revolutions per minute) in 900 ml of acetate buffer pH 4.5 + 0.15% SDS.
  • the release criterion is then fulfilled if all 6 test specimens have released at least 85% of active ingredient (I) into the release medium after an investigation period of 30 minutes. d for immediate release tablet based on solid
  • the pharmaceutical dosage form (tablet) of Example 1 is prepared by dissolving the solid dispersion base and active ingredient (I) in organic solvent. In the course of a fluidized bed granulation, this solution is sprayed as granulating fluid on the initial charge of the disintegration promoter (carrier). After drying and sieving the granulates are resulting. Organic solvents may be ethanol, acetone or combinations thereof. The resulting granulate is mixed together with added disintegration promoter. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
  • the pharmaceutical dosage form (tablet) of Example 2 is prepared by mixing the active ingredient (I) together with microcrystalline cellulose, lactose and croscarmellose sodium. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
  • the pharmaceutical dosage form (tablet) of Example 4 is prepared by mixing the active ingredient (I) together with a sugar alcohol mixture. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
  • the pharmaceutical dosage form (tablet) of Example 3 is prepared by mixing the active ingredient (I) together with microcrystalline cellulose, lactose and parts of croscarmellose sodium. Afterwards the mixture is roller-compacted and grinded. The resulting granulate is mixed with the remaining croscarmellose sodium. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
  • the pharmaceutical dosage form (granulate) of Example 5 is prepared by mixing the active ingredient (I) together with microcrystalline cellulose, lactose and croscarmellose sodium. Afterwards the blend is roller-compacted and grinded to result in the roller compacted granulate. In the roller compacted granulate the active ingredient (I) is present in an amount of 50 mg per 99 mg final granulate.
  • Example 1 (comparison example): Immediate release tablet of (4>S -2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 - methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola- 2(l,2),7(l)-dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I)), based on an amorphous solid dispersion
  • Example 3 Immediate release tablet of (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-l 4 - (trifluoromethyl)-3 2 H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 7 4 -carboxamide (active ingredient (I)), based on dry granulation
  • Film coating c) optional a) intragranular; b) extragranular; c) tablets can optionally be coated
  • Pharmaburst comprises spray-dried mannitol and sorbitol and can additionally comprise a disintegrant, such as crospovidone.
  • the sugar alcohol mixture mentioned in example 4 is a mixture comprising mannitol and sorbitol and can additionally comprise a disintegrant, such as crospovidone.
  • Example 5 roller compacted granulate of (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo- l 4 -(trifluoromethyl)-3 2 //-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)- dibenzenaheptaphane-7 4 -carboxamide (active ingredient (I))
  • the pharmaceutical dosage form comprising the active ingredient (I) is administered to animals via oral administration. Blood samples are taken from the test animals. The pharmacokinetic parameters such as area under the curve (AUC) and maximum concentration (Cmax) after oral administration are determined. Further corresponding pharmacokinetic parameters after oral administration are calculated. The primary pharmacokinetic parameters clearance (CL) and distribution volume (Vss) are calculated as follows:
  • Example 2 By using manufacturing techniques such as direct compression (Example 2) or dry granulation (Example 5) followed by tablet compression (Example 3) comparable dissolution results to the amorphous solid dispersion from Example 1 could be shown. All examples have released at least 85% of active ingredient (I) into the release medium after 30 minutes. In addition to this, both techniques (Example 2 and Example 3) are able to reduce the disintegration time tremendously from 13 minutes in Example 1 to 2 minutes in Example 2 and 3. To increase the patient compliance and improve therefore the clinical effect of the treatment the tablet sizes could be significantly reduced from 12x6mm oval shaped for Example 1 to 7 mm round shaped for Examples 2 and 3 to facilitate swallowing.
  • manufacturing techniques such as direct compression (Example 2) or dry granulation (Example 5) followed by tablet compression (Example 3)
  • Example 3 By using manufacturing techniques such as direct compression (Example 2) or dry granulation (Example 5) followed by tablet compression (Example 3) comparable dissolution results to the amorphous solid dis
  • Example 4 a formulation of an orally dispersible tablet is shown. For this example, comparable dissolution results to the amorphous solid dispersion from Example 1 could be shown.
  • the Example 4 released at least 85% of active ingredient (I) into the release medium after 30 minutes. This technique benefits from the fact, that no fluids are necessary for application of the tablet.
  • the tablet disintegrates in less than one minute directly in the mouth and facilitate therefore both swallowing of the tablet as well as patient compliance.
  • Examples 2, 3, 4 and 5 are prepared without using water or organic solvents or heat in which the active ingredient (I) is present and stable in an amorphous form. This reveals a manufacturing process both, suitable for a large industrial scale and sustainable for the global environment at the same time.
  • organic solvents on a yearly basis, the total amount approximately 300 tons of organic solvents will be saved assuming a current forecasted need of approx. 50 tons of active ingredient (I) per year. Therefore, the newly developed formulations in Example 2 to 5 clearly improve the sustainability aspects of the product, to which an energy conscious process without heat also contributes.
  • the oral solid dosage form is tested in a rigid basket-rack apparatus.
  • the six test specimens are placed individually in a tube of the basket and a disk is added.
  • the apparatus is operated by using water as a medium at 37 +/- 2°C.
  • Example 1 Example 2 Example 3 Example 4

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzena-heptaphane-74-carboxamide (active ingredient (I)), characterized in that the active ingredient (I) is present in amorphous form and is immediately released from the solid pharmaceutical dosage forms for oral administration, and also methods for the preparation thereof, use thereof as medicaments, and also use thereof for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

Description

Pharmaceutical dosage forms
Figure imgf000002_0001
-24-chloro-4-ethvl-7 -fluoro-3 -i
Figure imgf000002_0002
-3 ,5- dioxo-l4-(trifluoromethvl)-32H-6-aza-
Figure imgf000002_0003
-11,2.
Figure imgf000002_0004
Figure imgf000002_0005
:-74-carboxamide
The present invention relates to solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide (active ingredient (I)), characterized in that the active ingredient (I) is present in amorphous form and is immediately released from the solid pharmaceutical dosage forms for oral administration, and also methods for the preparation thereof, use thereof as medicaments, and also use thereof for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.
The active ingredient (I), (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide, also named as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l- yl]phenyl}-5-methoxy-2-oxopyridin-l(2H)-yl]butanoyl}amino)-2-fluorobenzamide, is known from WO 2017/005725 and has the following formula:
Figure imgf000002_0006
Active ingredient (I)
The active ingredient (I) acts as a factor Xia inhibitor and, owing to this specific mechanism of action, is, after oral administration, useful in the treatment and/or prophylaxis of disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, in particular cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non-cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis. To develop a solid pharmaceutical dosage form for oral administration, active ingredient (I), (4S - 24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide, is used as amorphous form.
In cases of diseases which require treatment over a lengthy period, or for the long-term prophylaxis of diseases, it is desirable to keep the frequency of intake of medicaments as low as possible and the tablet size as small as possible. This is not only more convenient for the patient, it also increases the reliability of treatment by reducing the disadvantages of irregular intake (improvement in compliance). In order to increase compliance, particularly in older patients, the tablets should be as small as possible, i.e. have a high concentration of active ingredient, particularly with regard to the higher dosage strengths.
During course of development, it was found that the active ingredient (I) in the amorphous form has a poor solubility in water. Oral administration of poorly soluble active ingredients is often problematic resulting in insufficient bioavailability of the active ingredient (I). An oral solid pharmaceutical dosage form, such as a tablet, should provide the release of substantially all of the active ingredient (I) immediately and provide sufficient dissolution properties. The solid pharmaceutical dosage form should also have excellent properties which enable the manufacture of the solid pharmaceutical dosage form in industrial scale since it is needed in a large number of patients where at the same time using a sustainable manufacturing process.
The majority of solid drugs and dosage forms are prepared in the crystalline state, characterized by a regular ordered lattice structure. These physical structures are generally thermodynamically stable and are relatively simple to study using techniques such as differential scanning calorimetry and X- ray diffraction. Amorphous materials are thermodynamically unstable and will tend to revert to the crystalline form on storage. The mechanical properties and vapour sorption profiles of amorphous systems may be markedly different from the crystalline material, while the chemical reactivity of amorphous drugs may be greater. The amorphous state is, by definition, metastable with regard to the crystalline material, hence amorphous drugs will tend to revert to the crystalline form over a period of time. Prediction of the timescales involved is clearly critical and yet may be difficult to achieve. It has been shown that rates of drug degradation may be enhanced in the amorphous state compared to the crystalline material. [Craig et al. in: The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems. International Journal of Pharmaceutics 179 (1999) 179-207]
The problems associated with stability, both physical and chemical of amorphous drugs and systems is the reason why amorphous approaches without stabilizing measures are not often followed.
Besides creating freeze dried systems in which the amorphous state of a drug (and excipients) is stabilized, creating of so-called amorphous solid dispersions (ASDs) is well known as stabilizing measure for originally amorphous materials as well as formerly crystalline materials and especially used for oral dosage forms.
Even those stabilized systems show limitations regarding physical and chemical stability [Serajuddin in: Solid Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs. Journal of Pharmaceutical Sciences Vol. 88, No. 10 (1999) 1058-1066] and developing amorphous drug formulation is still a significant undertaking with challenges (e.g. bioavailability, physical stability, chemical stability, and manufacturing).
The challenges are even higher when developing an amorphous drug and processing it via direct compression.
Only few attempts have been made to develop a stable oral dosage form manufactured by direct compression and comprising an amorphous drug.
Sun et al. loaded amorphous active pharmaceutical ingredients/drugs into mesoporous silica (Aeroperl®) which enabled robust formulations with good content uniformity and manufacturability as well as good physical stability and dissolution rate. [Sun et al in: International Journal of Pharmaceutics. 539 (1-2) (2018) 184-189]
DE 10 2010 005 124 Al describes a solid oral dosage form manufactured via direct tableting/direct compression and comprising amorphous Lecanidipine and a hydrogelling agent, namely Hypromellose, incorporated as stabilizing excipient.
WO 2009/138224 discloses a pharmaceutical composition comprising drosperinone substantially in amorphous form and a carrier selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC), and the drosperinone and carrier are present in co-milled state. By co-milling a two-phase system of distinct drosperinone and carrier particles results which shall stabilize the amorphous form of the drug.
WO2022/189278 describes an amorphous solid dispersions (ASD) and solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena- heptaphane-74-carboxamide.
The most relevant technologies for the manufacture of stabilizing an amorphous drug in so called amorphous solid dispersions (ASDs) are based on two major distinct processes: solvent evaporation and melting. Some mechanical processes, such as ball milling or grinding, are also able to induce some amorphization. [Breitenbach in: European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107-117] All have in common that they are energy- and cost-intensive and/or bear an ecological and hazardous risk. Amorphous solid dispersions use specific carriers that amorphized the drug substance and stabilize it in the solid state. Incorporating additional stabilizing excipients results in increased tablet weight and tablet size which is known to be unfavorable for patient's compliance. Additionally, it is worth to mention that amorphous materials in ASDs eventually revert to their crystalline form, albeit at a slow rate. [Ma in: Journal of Drug Delivery Science and Technology 50 (2019) 113-124] In addition, when ASDs are exposed to moisture (e.g., during storage under high humidity conditions), the presence of water significantly increases the mobility of the drug and reduces the ability of polymers to inhibit recrystallization. Therefore, pharmaceutical dosage forms comprising ASDs may require additional moisture -protective measures such as special coatings and/or application of specialized product packaging materials which act as moisture barriers or moisture adsorbers (desiccants). As examples Lopinavir und Ritonavir are provided as fixed dose combination tablets (KALETRA®) which are coated with polyvinylalcohol polymer which protects the active ingredients from moisture, oxygen and other environmental components, and Etravirin tablets (INTELENCE®) are needed to be marketed in bottles which contain three desiccant pouches per bottle to keep the tablets dry.
Solid pharmaceutical dosage forms which are manufactured via tabletting may optionally be roller compacted. As many materials are not suitable for direct compression often a granulation step takes place prior to tableting. Roller compaction and subsequently dry granulation of the compacted material is beside wet granulation one common way to produce granules, which gained in importance for the pharmaceutical industry. [Mosig in: Powder Technology 266 (2014) 156-166]
This method allows the granulation of materials sensitive to moisture and heat. The process is environmental friendly, as no removing of solvents is necessary, and scale up is easily feasible.
A major advantage is the continuous production of granules leading to a reduction of costs.
However, the resulting tablets show inferior tensile strength compared with other granulation techniques. This is due to the limited binding potential which is partially consumed in the first compression step. [Herting in: International Journal of Pharmaceutics 338 (2007) 110-118].
The orally disintegrating tablet (ODT) serves as a special type of tablets. They are attractive to many patient groups such as the elderly, children, and patients who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/diets have difficulties swallowing these dosage forms. Those who are traveling or have little access to water are similarly affected. To fulfil these medical needs, pharmaceutical technologists have developed a novel oral dosage form known as orally disintegrating tablets (ODTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take it water. Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms. [Hirani in: Tropical Journal of Pharmaceutical Research, April 2009, 8 (2), 161-172]
ODTs can be manufactured by different processes like lyophilisation, moulding and sublimation, using a sugar-floss system or direct compression. The process of direct compression is convenient and cost-effective, but is highly influenced by the characteristics of the active pharmaceutical ingredient (API) as well as the used excipients, like flowability, compressibility and compactability. Therefore, excipients that offer excellent compaction properties should be preferably used. Excipients for ODTs have to be selected based on material characteristics (plastic, elastic or brittle material) and desired functionalities like defined particle size distribution, good flowability, enhanced compactability or fast disintegration. Mannitol represents an often used excipient for fast-dissolving drug formulations. However, when used as untreated powder, the poor flowability, insufficient binding properties and compactability are limiting factors. Hence, coprocessed excipients with mannitol are an option. Co-processing means the interacting of two or more excipients at the subparticle level, due to co-spray-drying, cospray-agglomerating or cogranulating, which led to an improved functionality. [Stoltenberg in: Eur. J. Pharm. Biopharm. 78 (2011) 662-669] Co-processed mannitol as used in the present invention is marketed under various tradenames such as Pharmaburst®. However, mannitol is known to induce crystallization of an amorphous drug even when stabilized in an amorphous spray-dried dispersion. [Leane in: Drug Dev Tech 18(2) (2013) 359-366] Excipients such as fillers such as mannitol have been shown in the literature to have effects on polymorphic transformations during wet granulation so the potential for excipient-induced physical instability does exist. Therefore, it was to be expected that a mannitol comprising co-processed excipient system such as Pharmaburst® will induce crystallization of an amorphous drug in a pharmaceutical dosage form, especially when manufactured without any stabilizing measures.
Additionally, it is known from literature that compression induces demixing which is of even greater importance when leading to amorphous phase separation and finally instability of drugs in amorphous form as described in [Ayenew in: European Journal of Pharmaceutics and Biopharmaceutics 81 (2012) 207-213].
Several orally disintegrating dosage forms are hygroscopic and cannot maintain physical integrity under normal conditions of temperature and humidity. Hence, they need protection from humidity which calls for specialized product packaging. [Hirani in: Tropical Journal of Pharmaceutical Research, April 2009, 8 (2), 161-172] As elaborated above, moisture-uptake is one factor which increases the risk of conversion of amorphous drugs into their crystalline form.
The aim of the development was, therefore, to provide solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- l4-(trifluoro- methyl)-32H-6-aza-3(4, l)-pyridina-l (l)-[ 1 ,2,3]triazola-2( 1 ,2),7(l)-dibenzenaheptaphane-74- carboxamide (active ingredient (I)), where the active ingredient (I) is present in amorphous form and the oral solid pharmaceutical dosage forms show a superior dissolution behaviour and a good bioavailability. The solid pharmaceutical dosage form should also have excellent properties which enable the manufacture of the solid pharmaceutical dosage form in industrial scale. Furthermore, the amorphous form of the active ingredient (I) shall be stable in the solid pharmaceutical dosage forms during long-term storage. Crystallization needs to be prevented in any case since, crystallization of the active ingredient (I) results in a lower dissolution rate and a lower bioavailability of the active ingredient (I).
Surprisingly, a solid pharmaceutical dosage form is prepared without using water, organic solvents or heat in which the active ingredient (I) is present and stable in an amorphous form. This solid pharmaceutical dosage form shows a superior dissolution behaviour and a good bioavailability and in addition, excellent tablet properties resulting from a manufacturing process that enables large industrial scale manufacturing, if needed also a continuous manufacturing process without individual batches, and sustainability at the same time.
Surprisingly in the present invention it was possible to show excellent tablet properties including tablet hardness although it could be roller compacted.
Surprisingly the present invention describes a pharmaceutical dosage form manufactured by a process which is not based on solvent evaporation or melting and in which the comprised amorphous drug is chemically and physically long-term stable.
Surprisingly the present invention describes a pharmaceutical dosage form provided as orally disintegrating tablet (ODT) manufactured by compression and comprising mannitol in which the comprised amorphous drug is chemically and physically long-term stable.
Solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form characterized in that the dosage form is
A) a roller compacted granulate which is obtained by roller compacting and grinding a mixture of active ingredient (I) in amorphous form and excipients or
B) an immediate release tablet where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to an immediate release tablet or
C) an immediate release tablet which is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients or D) an orally dispersible tablet containing active ingredient (I) in amorphous form and excipients.
Solid pharmaceutical dosage forms for oral administration comprising (45)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form characterized in that the dosage form is
A) a roller compacted granulate which is obtained by roller compacting and grinding a mixture of active ingredient (I) in amorphous form and excipients or
B) an immediate release tablet where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to an immediate release tablet or
C) an immediate release tablet which is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients or
D) an orally dispersible tablet containing active ingredient (I) in amorphous form and excipients, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
Solid pharmaceutical dosage forms based on direct compression and manufacturing processes thereof as such are known.
The most frequent challenges to prepare a solid pharmaceutical dosage form comprising active ingredient (I) in amorphous form are the ratio of drug and excipients needed to facilitate the required increase in release rate and bioavailability as well as the selection of an appropriate manufacturing process and its scale-up for safe-guarding physical and chemical stability of the amorphous form of the active ingredient (I) whilst at the same time being manufacturable in large industrial scale.
Furthermore, a specific manufacturing process without using water, organic solvents or heat allows to manufacture the solid pharmaceutical dosage forms for oral administration comprising (45)-24- chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoro-methyl)-32H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in form of a roller compacted granulate or a tablet with good tablet hardness and low brittleness enabling manufacture of the tablets in large industrial scale. The solid pharmaceutical dosage forms are robust against variations in the manufacturing process during operation and technical transfer such that the properties of the solid pharmaceutical dosage forms are not affected.
It was surprisingly found that an immediate release tablet prepared without using water or organic solvents or heat comprising active ingredient (I) in amorphous form according to the present invention shows a superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent properties which enable the manufacture of the solid pharmaceutical dosage form in industrial scale and, if needed also a continuous manufacturing process without individual batches, since it is needed in a large number of patients where at the same time using a sustainable manufacturing process.
The present invention provides a process where the active ingredient (I) is used in its amorphous form and mixed together with other excipients. This mixture may than be roller compacted. Afterwards a disintegration promoter may be added and mixed again. Finally, the lubricant may be added and mixed again. This mixture is used as the granulate as such or it is used to manufacture tablets. The tablets may optionally be coated.
The methods and excipients chosen for the present invention are in some aspects in contrast to the methods and excipients known by the person skilled in the art and which are known as common to prepare immediate release tablets without using water or organic solvents or heat comprising active ingredient (I) in amorphous form.
1) The solid pharmaceutical dosage form
The present invention provides solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, which are prepared without using water or organic solvents or heat.
The present invention provides also solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients, which are prepared without using water or organic solvents or heat.
The present invention provides also solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients such as sweeteners, flavoring agents and colorants, which are prepared without using water or organic solvents or heat.
The present invention provides solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, which are prepared without using water or organic solvents or heat, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
The present invention provides solid pharmaceutical dosage forms A) for oral administration comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one disintegration promoter, and c) at least one filler.
The present invention also provides solid pharmaceutical dosage forms A) for oral administration comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one disintegration promoter, and c) at least one filler, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
The present invention provides solid pharmaceutical dosage forms B) or C) for oral administration comprising d) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, e) at least one lubricant, f) at least one disintegration promoter, and g) at least one filler.
The present invention also provides solid pharmaceutical dosage forms B) or C) for oral administration comprising d) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, e) at least one lubricant, f) at least one disintegration promoter, and g) at least one filler, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
The present invention provides solid pharmaceutical dosage forms D) for oral administration comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, and c) at least one filler or disintegration promoter.
The present invention provides solid pharmaceutical dosage forms D) for oral administration comprising h) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, i) at least one lubricant, and j) at least one filler or disintegration promoter, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
The present invention provides solid pharmaceutical dosage forms D) for oral administration comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, and c) at least one filler or disintegration promoter, wherein the disintegration time is maximal 3 minutes according to disintegration method of the European Pharmacopoeia using the rigid basket-rack apparatus with disk.
1 A) roller compacted granulate (solid pharmaceutical dosage form A))
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is a roller compacted granulate which is obtained by roller compacting and grinding a mixture of active ingredient (I) in amorphous form and excipients.
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is a roller compacted granulate which is obtained by roller compacting and grinding a mixture of active ingredient (I) in amorphous form and excipients, which is prepared without using water or organic solvents or heat.
The present invention provides solid pharmaceutical dosage forms for oral administration, which are a roller compacted granulate, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one disintegration promoter, and c) at least one filler.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are a roller compacted granulate, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and c) at least one filler in an amount of 2 mg up to 150 mg.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are a roller compacted granulate, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) croscarmellose sodium as disintegration promoter, and c) microcrystalline cellulose and lactose as filler.
In general, the advantage of a roller compacted granulate is the improved flowability of the granulate compared to the initial powder mixture. It is known from literature that compression induces demixing which is of even greater importance when leading to amorphous phase separation and finally instability of drugs in amorphous form as described in Ayenew, see above.
The advantage of the present invention is that the mixture can be roller compacted without losing its superior dissolution behaviour and a good bioavailability of the active ingredient (I). In addition, the compression of the mixture reduces the risk of inhomogeneous distribution of active ingredient (I) in amorphous form in the solid pharmaceutical dosage form.
Surprisingly, the amorphous form of active ingredient (I) is long-term stable in the roller compacted granules comprising of well-known standard excipients without the means of any stabilizer (e.g. polymer in an ASD matrix or gelling agents as described above).
To ensure a superior dissolution the roller compaction force [kN/cm] and the gap [mm] has to be well controlled in the roller compaction process. The roller compaction force is preferred between 0.1 and 5.0 kN/cm and the gap between 1.0 bis 6.0 mm. Preferred is that the roller compaction force is low when the gap is small, and that the roller compaction force is high when the gap is wide. Most preferred is a roller compaction force of 2 kN/cm and a gap of 3 mm.
Roller compaction is not known as a method to stabilize the amorphous form of an active ingredient. Therefore, it could be surprisingly proven, that the roller compaction process is suitable to manufacture a solid pharmaceutical dosage form where the amorphous form of active ingredient (I) is long-term stable.
IB) an immediate release tablet containing roller compacted granulate (solid pharmaceutical dosage form B))
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to an immediate release tablet.
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to an immediate release tablet, which is prepared without using water or organic solvents or heat.
The present invention provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet containing roller compacted granulate, comprising a) (45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, c) at least one disintegration promoter, and d) at least one filler.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet containing roller compacted granulate, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 0.5 mg up to 7 mg, c) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and d) at least one filler in an amount of 2 mg up to 150 mg.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet containing roller compacted granulate, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) magnesium stearate as lubricant, c) croscarmellose sodium as disintegration promoter, and d) microcrystalline cellulose and lactose as filler.
In general, the advantage of a roller compacted granulate is the improved flowability of the granulate compared to the initial powder mixture. It is known from literature that compression induces demixing which is of even greater importance when leading to amorphous phase separation and finally instability of drugs in amorphous form as described in Ayenew, see above.
From literature it is well known that roller compacted solid pharmaceutical dosage forms tend to suffer from final tablet hardness or slowed down dissolution behavior. The advantage of the present invention is that the mixture can be roller compacted without losing its superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent tableting properties. The resulting tablets show excellent tablet hardness. In addition, the compression of the mixture reduces the risk of inhomogeneous distribution of active ingredient (I) in amorphous form in the solid pharmaceutical dosage form.
Surprisingly the amorphous form of active ingredient (I) is long-term stable in the tablet based on roller compacted granules. The tablet comprises only well-known standard excipients without the means of any stabilizer (e.g. polymer in an ASD matrix or gelling agents as described above).
To ensure a superior dissolution the roller compaction force [kN/cm] and the gap [mm] has to be well controlled in the roller compaction process. The roller compaction force is preferred between 0.1 and 5.0 kN/cm and the gap between 1.0 bis 6.0 mm. Preferred is that the roller compaction force is low when the gap is small, and that the roller compaction force is high when the gap is wide. Most preferred is a roller compaction force of 2 kN/cm and a gap of 3 mm.
Roller compaction itself is not known as a method to stabilize the amorphous form of an active ingredient. Therefore, it could be surprisingly proven, that tablets based on roller compacted granules can be manufactured, where the amorphous form of active ingredient (I) is long-term stable.
1C) immediate release tablet which is based on direct compression (solid pharmaceutical dosage form C))
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet which is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients.
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is an immediate release tablet which is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients, which is prepared without using water or organic solvents or heat. The present invention provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet which is based on direct compression, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, c) at least one disintegration promoter, and d) at least one filler.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet which is based on direct compression, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 0.5 mg up to 7 mg, c) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and d) at least one filler in an amount of 2 mg up to 150 mg.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are an immediate release tablet which is based on direct compression, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) magnesium stearate as lubricant, c) croscarmellose sodium as disintegration promoter, and d) microcrystalline cellulose and lactose as filler.
The advantage of the present invention is that the amorphous form of active ingredient (I) is longterm stable in an immediate release tablet which is based on direct compression without any means of stabilization (e.g. polymer in an ASD matrix or gelling agents as described above) while at the same time showing a superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent tablet properties. The resulting tablets show excellent tablet hardness.
Surprisingly, this can be achieved by using well-known, non-stabilizing excipients. 1 D) orally dispersible tablet (solid pharmaceutical dosage form D))
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is an orally dispersible tablet containing active ingredient (I) in amorphous form and excipients.
The present invention provides a solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form which is an orally dispersible tablet containing active ingredient (I) in amorphous form and excipients, which is prepared without using water or organic solvents or heat.
The present invention provides solid pharmaceutical dosage forms for oral administration, which are an orally dispersible tablet, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, and c) at least one filler or disintegration promoter.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are an orally dispersible tablet, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 2 mg up to 30 mg, and c) at least one filler or disintegration promoter in an amount of 20 mg up to 700 mg.
The present invention also provides solid pharmaceutical dosage forms for oral administration, which are an orally dispersible tablet, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) magnesium stearate as lubricant, and c) a sugar alcohol mixture as filler or disintegration promoter.
Surprisingly, the advantage of the present invention is that the amorphous form of active ingredient (I) can be formulated in an orally dispersible tablet by without any means of stabilization while at the same time showing a superior dissolution behaviour and a good bioavailability of the active ingredient (I) as well as excellent disintegration behavior.
In General
For oral administration, the roller compacted granulate comprising the active ingredient (I) in amorphous form can be formulated into solid or liquid preparations such as tablets, sachets, capsules, dragees, chewable tablets, effervescent tablets, dispersible tablets, troches, lozenges, melts, or suspensions, and may be prepared according to the methods known to the art of the manufacture of pharmaceutical compositions.
The pharmaceutical dosage form according to the present invention is a tablet.
The pharmaceutical dosage form according to the present invention is an immediate release tablet.
The pharmaceutical dosage form according to the present invention is a tablet, where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to a tablet, the tablet optionally is covered with a coating, preferably the tablet is covered with a coating.
The pharmaceutical dosage form according to the present invention is a tablet, where the tablet is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients, the tablet optionally is covered with a coating, preferably the tablet is covered with a coating.
The pharmaceutical dosage form according to the present invention is also an orally dispersible tablet, where the tablet is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients.
(45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) is present in a tablet in an amount of 2 mg up to 100 mg, preferred in an amount of 5 mg up to 50 mg, also preferred in an amount of 20 mg up to 50 mg, more preferred in an amount of 50 mg.
The solid pharmaceutical dosage form, especially in form of a tablet, as well as the roller compacted granulate are expected to be storage stable for an extended period of time, preferably long-term stable.
The solid pharmaceutical dosage form, especially in form of a tablet, as well as the roller compacted granulate are storage stable for at least 3 months, preferred for at least 6 months, also preferred for at least 12 months, also preferred for at least 24 months, also preferred for at least 30 months and more preferred for at least 48 months.
Long-term storage means storage for more than 24 months.
Storage stable means stable with a maximum of 10% degradation of the active ingredient (I), preferred with a maximum of 3% degradation of the active ingredient (I), and with preservation of the amorphous form of the active ingredient (I).
Storage conditions for evaluation of the stability are in example closed container 25°C/60% relative humidity or closed container 30°C/75% relative humidity or open container 25°C/60% relative humidity or open container 40°C/75% relative humidity (stress conditions).
The surprisingly excellent stability behavior of the solid pharmaceutical dosage form containing active ingredient (I), even at stress conditions (open storage at 40°C and 75% relative humidity for 6 months) allows for non-protective packaging (e.g blisters or High Density Polyethylene (HDPE) bottles without desiccant) of the pharmaceutical dosage form of active ingredient (I).
In the context of the present invention, immediate release tablets are particularly those which have released at least 85% of active ingredient (I) into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle). The rotation speed of the stirrer is 75 rpm (revolutions per minute) in 900 ml release medium.
According to the present invention the release medium is acetate buffer pH 4.5 + 0.15% SDS. SDS is the abbreviation for sodium dodecyl sulfate also called sodium lauryl sulfate.
The pharmaceutical dosage form according to the present invention is also an orally dispersible tablet characterized by a disintegration of maximal 3 minutes according to disintegration method of the European Pharmacopoeia using the rigid basket-rack apparatus with disk. The apparatus is operated by using water as a medium at 37 +/- 2°C and have released at least 85% of active ingredient (I) into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle). The rotation speed of the stirrer is 75 rpm (revolutions per minute) in 900 ml release medium.
According to the present invention the release medium is acetate buffer pH 4.5 + 0.15% SDS. SDS is the abbreviation for sodium dodecyl sulfate also called sodium lauryl sulfate.
The present invention further relates to the use of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy- 32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( 1)- dibenzenaheptaphane-74-carboxamide (I) in amorphous form for preparing a solid pharmaceutical dosage form for oral administration according to the invention.
The active ingredient (I) is present in the pharmaceutical dosage forms according to the invention in amorphous form. In the context of the present invention, “excipients” are fillers, lubricants, disintegration promoters, sweeteners, flavoring agents and colorants. It may therefore come to happen that a person skilled in the art assigns similar or even identical substances to be member of more than one of the above- mentioned groups of substances. Within the context of the present invention, the functional descriptions of the substances are however intentionally filled with specific substances to clarify their respective property assigned to them.
The expression ‘pharmaceutically acceptable’ refers to those excipients, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
Fillers that can be used in the formulation according to the present invention are those selected from the list consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins or Pharmaburst®. Preferred as filler is microcrystalline cellulose or lactose or a combination thereof or Pharmaburst®.
In the context of the present invention a filler can also be used as a binder.
Binders that can be used are cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins or hypromellose (e.g. hypromellose 3 cP). Preferred as binder is hypromellose (e.g. hypromellose 3 cP).
Lubricants prevent ingredients from sticking, e.g. to production equipment. Lubricants that can be used in the formulation according to the present invention are those selected from the list consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydogenated vegetable fat or oil, polyethylenglycol and talc. Preferred lubricants according to the present invention are those selected from the list consisting of magnesium stearate, stearic acid and talc. Very preferred as lubricant is magnesium stearate.
Disintegration promoter expand and dissolve when wet. They can be used to break the dosage form apart in the digestive tract, releasing the active ingredients. Disintegration promoters suitable in the context of the present invention are those selected from the list consisting of alginic acid, crosslinked polyvinylpyrrolidone, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium) or microcrystalline cellulose or a combination of croscarmellose sodium and microcrystalline cellulose. Preferred as a disintegration promoter is croscarmellose sodium or cross-linked polyvinylpyrrolidone. Very preferred as a disintegration promoter is croscarmellose sodium.
Preferred as sweetener is a pharmaceutically acceptable excipients that has a similar taste to sugar. Sweeteners suitable in the context of the present invention are those selected from the list consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol. In the context of the present invention sweeteners are added in amounts known for persons skilled in the art.
In the context of the present invention flavoring agents are pharmaceutically acceptable excipients appropriate to improve or give an agreeable taste of a pharmaceutical dosage form to complement its effect and also to increase its elegance. In the context of the present invention flavoring agents are natural flavoring substances obtained from plant or animal raw materials, nature-identical flavoring substances obtained by synthesis or isolated through chemical processes, which are chemically and organoleptically identical to flavoring substances naturally present in products intended for human consumption and artificial flavoring substances. In the context of the present invention flavoring agents are added in amounts known for persons skilled in the art. Flavoring agents suitable in the context of the present invention are those selected from the list consisting of synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart. In the context of the present invention flavoring agents are added in amounts known for persons skilled in the art.
In the context of the present invention colorants are pharmaceutically acceptable excipients appropriate to color an uncolored pharmaceutical dosage form or to enhance its color, to minimize batch-to-batch variations or to replace a color already present to complement its effect and also to increase its elegance. It can be any dyes, lakes or pigment such as indigo carmine, riboflavine and titanium dioxide. In the context of the present invention colorants are added in amounts known for persons skilled in the art.
In the context of the present invention the optional coating is carried out with addition of customary coating and film-forming agents familiar to the person skilled in the art, such as hydroxy- propylcellulose, hydroxypropylmethylcellulose (Hypromellose), ethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (e.g. polyethylene glycol 3350), glycerol triacetate or triethyl citrate, and/or colorants/pigments such as, for example, titanium dioxide, iron oxide (e.g. red iron oxide, yellow iron oxide), indigotin or suitable colour lakes, and/or antitacking agents such as talc, and/or opacifiers such as titanium dioxide. As optional coating and film-forming agents according to the present invention, Hypromellose and polyethylene glycol are preferred, as colorant iron oxide red is preferred and as opacifier titanium dioxide is preferred. A preferred mixture of coating substances may be about 60 wt.% hydroxypropylmethylcellulose, about 17.5 wt.% ferric oxide yellow, about 0.25 wt.% ferric oxide red and about 20 wt.% polyethylene glycol.
A mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available under the trade name Opadry®. Opadry 14F94373® is a mixture of about 60 wt.% hydroxypropylmethylcellulose, about 19.4 wt.% titanium dioxide, about 0.6 wt.% ferric oxide red and about 20 wt.% polyethylene glycol. The ready-to-use coating system available under the trade name Opadry® is preferred.
Preferably the coating is about 0.5% to 10% by weight of the coated tablet formulation, preferably 0.5% to 4.5% by weight of the coated tablet formulation, more preferably about 1.5% to 4.5% by weight of the coated tablet formulation.
(45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) and excipients are present in the solid pharmaceutical dosage form in a ratio of active ingredient (I) to excipients of 1 to 0.5 up to 1 to 20. Preferred is a ratio of active ingredient (I) to excipients of 1 to 0.5 up to 1 to 10, also preferred is a ratio of active ingredient (I) to excipients of 1 to 0.5 up to 1 to 5 and more preferred is a ratio of active ingredient (I) to excipients of 1 to 2 and very preferred is a ratio of active ingredient (I) to excipients of 1 to 1.6. Especially a ratio of active ingredient (I) to excipients of 1 to 1.6 enables high drug-load and small tablet sizes.
2) The manufacturing process of the solid pharmaceutical dosage forms
The present invention provides a process for preparing solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- 14- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) in amorphous form, which are prepared without using water or organic solvents or heat.
The present invention provides also a process for preparing solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients, which are prepared without using water or organic solvents or heat.
The present invention provides also a process for preparing solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) in amorphous form and further pharmaceutical acceptable excipients such as sweeteners, flavoring agents and colorants, which are prepared without using water or organic solvents or heat.
Surprisingly, the manufacturing process without water, organic solvents or heat allows, that (4S - 24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) is long-term stable in the pharmaceutical dosage form. In addition, no stabilizing measures, known by persons skilled in the art are needed. Compared to other formulation using e.g., amorphous solid dispersions, the manufacturing process without any water, organic solvents or head, allows clearly smaller tablet sizes, facilitating swallowing on the one hand and a higher number of tablets per batch for the industry on the other hand.
2A) Manufacturing process of roller compacted granulate (solid pharmaceutical dosage form A))
The present invention provides a process for preparing roller compacted granulate containing (4S)- 24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)), characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with at least one filler and parts of disintegration promoter, ii) and the resulting mixture is roller-compacted and grinded, and iii) the resulting granulate is mixed with the remaining disintegration promoter.
The present invention provides also a process for preparing roller compacted granulate containing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-74-carboxamide (active ingredient (I)), characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) and the resulting mixture is roller-compacted and grinded, and iii) the resulting granulate is mixed with the remaining croscarmellose sodium.
Roller compacted granulate containing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) producible by one of the processes mentioned above.
Roller compacted granulate containing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) produced by one of the processes mentioned above.
The roller compacted granulate may be converted into a pharmaceutical dosage form comprising, for example, tabletting, filling into capsules, preferably hard gelatine capsules, or filling as sachets, in each case according to customary methods familiar to the person skilled in the art, if appropriate with addition of further pharmaceutically suitable excipients. of an immediate release tablet
Figure imgf000024_0001
roller
Figure imgf000024_0002
Figure imgf000024_0003
form B))
The present invention provides a process for preparing solid pharmaceutical dosage forms containing roller compacted granulate for oral administration comprising (4 )-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with at least one filler and parts of disintegration promoter, ii) and the resulting mixture is roller-compacted and grinded, iii) the resulting granulate is mixed with the remaining disintegration promoter, iv) lubricant is added to the mixture and mixed again, v) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, vi) the tablet is optionally coated to receive the pharmaceutical dosage form. The present invention provides also a process for preparing solid pharmaceutical dosage forms containing roller compacted granulate for oral administration comprising (4 )-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) and the resulting mixture is roller-compacted and grinded, iii) the resulting granulate is mixed with the remaining croscarmellose sodium, iv) magnesium stearate is added to the mixture and mixed again, v) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, vi) the tablet is optionally coated to receive the pharmaceutical dosage form.
The present invention provides also a process for preparing solid pharmaceutical dosage forms containing roller compacted granulate for oral administration comprising (4 )-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) and the resulting mixture is roller-compacted and grinded, iii) the resulting granulate is mixed with the remaining croscarmellose sodium, iv) magnesium stearate is added to the mixture and mixed again, v) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, the tablet is optionally coated to receive the pharmaceutical dosage form, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
Solid pharmaceutical dosage forms for oral administration comprising (4.S')-24-chloro-4-cthyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l (l)-[ 1 ,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form producible by one of the processes mentioned above.
Solid pharmaceutical dosage forms for oral administration comprising (45)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form produced by one of the processes mentioned above. of an immediate release tablet which is based on direct
Figure imgf000026_0001
Figure imgf000026_0002
form C))
The present invention provides a process for preparing an immediate release tablet which is based on direct compression for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35- methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with at least one filler and parts of disintegration promoter, ii) lubricant is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, iv) the immediate release tablet is optionally coated.
The present invention provides also a process for preparing an immediate release tablet which is based on direct compression for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35- methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) magnesium stearate is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, iv) the immediate release tablet is optionally coated.
The present invention provides also a process for preparing an immediate release tablet which is based on direct compression for oral administration comprising (45)-24-chloro-4-ethyl-73-fluoro-35- methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) magnesium stearate is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, iv) the immediate release tablet is optionally coated, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
Immediate release tablet which is based on direct compression for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form producible by one of the processes mentioned above.
Immediate release tablet which is based on direct compression for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza-3(4,l)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form produced by one of the processes mentioned above.
2D) Manufacturing process of an orally dispersible tablet (solid pharmaceutical dosage form D))
The present invention provides a process for preparing an orally dispersible tablet for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- 14-
(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with at least one filler or disintegration promoter, ii) lubricant is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an orally dispersible tablet.
The present invention provides also a process for preparing an orally dispersible tablet for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- 14- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with a sugar alcohol mixture, ii) magnesium stearate is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an orally dispersible tablet.
The present invention provides also a process for preparing an orally dispersible tablet for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- 14- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with a sugar alcohol mixture, ii) magnesium stearate is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an orally dispersible tablet, wherein at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
The present invention provides also a process for preparing an orally dispersible tablet for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- 14- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with a sugar alcohol mixture, ii) magnesium stearate is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an orally dispersible tablet, wherein the disintegration time is maximal 3 minutes according to disintegration method of the European Pharmacopoeia using the rigid basket-rack apparatus with disk.
The sugar alcohol mixture is a mixture comprising mannitol. The sugar alcohol mixture can additionally to mannitol contain sorbitol and a disintegrant, such as crospovidone.
Orally dispersible tablet for oral administration comprising (4 )-24-chloro-4-ethyl-73-fluoro-35- methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form producible by one of the processes mentioned above.
Orally dispersible tablet for oral administration comprising (4 )-24-chloro-4-ethyl-73-fluoro-35- methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 Jtriazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form produced by one of the processes mentioned above.
Medicaments and use
Administration of the oral solid dosage form comprising amorphous active ingredient (I) and manufactured by a large industrial scale process which leads to high relative bioavailability in human ranging from 85% up to even 100%, preferred ranking from 88% up to even 100%.
The present invention further provides medicaments comprising a solid pharmaceutical dosage form for oral administration in accordance with the invention comprising the active ingredient (I).
The present invention further relates to the use of solid pharmaceutical dosage forms for oral administration in accordance with the invention comprising the active ingredient (I) and for preparing a medicament for the treatment and/or prophylaxis of disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, in particular cardiovascular disorders including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as disorders in the cerebrovascular arteries and other disorders, leading to transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic as well as non- cardioembolic strokes, and/or disorders of peripheral arteries, leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
The present invention further relates to the use of solid pharmaceutical dosage forms for oral administration in accordance with the invention comprising the active ingredient (I) for prophylaxis, secondary prophylaxis and/or treatment of disorders, particularly myocardial infarction, ischemic strokes including cardioembolic as well as non-cardioembolic strokes, acute limb ischemia, reocclusions and restenoses after interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
Below, the invention is illustrated in detail by preferred working examples; however, the invention is not limited to these examples. Unless indicated otherwise, all amounts given refer to mg of dosage form.
Figure imgf000030_0001
IR tablet: immediate release tablet
SDS: sodium dodecyl sulfate also called sodium lauryl sulfate rh: relative humidity
Active ingredient (I) crystalline means active ingredient (I) in crystalline modification I.
ODT : orally dispersible tablet
ASD matrix: amorphous solid dispersion matrix
FeSSIV : Fed State Simulated Intestinal Fluid
FaSSIV: Fasted State Simulated Intestinal Fluid kN/cm: Kilonewton per centimeter dry granulation is used synonym to roller compaction
1. Preparation of active ingredient (I) in amorphous form
Active ingredient (I) is (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide, also named as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l- yl]phenyl}-5-methoxy-2-oxopyridin-l(2H)-yl]butanoyl}amino)-2-fluorobenzamide, which can be prepared according to WO 2017/005725 Example 234 and Example 235 in the amorphous form.
2. Release / Dissolution method
According to the European Pharmacopoeia, 10th Edition, last revision of monograph 01/2016, the oral solid dosage form is tested with apparatus 2 (paddle). The rotation speed of the stirrer is 75 rpm (revolutions per minute) in 900 ml of acetate buffer pH 4.5 + 0.15% SDS. The release criterion is then fulfilled if all 6 test specimens have released at least 85% of active ingredient (I) into the release medium after an investigation period of 30 minutes. d for immediate release tablet based on
Figure imgf000031_0001
solid
Figure imgf000031_0002
Figure imgf000031_0003
The pharmaceutical dosage form (tablet) of Example 1 is prepared by dissolving the solid dispersion base and active ingredient (I) in organic solvent. In the course of a fluidized bed granulation, this solution is sprayed as granulating fluid on the initial charge of the disintegration promoter (carrier). After drying and sieving the granulates are resulting. Organic solvents may be ethanol, acetone or combinations thereof. The resulting granulate is mixed together with added disintegration promoter. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
4. Preparation method for immediate release tablet based on direct compression
2
The pharmaceutical dosage form (tablet) of Example 2 is prepared by mixing the active ingredient (I) together with microcrystalline cellulose, lactose and croscarmellose sodium. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
The pharmaceutical dosage form (tablet) of Example 4 is prepared by mixing the active ingredient (I) together with a sugar alcohol mixture. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
5. Preparation method for immediate release tablet based on dry granulation and
The pharmaceutical dosage form (tablet) of Example 3 is prepared by mixing the active ingredient (I) together with microcrystalline cellulose, lactose and parts of croscarmellose sodium. Afterwards the mixture is roller-compacted and grinded. The resulting granulate is mixed with the remaining croscarmellose sodium. Afterwards lubricant is added to the mixture and mixed again. The ready to press mixture thus obtained is compressed to produce tablets. The tablets may then be coated with pigments which are suspended in an aqueous solution composed of coating and film-forming agents. In the tablets the active ingredient (I) is present in an amount of 50 mg.
6. Preparation method for a roller compacted granulate Example 5
The pharmaceutical dosage form (granulate) of Example 5 is prepared by mixing the active ingredient (I) together with microcrystalline cellulose, lactose and croscarmellose sodium. Afterwards the blend is roller-compacted and grinded to result in the roller compacted granulate. In the roller compacted granulate the active ingredient (I) is present in an amount of 50 mg per 99 mg final granulate.
7. Compositions of the dosage form in mg/dosage form
Example 1 (comparison example): Immediate release tablet of (4>S -24-chloro-4-ethyl-73-fluoro-35- methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)), based on an amorphous solid dispersion
Pharmaceutical dosage form Amount (mg)
Drug substance
Active ingredient (I) in amorphous form 50.0
Tablet core
Polyvinylpyrrolidone (solid dispersion base) 100.0
Croscarmellose sodium (disintegration promoter / carrier) 65.0
Magnesium stearate (lubricant) 1.0
Ethanol a) (organic solvent) 150.0
Acetone a) (organic solvent) 150.0
Weight (uncoated tablet) 216.0
Film coating b) optional a) Solvents are quantitatively removed during the manufacturing process; b) tablets can optionally be coated Example 2: Immediate release tablet of (45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( 1)- dibenzenaheptaphane-74-carboxamide (active ingredient (I)), based on direct compression
Pharmaceutical dosage form Amount (mg)
Drug substance
Active ingredient (I) in amorphous form 50.0
Tablet core
Microcrystalline cellulose (filler) 48.7
Croscarmellose sodium (disintegration promoter) 15.0
Magnesium stearate (lubricant) 1.3
Lactose (filler) 15.0
Weight (uncoated tablet) 130.0
Film coating a) optional a) tablets can optionally be coated
Example 3: Immediate release tablet of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)), based on dry granulation
Pharmaceutical dosage form Amount (mg)
Drug substance
Active ingredient (I) in amorphous form 50.0
Tablet core
Microcrystalline cellulose a) (filler) 15.0
Croscarmellose sodium (disintegration promoter) 15.0 a) + 40.0 b)
Magnesium stearate b) (lubricant) 1.3
Lactose a) (filler) 19.0
Weight (uncoated tablet) 140.0
Film coating c) optional a) intragranular; b) extragranular; c) tablets can optionally be coated Example 4: Immediate release tablet of (45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (active ingredient (I)), based on direct compression
Pharmaceutical dosage form Amount (mg)
Drug substance
Active ingredient (I) in amorphous form 50.0
Tablet core
Sugar alcohol mixture a) (filler / disintegration promoter) 435.0
Magnesium stearate (lubricant) 15.0
Weight (uncoated tablet) 500.0 a) These materials are also available under the trade name Pharmaburst, for example Pharmaburst Cl, Pharmaburst Bl and Pharmaburst B2 from SPI Pharma. Pharmaburst comprises spray-dried mannitol and sorbitol and can additionally comprise a disintegrant, such as crospovidone.
The sugar alcohol mixture mentioned in example 4 is a mixture comprising mannitol and sorbitol and can additionally comprise a disintegrant, such as crospovidone.
Example 5: roller compacted granulate of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- l4-(trifluoromethyl)-32//-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)- dibenzenaheptaphane-74-carboxamide (active ingredient (I))
Pharmaceutical dosage form Amount (mg)
Drug substance
Active ingredient (I) in amorphous form 50.0
Microcrystalline cellulose (filler) 15.0
Croscarmellose sodium (disintegration promoter) 15.0
Lactose (filler) 19.0
Weight (granulate) 99.0
8. Bioavailabilitv, dissolution, disintegration and results
8.1 Bioavailabilitv
For the investigation of the bioavailability, the pharmaceutical dosage form comprising the active ingredient (I) is administered to animals via oral administration. Blood samples are taken from the test animals. The pharmacokinetic parameters such as area under the curve (AUC) and maximum concentration (Cmax) after oral administration are determined. Further corresponding pharmacokinetic parameters after oral administration are calculated. The primary pharmacokinetic parameters clearance (CL) and distribution volume (Vss) are calculated as follows:
Figure imgf000035_0001
8.2 Dissolution
By using manufacturing techniques such as direct compression (Example 2) or dry granulation (Example 5) followed by tablet compression (Example 3) comparable dissolution results to the amorphous solid dispersion from Example 1 could be shown. All examples have released at least 85% of active ingredient (I) into the release medium after 30 minutes. In addition to this, both techniques (Example 2 and Example 3) are able to reduce the disintegration time tremendously from 13 minutes in Example 1 to 2 minutes in Example 2 and 3. To increase the patient compliance and improve therefore the clinical effect of the treatment the tablet sizes could be significantly reduced from 12x6mm oval shaped for Example 1 to 7 mm round shaped for Examples 2 and 3 to facilitate swallowing.
In Example 4 a formulation of an orally dispersible tablet is shown. For this example, comparable dissolution results to the amorphous solid dispersion from Example 1 could be shown. The Example 4 released at least 85% of active ingredient (I) into the release medium after 30 minutes. This technique benefits from the fact, that no fluids are necessary for application of the tablet. The tablet disintegrates in less than one minute directly in the mouth and facilitate therefore both swallowing of the tablet as well as patient compliance.
Examples 2, 3, 4 and 5 are prepared without using water or organic solvents or heat in which the active ingredient (I) is present and stable in an amorphous form. This reveals a manufacturing process both, suitable for a large industrial scale and sustainable for the global environment at the same time. By the elimination of organic solvents, on a yearly basis, the total amount approximately 300 tons of organic solvents will be saved assuming a current forecasted need of approx. 50 tons of active ingredient (I) per year. Therefore, the newly developed formulations in Example 2 to 5 clearly improve the sustainability aspects of the product, to which an energy conscious process without heat also contributes.
8.3 Disintegration method
According to the European Pharmacopoeia, 10th Edition, last revision of monograph 01/2020, the oral solid dosage form is tested in a rigid basket-rack apparatus. The six test specimens are placed individually in a tube of the basket and a disk is added. The apparatus is operated by using water as a medium at 37 +/- 2°C.
Table 1: Comparison of tablet characteristics of examples 1 to 4
Example 1 Example 2 Example 3 Example 4
Tablet weight (uncoated) [mg] 216 130 140 500
Tablet format [mm] 12x6, oval 7, round 7, round 16x7, oval
Disintegration time [min] 13 2 2 < 1
Dissolution at 30 min timepoint [%]99 91 88 95 9. Solubility
The solubility of the active ingredient (I) in amorphous form and the crystalline form were determined in different solvents. The results are presented in Table 2.
Table 2: Solubility of active ingredient (I) in amorphous form and crystalline form in different solvents
Figure imgf000036_0001
” mg/L after 24h; 25°C

Claims

Patent claims
1. Solid pharmaceutical dosage form for oral administration comprising (4S)-24-chloro-4- ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluorornethyl)-32H-6-aza-3(4,l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form characterized in that the dosage form is
A) a roller compacted granulate which is obtained by roller compacting and grinding a mixture of active ingredient (I) in amorphous form and excipients or
B) an immediate release tablet where the mixture of active ingredient (I) in amorphous form and excipients is roller compacted and grinded with excipients to obtain roller compacted granulate which is then compressed to an immediate release tablet or
C) an immediate release tablet which is based on direct compression of a mixture of active ingredient (I) in amorphous form and excipients or
D) an orally dispersible tablet containing active ingredient (I) in amorphous form and excipients.
2. Solid pharmaceutical dosage form A) for oral administration according to Claim 1, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74- carboxamide (active ingredient (I)) in amorphous form, b) at least one disintegration promoter, and c) at least one filler.
3. Solid pharmaceutical dosage form B) or C) for oral administration according to Claim 1, comprising d) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74- carboxamide (active ingredient (I)) in amorphous form, e) at least one lubricant, f) at least one disintegration promoter, and g) at least one filler.
4. Solid pharmaceutical dosage form D) for oral administration according to Claim 1, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form, b) at least one lubricant, and c) at least one filler or disintegration promoter.
5. Solid pharmaceutical dosage form for oral administration according to Claims 1 to 4, characterized in that at least 85% of active ingredient (I) are released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using apparatus 2 (paddle).
6. Solid pharmaceutical dosage form for oral administration, which is a roller compacted granulate, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and c) at least one filler in an amount of 2 mg up to 150 mg.
7. Solid pharmaceutical dosage form for oral administration, which is an immediate release tablet containing roller compacted granulate, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 0.5 mg up to 7 mg, c) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and d) at least one filler in an amount of 2 mg up to 150 mg.
8. Solid pharmaceutical dosage form for oral administration, which is an immediate release tablet which is based on direct compression, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 0.5 mg up to 7 mg, c) at least one disintegration promoter in an amount of 2 mg up to 100 mg, and d) at least one filler in an amount of 2 mg up to 150 mg.
9. Solid pharmaceutical dosage form for oral administration, which is an orally dispersible tablet, comprising a) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form in an amount of 2 mg up to 100 mg, b) at least one lubricant in an amount of 2 mg up to 30 mg, and c) at least one filler or disintegration promoter in an amount of 20 mg up to 700 mg.
10. Solid pharmaceutical dosage form for oral administration comprising (4.S')-24-chloro-4- ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4,l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in amorphous form according to Claims 1 to 8, which is prepared without using water or organic solvents or heat.
11. Process for preparing roller compacted granulate containing (4S)-24-chloro-4-ethyl-73- fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina-l ( 1)- [l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient (I)), characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) and the resulting mixture is roller-compacted and grinded, and iii) the resulting granulate is mixed with the remaining croscarmellose sodium.
12. Process for preparing solid pharmaceutical dosage forms containing roller compacted granulate for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy- 32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( 1)- dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) and the resulting mixture is roller-compacted and grinded, iii) the resulting granulate is mixed with the remaining croscarmellose sodium, iv) magnesium stearate is added to the mixture and mixed again, v) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, vi) the tablet is optionally coated to receive the pharmaceutical dosage form.
13. Process for preparing an immediate release tablet which is based on direct compression for oral administration comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3 ]triazola-2( 1 ,2),7( 1)- dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with microcrystalline cellulose, lactose and parts of croscarmellose sodium, ii) magnesium stearate is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an immediate release tablet, iv) the immediate release tablet is optionally coated.
14. Process for preparing an orally dispersible tablet for oral administration comprising (4S)-
24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1)- pyridina- 1(1)-[1,2,3] triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-74-carboxamide (active ingredient (I)) in the amorphous form, characterized in that i) (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32//-6-aza- 3(4,1) -pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l) -dibenzenaheptaphane-74-carboxamide (active ingredient (I)) the amorphous form is initially mixed together with a sugar alcohol mixture, ii) magnesium stearate is added to the mixture and mixed again, iii) the resulting ready-to-press mixture is compressed to receive an orally dispersible tablet.
15. Solid pharmaceutical dosage forms for oral administration comprising (4S)-24-chloro-4- ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (active ingredient
(I)) in the amorphous form produced by one of the processes according to claims 10 to 14.
PCT/EP2024/057910 2023-03-31 2024-03-25 Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32 h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide Pending WO2024200335A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2024248738A AU2024248738A1 (en) 2023-03-31 2024-03-25 Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
KR1020257032237A KR20250164210A (en) 2023-03-31 2024-03-25 Pharmaceutical dosage form comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
CN202480020029.8A CN120936342A (en) 2023-03-31 2024-03-25 Pharmaceutical formulations containing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzohepta-74-carboxamide
MX2025011252A MX2025011252A (en) 2023-03-31 2025-09-23 PHARMACEUTICAL DOSAGE FORMS COMPRISING (4<i>S</i>)-2<sup>4</sup>-CHLORO-4-ETHYL-7<sup>3</sup>-FLUORO-3<sup>5</sup>-METHOXY-3<sup>2</sup>,5- DIOXO-1<sup>4</sup>-(TRIFLUOROMETHYL)-3<sup>2
CONC2025/0013103A CO2025013103A2 (en) 2023-03-31 2025-09-25 Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzene-heptaphan-74-carboxamide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23165858 2023-03-31
EP23165858.4 2023-03-31

Publications (1)

Publication Number Publication Date
WO2024200335A1 true WO2024200335A1 (en) 2024-10-03

Family

ID=85795446

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/057910 Pending WO2024200335A1 (en) 2023-03-31 2024-03-25 Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32 h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide

Country Status (6)

Country Link
KR (1) KR20250164210A (en)
CN (1) CN120936342A (en)
AU (1) AU2024248738A1 (en)
CO (1) CO2025013103A2 (en)
MX (1) MX2025011252A (en)
WO (1) WO2024200335A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009138224A1 (en) 2008-05-14 2009-11-19 Helm Ag Pharmaceutical composition comprising drospirenone
DE102010005124A1 (en) 2010-01-19 2012-03-01 Stada Arzneimittel Ag Solid pharmaceutical composition comprising lercanidipine
WO2017005725A1 (en) 2015-07-09 2017-01-12 Bayer Pharma Aktiengesellschaft Substituted oxopyridine derivatives
WO2020126682A1 (en) * 2018-12-17 2020-06-25 Bayer Aktiengesellschaft Substituted oxopyridine derivatives for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications
WO2022189278A1 (en) 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)- dibenzenaheptaphane-74-carboxamide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009138224A1 (en) 2008-05-14 2009-11-19 Helm Ag Pharmaceutical composition comprising drospirenone
DE102010005124A1 (en) 2010-01-19 2012-03-01 Stada Arzneimittel Ag Solid pharmaceutical composition comprising lercanidipine
WO2017005725A1 (en) 2015-07-09 2017-01-12 Bayer Pharma Aktiengesellschaft Substituted oxopyridine derivatives
WO2020126682A1 (en) * 2018-12-17 2020-06-25 Bayer Aktiengesellschaft Substituted oxopyridine derivatives for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications
WO2022189278A1 (en) 2021-03-09 2022-09-15 Bayer Aktiengesellschaft Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)- dibenzenaheptaphane-74-carboxamide

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"European Pharmacopoeia", January 2020
AYENEW, EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 81, 2012, pages 207 - 213
BREITENBACH, EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 54, 2002, pages 107 - 117
CRAIG ET AL.: "The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 179, 1999, pages 179 - 207, XP009100532, DOI: 10.1016/S0378-5173(98)00338-X
HERTING, INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 338, 2007, pages 110 - 118
HIRANI, TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH, vol. 8, no. 2, April 2009 (2009-04-01), pages 161 - 172
KANEFENDT FRIEDERIKE ET AL: "Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian", CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, vol. 12, no. 2, 11 December 2022 (2022-12-11), GB, pages 219 - 230, XP093172986, ISSN: 2160-763X, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cpdd.1207> DOI: 10.1002/cpdd.1207 *
LEANE, DRUG DEV TECH, vol. 18, no. 2, 2013, pages 359 - 366
MA, JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY, vol. 50, 2019, pages 113 - 124
MASIH ASHISH ET AL: "FAST DISSOLVING TABLETS: A REVIEW", INTERNATIONAL JOURNAL OF CURRENT PHARMACEUTICAL RESEARCH, vol. 9, no. 2, 1 March 2017 (2017-03-01), IN, pages 8, XP093174702, ISSN: 0975-7066, Retrieved from the Internet <URL:http://innovareacademics.in/journals/index.php/ijcpr/article/viewFile/17382/9673> DOI: 10.22159/ijcpr.2017v9i2.17382 *
MOSIG, POWDER TECHNOLOGY, vol. 266, 2014, pages 156 - 166
SERAJUDDIN: "Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 88, no. 10, 1999, pages 1058 - 1066, XP000851882, DOI: 10.1021/js980403l
STOLTENBERG, EUR. J. PHARM. BIOPHARM., vol. 78, 2011, pages 662 - 669
SUN ET AL., INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 539, no. 1-2, 2018, pages 184 - 189

Also Published As

Publication number Publication date
CN120936342A (en) 2025-11-11
MX2025011252A (en) 2025-10-01
KR20250164210A (en) 2025-11-24
CO2025013103A2 (en) 2025-10-09
AU2024248738A1 (en) 2025-09-11

Similar Documents

Publication Publication Date Title
JP6934932B2 (en) Solid pharmaceutical composition of androgen receptor antagonist
US12357627B2 (en) Pharmaceutical compositions of cabozantinib
JPH0251402B2 (en)
JPWO2008129846A1 (en) Pharmaceutical composition
NO330260B1 (en) Oral solid composition comprising levodopa / carbidopa / entacapone, method of preparation thereof, and use of a composition comprising levodopa / carbidopa / entacapone for the manufacture of a medicament for the treatment of Parkinson&#39;s disease.
JP2025134801A (en) Composition having improved solubility and bioavailability of olaparib
US20240173310A1 (en) Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-14-(trifluoromethyl)-32h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
CA3029543C (en) Immediate release pharmaceutical composition of iron chelating agents
US20130236544A1 (en) Stable pharmaceutical compositions of fesoterodine
AU2025202791A1 (en) Orally disintegrating pharmaceutical compositions of apixaban
JP2007516188A (en) Novel solid pharmaceutical composition comprising amisulpride
WO2024200335A1 (en) Pharmaceutical dosage forms comprising (4s)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5- dioxo-14-(trifluoromethyl)-32 h-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide
WO2008068778A2 (en) Extended release pharmaceutical composition of pramipexole
US20100317642A1 (en) Pharmaceutical composition of orlistat
KR20150003859A (en) Delayed Release Pharmaceutical Compositions of Salsalate
US20110195117A1 (en) Controlled release compositions of ropinirole
KR20120122558A (en) Sustained-release pharmaceutical composition comprising donepezil or pharmaceutically acceptable salt thereof having improved dissolution stability and method for manufacturing the same
EP4647130A2 (en) Pharmaceutical composition comprising eliglustat
WO2025051851A1 (en) Pharmaceutical dosage forms comprising 2-(2-chlorophenyl)-n-[4-(4-cyano-1h-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

Legal Events

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

Ref document number: 24712530

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 824616

Country of ref document: NZ

Ref document number: AU2024248738

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 824616

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2024248738

Country of ref document: AU

Date of ref document: 20240325

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 202517086754

Country of ref document: IN

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112025017947

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: KR1020257032237

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 202517086754

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2024712530

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024712530

Country of ref document: EP

Effective date: 20251031