Pharmaceutical formulations containing (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)-dibenzenaheptaphan-74-carboxamide

Abstract

The present invention relates to a solid pharmaceutical dosage form for oral administration containing (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzena-heptafane-7 4 -carboxamide (active ingredient (I)), characterized in that the active ingredient (I) is present in an amorphous form and is immediately released from the solid pharmaceutical dosage form for oral administration, a method for preparing the same, its use as a medicine, and its use for the treatment and / or prevention of diseases, particularly cardiovascular diseases, preferably thrombotic or thromboembolic diseases, and edema, and eye diseases. 【Chemical formula 1】 TIFF2026509613000011.tif37158

Description

Technical Field

[0001] The present invention relates to a solid pharmaceutical dosage form for oral administration containing (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzena-heptafane-7 4 -carboxamide (active ingredient (I)), characterized in that the active ingredient (I) is present in an amorphous form and is immediately released from the solid pharmaceutical dosage form for oral administration, a method for preparing the same, and its use as a medicine, and its use for the treatment and / or prevention of diseases, particularly cardiovascular diseases, preferably thrombotic or thromboembolic diseases, and edema, and eye diseases.

Background Art

[0002] (4S)-2 of the active ingredient (I), also known as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridine-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafane-7 4 -carboxamide is known from WO2017 / 005725 and has the following formula:

Chemical Formula

[0003] The active ingredient (I) acts as a factor XIa inhibitor, and through this specific mechanism of action, after oral administration, is useful for the treatment and / or prevention of diseases, preferably thrombotic or thromboembolic diseases and / or thrombotic or thromboembolic complications, particularly cardiovascular diseases including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as diseases of the cerebrovascular arteries and other diseases leading to transient ischemic attacks (TIAs), ischemic stroke including cardiogenic and non-cardiogenic embolic strokes, and / or peripheral artery diseases leading to peripheral artery disease including peripheral artery occlusion, acute limb ischemia, amputation, reocclusion and restenosis after interventions such as angioplasty, stent implantation or surgery and bypass, and / or stent thrombosis.

[0004] To develop a solid drug dosage form for oral administration, the active ingredients (I) and (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide is used in an amorphous form.

[0005] For diseases requiring long-term treatment, or for the long-term prevention of disease, it is desirable to keep the frequency of medication intake as low as possible and the tablet size as small as possible. This is not only more convenient for the patient but also enhances the reliability of treatment (improves compliance) by reducing the disadvantages of irregular intake. To improve compliance especially in elderly patients, tablets should be as small as possible, meaning they should contain a high concentration of the active ingredient, particularly at higher dose strengths.

[0006] During development, it was discovered that the amorphous form of the active ingredient (I) is poorly soluble in water. Oral administration of poorly soluble active ingredients often presents problems, resulting in insufficient bioavailability of the active ingredient (I). Oral solid drug dosage forms, such as tablets, should provide virtually all immediate release of the active ingredient (I) and exhibit sufficient solubility. Solid drug dosage forms are also needed in large numbers of patients and should therefore possess excellent properties that enable the industrial-scale production of solid drug dosage forms using sustainable manufacturing processes.

[0007] Most solid drugs and dosage forms are prepared in a crystalline state characterized by a regular, ordered lattice structure. These physical structures are generally thermodynamically stable and relatively easy to study using techniques such as differential scanning calorimetry and X-ray diffraction. Amorphous materials are thermodynamically unstable and tend to revert to crystalline form during storage. While the mechanical properties and vapor sorption profiles of amorphous systems can differ significantly from those of crystalline materials, the chemical reactivity of amorphous drugs can be greater. The amorphous state is, by definition, metastable with respect to crystalline materials, and therefore, amorphous drugs tend to revert to crystalline form over time. Predicting the timescales involved is clearly important but can be difficult to achieve. It has been shown that the rate of drug degradation can be enhanced in the amorphous state compared to crystalline materials [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].

[0008] Problems related to the physical and chemical stability of amorphous drugs and systems are the reason why amorphous approaches without stabilization measures are often not employed.

[0009] In addition to producing freeze-dried systems in which the amorphous state of drugs (and excipients) is stabilized, the preparation of so-called amorphous solid dispersions (ASDs) is a well-known means of stabilizing materials that were originally amorphous or previously crystalline, and is particularly used in oral dosage forms.

[0010] Even these stabilized systems exhibit limitations in terms of 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 the development of amorphous drug formulations remains an important undertaking with challenges (e.g., bioavailability, physical stability, chemical stability, and manufacturing).

[0011] The challenges are even greater when developing amorphous drugs and processing them directly by compression.

[0012] There have been few attempts to develop stable oral dosage forms containing amorphous drugs, which are manufactured by direct compression.

[0013] Sun et al. filled amorphous active pharmaceutical ingredients / drugs into mesoporous silica (Aeroperl®), enabling 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].

[0014] DE 10 2010 005 124 A1 describes a solid oral dosage form manufactured by direct tableting / direct compression, containing amorphous lecanidipine and a hydrogelling agent incorporated as a stabilizing excipient, namely hypromellose.

[0015] WO2009 / 138224 discloses a pharmaceutical composition comprising drosperinone in a substantially amorphous form and a carrier selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and microcrystalline cellulose (MCC), wherein the drosperinone and carrier exist in a co-ground state. Co-grounding of the two-phase system of separate drosperinone and carrier particles stabilizes the amorphous form of the drug.

[0016] WO2022 / 189278 contains (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Amorphous solid dispersions (ASDs) and solid drug dosage forms for oral administration containing carboxamide are described.

[0017] The most relevant techniques for manufacturing and stabilizing amorphous drugs in so-called amorphous solid dispersions (ASDs) are based on two main distinct processes: solvent evaporation and melting. Several mechanical processes, such as ball milling or grinding, can also induce some degree of amorphousness [Breitenbach in: European Journal of Pharmaceutics and Biopharmaceutics 54(2002)107-117]. All have in common that they are energy-intensive, cost-intensive, and / or carry ecological and hazardous risks. Amorphous solid dispersions use specific carriers that amorphousize the active pharmaceutical ingredient and stabilize it in a solid state. Incorporating additional stabilizing excipients increases tablet weight and size, which is known to be undesirable for patient compliance. Furthermore, it is worth mentioning that amorphous materials in ASDs will eventually revert to their crystalline form, albeit at a slow rate [Ma in: Journal of Drug Delivery Science and Technology 50(2019)113-124]. Furthermore, when ASD is exposed to moisture (e.g., during storage under high humidity conditions), the presence of water significantly increases the drug's mobility and reduces the polymer's ability to inhibit recrystallization. Therefore, pharmaceutical dosage forms containing ASD may require additional moisture protection measures, such as the application of special coatings and / or special product packaging materials that act as moisture barriers or moisture adsorbents (desiccant). For example, lopinavir and ritonavir are offered as fixed-dose formulation tablets (KALETRA®) coated with a polyvinyl alcohol polymer that protects the active ingredient from moisture, oxygen, and other environmental components, and etravirine tablets (INTELENCE®) need to be marketed in bottles containing three desiccant pouches per bottle to keep the tablets dry.

[0018] Solid pharmaceutical dosage forms manufactured by tableting may optionally be roller-compressed. Since many materials are not suitable for direct compression, a granulation process is often performed before tableting. Roller compression and subsequent dry granulation of compressed materials, in addition to wet granulation, is one common method for producing granules and is gaining importance in the pharmaceutical industry [Mosig in: Powder Technology 266(2014)156-166].

[0019] This method enables the granulation of moisture and heat-sensitive materials. The process is environmentally friendly because it does not require solvent removal and is easily scaled up.

[0020] The main advantage is the continuous production of granules, which leads to cost reductions.

[0021] However, the resulting tablets exhibit inferior tensile strength compared to those produced using other granulation techniques. This is because the binding potential partially consumed in the first compression step is limited [Herting in: International Journal of Pharmaceutics 338(2007)110-118].

[0022] Orally disintegrating tablets (ODTs) function as a specialized type of tablet. They are appealing to many patient groups, including the elderly and children, and patients who are mentally retarded, uncooperative, nauseous, or have reduced fluid / food intake may have difficulty swallowing these dosage forms. People traveling or with limited access to water are similarly affected. To meet these medical needs, pharmaceutical engineers have developed a novel oral dosage form known as orally disintegrating tablets (ODTs), which rapidly disintegrate in saliva, usually within seconds, without the need for water intake. Drug dissolution and absorption, as well as the onset of clinical effect and drug bioavailability, can be significantly greater than those observed with conventional dosage forms [Hirani in: Tropical Journal of Pharmaceutical Research, April 2009, 8(2), 161-172].

[0023] ODTs can be manufactured using a sugar floss system or direct compression, through different processes such as freeze-drying, molding, and sublimation. While the direct compression process is convenient and cost-effective, it is heavily influenced by the properties of the active pharmaceutical ingredient (API) and the excipients used, such as fluidity, powder compressibility, and compactability. Therefore, excipients that provide excellent compressibility should preferably be used. Excipients for ODTs must be selected based on material properties (plasticity, elasticity, or brittleness) and desired functionality, such as a defined particle size distribution, good fluidity, enhanced compressibility, or rapid collapse. Mannitol is an excipient often used in rapidly soluble drug formulations. However, when used as an untreated powder, insufficient fluidity, poor binding properties, and compressibility are limiting factors. Therefore, excipients co-treated with mannitol are an option. Co-treatment means that two or more excipients are interacted at the subparticle level by co-spray drying, co-spray agglomeration, or co-granulation, thereby improving functionality [Stoltenberg in: Eur.J.Pharm.Biopharm.78(2011)662-669]. The co-treated mannitol used in the present invention is commercially available under various trade names such as Pharmaburst®. However, mannitol is known to induce crystallization of amorphous drugs even when stabilized in amorphous spray-dried dispersions [Leane in: Drug Dev Tech 18(2)(2013)359-366]. Since the literature has shown that excipients such as mannitol and other fillers affect polymorphic transformation during wet granulation, there is a possibility of excipient-induced physical instability. Therefore, mannitol containing co-treated excipient systems such as Pharmaburst® was expected to induce crystallization of amorphous drugs in pharmaceutical dosage forms, especially when manufactured without stabilization measures.

[0024] Furthermore, as described in [Ayenew in: European Journal of Pharmaceutics and Biopharmaceutics 81(2012)207-213], the literature has shown that compression can induce even more significant segregation, which can lead to amorphous phase separation and ultimately to instability of the drug in its amorphous form.

[0025] Some orally disintegrating dosage forms are hygroscopic and cannot maintain physical integrity under normal temperature and humidity conditions. Therefore, they require protection from moisture and special product packaging [Hirani in: Tropical Journal of Pharmaceutical Research, April 2009, 8(2), 161-172]. As detailed above, hygroscopicity is one factor that increases the risk of amorphous drugs converting to their crystalline form. [Prior art documents] [Patent Documents]

[0026] [Patent Document 1] International Publication No. 2017 / 005725 Brochure [Patent Document 2] German Published Patent No. 102010005124A1 [Patent Document 3] International Publication No. 2009 / 138224 Pamphlet [Patent Document 4] International Publication No. 2022 / 189278 brochure [Non-patent literature]

[0027] [Non-Patent Document 1] Craig et al. in: International Journal of Pharmaceutics 179(1999)179-207 [Non-Patent Document 2] Serajuddin in:Journal of Pharmaceutical Sciences Vol.88,No.10(1999)1058-1066 [Non-licensed document 3] Sun et al in:International Journal of Pharmaceutics.539(1-2)(2018)184-189

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Non-licensed literature 9

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[0028] Therefore, the purpose of development is (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 The objective was to provide an orally administered solid pharmaceutical dosage form containing carboxamide (active ingredient (I)), wherein the active ingredient (I) is present in an amorphous form, and the oral solid pharmaceutical dosage form exhibits excellent dissolution behavior and good bioavailability. The solid pharmaceutical dosage form should also have excellent properties that enable the manufacture of the solid pharmaceutical dosage form on an industrial scale. Furthermore, the amorphous form of the active ingredient (I) must be stable in the solid pharmaceutical dosage form during long-term storage. Crystallization of the active ingredient (I) results in a lower dissolution rate and lower bioavailability of the active ingredient (I), so in all cases, crystallization must be prevented. [Means for solving the problem]

[0029] Remarkably, a solid pharmaceutical dosage form containing the active ingredient (I) and stable in an amorphous state is prepared without the use of water, organic solvents, or heat. This solid pharmaceutical dosage form exhibits excellent solubility and good bioavailability, and in addition, demonstrates superior tablet properties resulting from a manufacturing process that enables large-scale industrial production, continuous production processes without individual batches as needed, and sustainability at the same time.

[0030] Remarkably, in this invention, it was possible to exhibit excellent tablet properties, including tablet hardness, while still being capable of roller compression.

[0031] Surprisingly, the present invention describes a pharmaceutical dosage form that is produced by a process not based on solvent evaporation or melting, and in which the contained amorphous drug is chemically and physically stable over the long term.

[0032] Surprisingly, the present invention describes a pharmaceutical dosage form manufactured by compression and provided as an orally disintegrating tablet (ODT) containing mannitol, wherein the amorphous drug contained herein is chemically and physically stable over the long term.

[0033] Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)), wherein the dosage form is A) Roller-compressed granules obtained by roller-compressing and grinding a mixture of amorphous active ingredient (I) and an excipient, or B) A mixture of an amorphous active ingredient (I) and an excipient is roller-compressed to obtain roller-compressed granules together with the excipient, and then these are compressed to form immediate-release tablets, or C) Immediate-release tablets based on direct compression of a mixture of an amorphous active ingredient (I) and an excipient, or D) Orally disintegrating tablets containing an amorphous active ingredient (I) and excipients. A solid pharmaceutical dosage form characterized by the following:

[0034] Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)), wherein the dosage form is A) Roller-compressed granules obtained by roller-compressing and grinding a mixture of amorphous active ingredient (I) and an excipient, or B) A mixture of an amorphous active ingredient (I) and an excipient is roller-compressed to obtain roller-compressed granules together with the excipient, and then these are compressed to form immediate-release tablets, or C) Immediate-release tablets based on direct compression of a mixture of an amorphous active ingredient (I) and an excipient, or D) An orally disintegrating tablet containing an amorphous active ingredient (I) and an excipient, Herein, a solid pharmaceutical dosage form characterized in that, according to the release method of the European Pharmacopoeia using device 2 (paddle), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0035] Solid pharmaceutical dosage forms based on direct compression and their manufacturing methods are publicly known.

[0036] The most frequent challenges in preparing solid pharmaceutical dosage forms containing the active ingredient (I) in an amorphous form are determining the required drug-to-excipient ratio to facilitate the desired increase in release rate and bioavailability, as well as selecting and scaling up a manufacturing process that is appropriate to protect the physical and chemical stability of the amorphous form of the active ingredient (I) and is simultaneously capable of large-scale industrial production.

[0037] Furthermore, a specific manufacturing method that does not use water, organic solvents, or heat is (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - This enables the production of an orally administered solid pharmaceutical dosage form containing carboxamide (active ingredient (I)) in the form of roller-compressed granules or tablets with good tablet hardness and low brittleness, allowing for large-scale industrial-scale tablet production. The solid pharmaceutical dosage form is robust to variations in the manufacturing process during operation and technical transfer, and the properties of the solid pharmaceutical dosage form remain unaffected.

[0038] Remarkably, immediate-release tablets containing the amorphous active ingredient (I) according to the present invention, prepared without the use of water, organic solvents, or heat, were found to exhibit excellent solubility and good bioavailability of the active ingredient (I), as well as superior properties that enable the production of solid pharmaceutical dosage forms on an industrial scale, and, if necessary, a continuous manufacturing process without individual batches, using a sustainable manufacturing process, as these are required for a large number of patients.

[0039] The present invention provides a method for using the active ingredient (I) in its amorphous form and mixing it with other excipients. The mixture may then be roller-compressed. A disintegration accelerator may then be added and the mixture mixed again. Finally, a lubricant may be added and the mixture mixed again. The mixture may be used as is as granules or for manufacturing tablets. The tablets may optionally be coated.

[0040] The methods and excipients selected for the present invention are in some respects in contrast to methods and excipients known to those skilled in the art and which are commonly used to prepare immediate-release tablets containing an amorphous active ingredient (I) without the use of water, organic solvents, or heat.

[0041] 1) Solid drug dosage forms This invention relates to the amorphous form of (4S)-2 4 -Chloro-4-ethyl-73 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - To provide a solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)), which can be prepared without using water, organic solvents, or heat.

[0042] The present invention also relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration comprising carboxamide (active ingredient (I)) and further pharmaceutically acceptable excipients is provided, which is prepared without the use of water, organic solvents, or heat.

[0043] The present invention also relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration is provided, comprising carboxamide (active ingredient (I)) and further pharmaceutically acceptable excipients such as sweeteners, flavoring agents and coloring agents, which is prepared without the use of water, organic solvents, or heat.

[0044] The present invention also relates to a solid pharmaceutical dosage form for oral administration comprising the amorphous form of (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 4 -carboxamide (active ingredient (I)), which is prepared without using any of water, organic solvents, and heat, and at least 85% of the active ingredient (I) is released into the release medium after 30 minutes according to the European Pharmacopoeia release method using apparatus 2 (paddle).

[0045] The present invention relates to a solid pharmaceutical dosage form A) for oral administration, comprising a) the amorphous form of (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 4 -carboxamide (active ingredient (I)), b) at least one disintegrant, and c) at least one filler and provides a solid pharmaceutical dosage form A).

[0046] The present invention also relates to a solid pharmaceutical dosage form A) for oral administration, comprising a) the amorphous form of (4S)-2 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) at least one disintegration accelerator, and c) At least one filler Includes, Herein, we provide a solid pharmaceutical dosage form A) in which, according to the release method of the European Pharmacopoeia using device 2 (paddle), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0047] The present invention relates to a solid pharmaceutical dosage form B) or C) for oral administration, d) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), e) At least one lubricant, f) at least one disintegration accelerator, and g) At least one filler The present invention provides solid pharmaceutical dosage forms B) or C), including the above.

[0048] The present invention also relates to a solid pharmaceutical dosage form B) or C) for oral administration, d) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4-Carboxamide (active ingredient (I)), e) At least one lubricant, f) at least one disintegration accelerator, and g) At least one filler Includes, Herein, we provide solid pharmaceutical dosage forms B) or C), in which, according to the release method of the European Pharmacopoeia using device 2 (paddle), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0049] The present invention relates to a solid pharmaceutical dosage form D) for oral administration, a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) At least one lubricant, and c) At least one filler or disintegration accelerator The invention provides solid pharmaceutical dosage form D), including the above.

[0050] The present invention relates to a solid pharmaceutical dosage form D) for oral administration, h) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), i) at least one lubricant, and j) At least one filler or disintegration accelerator Includes, Herein, we provide a solid pharmaceutical dosage form D) in which, according to the release method of the European Pharmacopoeia using device 2 (paddle), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0051] The present invention relates to a solid pharmaceutical dosage form D) for oral administration, a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) At least one lubricant, and c) At least one filler or disintegration accelerator Includes, Here, we provide a solid pharmaceutical dosage form D) in which the disintegration time is up to 3 minutes, according to the European Pharmacopoeia disintegration method using a hard basket rack apparatus equipped with discs.

[0052] 1A) Roller-compressed granules (solid pharmaceutical dosage form A) This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)) is provided, which is a roller-compressed granule obtained by roller-compressing and grinding a mixture of the amorphous active ingredient (I) and an excipient.

[0053] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)), which is a roller-compressed granule obtained by roller-compressing and grinding a mixture of amorphous active ingredient (I) and an excipient, and is prepared without the use of water, organic solvents, or heat.

[0054] The present invention is a solid pharmaceutical dosage form for oral administration, which is a roller-compressed granule. a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) at least one disintegration accelerator, and c) At least one filler The present invention provides solid pharmaceutical dosage forms, including those containing the above.

[0055] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is a roller-compressed granule. a) (4S)-2 in amorphous form in quantities from 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-14 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) At least one disintegration accelerator in an amount ranging from 2 mg to 100 mg, and c) At least one filler in an amount ranging from 2 mg to 150 mg The present invention provides solid pharmaceutical dosage forms, including those containing the above.

[0056] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is a roller-compressed granule. a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) Croscarmellose sodium as a disintegration accelerator, and c) Microcrystalline cellulose and lactose as fillers The present invention provides solid pharmaceutical dosage forms, including those containing the above.

[0057] Generally, the advantage of roller-compressed granules is the improved fluidity of the granules compared to the initial powder mixture. As described by Ayenew (see above), the literature has shown that compression can induce segregation, which is even more important, in cases of amorphous phase separation and ultimately instability of the drug in amorphous form.

[0058] An advantage of the present invention is that the mixture can be roller-compressed without losing the excellent solubility and good bioavailability of the active ingredient (I). Furthermore, compression of the mixture reduces the risk of non-uniform distribution of the amorphous active ingredient (I) in the solid pharmaceutical dosage form.

[0059] Remarkably, the amorphous form of active ingredient (I) is stable for extended periods in roller-compressed granules containing well-known standard excipients, without the use of any stabilizers (e.g., polymers in the ASD matrix or the gelling agents mentioned above).

[0060] To ensure excellent dissolution, the roller compression force [kN / cm] and gap [mm] must be carefully controlled during the roller compression process. A roller compression force of 0.1 to 5.0 kN / cm is preferred, and a gap of 1.0 to 6.0 mm is preferred. A smaller gap results in a lower roller compression force, while a larger gap results in a higher roller compression force. The most preferred configuration is a roller compression force of 2 kN / cm and a gap of 3 mm.

[0061] Roller compression is not known as a method for stabilizing the amorphous form of the active ingredient. Therefore, surprisingly, the roller compression process has proven suitable for producing solid pharmaceutical dosage forms in which the amorphous form of the active ingredient (I) is stable over long periods.

[0062] 1B) Immediate-release tablets containing roller-compressed granules (solid drug dosage form B) The present invention relates to an immediate-release tablet, an amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4A solid pharmaceutical dosage form for oral administration containing -carboxamide (active ingredient (I)), wherein a mixture of the active ingredient (I) in amorphous form and an excipient is roller-compressed, pulverized together with the excipient to obtain roller-compressed granules, and then this is compressed into an immediate-release tablet, thereby providing a solid pharmaceutical dosage form.

[0063] The present invention relates to an immediate-release tablet, which is a solid pharmaceutical dosage form for oral administration, and is (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 4 -carboxamide (active ingredient (I)), which is a solid pharmaceutical dosage form for oral administration, wherein a mixture of the active ingredient (I) in amorphous form and an excipient is roller-compressed, pulverized together with the excipient to obtain roller-compressed granules, and then this is compressed into an immediate-release tablet, and is prepared without using any of water, organic solvents, and heat.

[0064] The present invention relates to a solid pharmaceutical dosage form for oral administration, which is an immediate-release tablet containing roller-compressed granules, and a) (4S)-2 in amorphous form 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 4 -carboxamide (active ingredient (I)), b) at least one lubricant, c) at least one disintegrant, and d) at least one filler and provides a solid pharmaceutical dosage form.

[0065] The present invention also relates to a solid pharmaceutical dosage form for oral administration, which is an immediate-release tablet containing roller-compressed granules, a) (4S)-2 in an amorphous form in an amount from 2 mg to 100 mg 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 4 -carboxamide (active ingredient (I)), b) at least one lubricant in an amount from 0.5 mg to 7 mg, c) at least one disintegrant in an amount from 2 mg to 100 mg, and d) at least one filler in an amount from 2 mg to 150 mg to provide a solid pharmaceutical dosage form.

[0066] The present invention also relates to a solid pharmaceutical dosage form for oral administration, which is an immediate-release tablet containing roller-compressed granules, a) (4S)-2 in an amorphous form 4 -chloro-4-ethyl-7 3 -fluoro-3 5 -methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 4 -carboxamide (active ingredient (I)), b) magnesium stearate as a lubricant, c) croscarmellose sodium as a disintegrant, and d) microcrystalline cellulose and lactose as fillers to provide a solid pharmaceutical dosage form.

[0067] Generally, the advantage of roller-compressed granules is the improved fluidity of the granules compared to the initial powder mixture. As described by Ayenew (see above), the literature has shown that compression can induce segregation, which is even more important, in cases of amorphous phase separation and ultimately instability of the drug in amorphous form.

[0068] From the literature, it is well known that roller-compressed solid pharmaceutical dosage forms tend to suffer from delayed final tablet hardness or dissolution behavior. The advantage of the present invention is that the mixture can be roller-compressed without losing the excellent dissolution behavior and good bioavailability of the active ingredient (I) and excellent tableting properties. The resulting tablets exhibit excellent tablet hardness. Furthermore, compression of the mixture reduces the risk of non-uniform distribution of the amorphous form of the active ingredient (I) in the solid pharmaceutical dosage form.

[0069] Remarkably, the amorphous form of active ingredient (I) remains stable for extended periods in tablets based on roller-compressed granules. The tablets contain only well-known standard excipients, without the use of any stabilizers (e.g., polymers in the ASD matrix or the gelling agents mentioned above).

[0070] To ensure excellent dissolution, the roller compression force [kN / cm] and gap [mm] must be carefully controlled during the roller compression process. A roller compression force of 0.1 to 5.0 kN / cm is preferred, and a gap of 1.0 to 6.0 mm is preferred. A smaller gap results in a lower roller compression force, while a larger gap results in a higher roller compression force. The most preferred configuration is a roller compression force of 2 kN / cm and a gap of 3 mm.

[0071] Roller compression itself is not known as a method for stabilizing the amorphous form of the active ingredient. Therefore, surprisingly, we were able to demonstrate that it is possible to manufacture tablets based on roller-compressed granules in which the amorphous form of the active ingredient (I) is stable over a long period of time.

[0072] 1C) Immediate-release tablets based on direct compression (solid drug dosage form C) This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)) is provided, which is a rapid-release tablet based on the direct compression of a mixture of amorphous active ingredient (I) and an excipient.

[0073] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)), which is a rapid-release tablet based on the direct compression of a mixture of amorphous active ingredient (I) and excipients, and is prepared without the use of water, organic solvents, or heat.

[0074] The present invention is a solid pharmaceutical dosage form for oral administration, which is a direct-compression, immediate-release tablet. a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4-Carboxamide (active ingredient (I)), b) At least one lubricant, c) At least one disintegration accelerator, and d) At least one filler The present invention provides solid pharmaceutical dosage forms, including those containing the above.

[0075] The present invention also provides an oral solid pharmaceutical dosage form, which is a direct-compression immediate-release tablet, a) (4S)-2 in amorphous form in quantities from 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) At least one lubricant in an amount of 0.5 mg to 7 mg, c) At least one disintegration accelerator in an amount ranging from 2 mg to 100 mg, and d) At least one filler in an amount ranging from 2 mg to 150 mg The present invention provides solid pharmaceutical dosage forms, including those containing the above.

[0076] The present invention also provides an oral solid pharmaceutical dosage form, which is a direct-compression immediate-release tablet, a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) Magnesium stearate as a lubricant c) croscarmellose sodium as a disintegrant promoter, and d) microcrystalline cellulose and lactose as fillers to provide a solid pharmaceutical dosage form containing the same.

[0077] The advantage of the present invention is that the amorphous form of the active ingredient (I) is stable for a long time in an immediate-release tablet based on direct compression without any means of stabilization (e.g., polymers in an ASD matrix or the above-mentioned gelling agents), and at the same time, it exhibits excellent dissolution behavior, good bioavailability, and excellent tablet properties of the active ingredient (I). The obtained tablets exhibit excellent tablet hardness.

[0078] Surprisingly, this can be achieved by using well-known non-stabilizing excipients.

[0079] 1D) Orally disintegrating tablets (solid drug dosage form D) The present invention relates to a solid pharmaceutical dosage form for oral administration containing the amorphous form of (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 4 -carboxamide (active ingredient (I)), which is a solid pharmaceutical dosage form that is an orally disintegrating tablet containing the amorphous form of the active ingredient (I) and excipients.

[0080] The present invention relates to a solid pharmaceutical dosage form for oral administration containing the amorphous form of (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-74 - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)), which is an orally disintegrating tablet containing the active ingredient (I) in amorphous form and excipients, and which is prepared without the use of water, organic solvents, or heat.

[0081] The present invention is a solid pharmaceutical dosage form for oral administration, which is an orally disintegrating tablet. a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) At least one lubricant, and c) At least one filler or disintegration accelerator The present invention provides a solid pharmaceutical dosage form containing the above.

[0082] The present invention also provides an orally disintegrating tablet, which is a solid pharmaceutical dosage form for oral administration. a) (4S)-2 in amorphous form in quantities from 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) At least one lubricant in an amount ranging from 2 mg to 30 mg, and c) At least one filler or disintegration accelerator in an amount ranging from 20 mg to 700 mg. The present invention provides a solid pharmaceutical dosage form containing the above.

[0083] The present invention also provides an orally disintegrating tablet, which is a solid pharmaceutical dosage form for oral administration. a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)), b) Magnesium stearate as a lubricant, and c) Sugar alcohol mixtures as fillers or disintegration accelerators The present invention provides a solid pharmaceutical dosage form containing the above.

[0084] Remarkably, an advantage of the present invention is that the amorphous form of the active ingredient (I) can be formulated into orally disintegrating tablets without any stabilization means, while simultaneously exhibiting excellent dissolution behavior, good bioavailability, and excellent disintegration behavior of the active ingredient (I).

[0085] Generally For oral administration, roller-compressed granules containing the amorphous active ingredient (I) can be formulated into solid or liquid preparations such as tablets, sachets, capsules, sugar-coated tablets, chewable tablets, effervescent tablets, dispersible tablets, lozenges, melts, or suspensions, and can be prepared according to methods known in the field of pharmaceutical composition manufacturing.

[0086] The pharmaceutical dosage form according to the present invention is a tablet.

[0087] The pharmaceutical dosage form according to the present invention is an immediate-release tablet.

[0088] The pharmaceutical dosage form according to the present invention is a tablet, in which a mixture of an amorphous active ingredient (I) and an excipient is roller-compressed and crushed together with the excipient to obtain roller-compressed granules, which are then compressed into tablets, which may optionally be coated, preferably the tablets are coated.

[0089] The pharmaceutical dosage form according to the present invention is a tablet, wherein the tablet is based on the direct compression of a mixture of an amorphous active ingredient (I) and an excipient, and the tablet may optionally be coated, preferably the tablet is coated.

[0090] The pharmaceutical dosage form according to the present invention is also an orally disintegrating tablet, in which the tablet is based on the direct compression of a mixture of an amorphous active ingredient (I) and an excipient.

[0091] (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is present in the tablet in an amount of 2 mg to 100 mg, preferably 5 mg to 50 mg, preferably 20 mg to 50 mg, and more preferably 50 mg.

[0092] Solid pharmaceutical dosage forms, particularly solid pharmaceutical dosage forms in the form of tablets, and roller-compressed granules are expected to be stable for long periods of time, and preferably are expected to be stable for long periods of time.

[0093] Solid pharmaceutical dosage forms, particularly solid pharmaceutical dosage forms in the form of tablets, and roller-compressed granules are stable for storage for at least 3 months, preferably at least 6 months, preferably at least 12 months, preferably at least 24 months, preferably at least 30 months, and more preferably at least 48 months.

[0094] Long-term storage means storage for more than 24 months.

[0095] Storage stability means that the product is stable even with a maximum degradation of 10% of the active ingredient (I), preferably a maximum degradation of 3% of the active ingredient (I), and is stable when stored in an amorphous form.

[0096] Storage conditions for evaluating stability include, for example, a sealed container at 25°C / 60% relative humidity, a sealed container at 30°C / 75% relative humidity, an open container at 25°C / 60% relative humidity, or an open container at 40°C / 75% relative humidity (stress conditions).

[0097] The remarkably excellent stability behavior of the solid pharmaceutical dosage form containing active ingredient (I) allows for unprotected packaging of the pharmaceutical dosage form containing active ingredient (I) (e.g., blister packs or high-density polyethylene (HDPE) bottles without desiccants), even under stress conditions (open storage for 6 months at 40°C and 75% relative humidity).

[0098] In relation to the present invention, the immediate-release tablets were prepared in accordance with the European Pharmacopoeia release method using apparatus 2 (paddle), releasing at least 85% of the active ingredient (I) into the release medium after 30 minutes. The rotation speed of the agitator was 75 rpm (revolutions per minute) in 900 ml of release medium.

[0099] According to the present invention, the release medium is acetate buffer pH 4.5 + 0.15% SDS. SDS is an abbreviation for sodium dodecyl sulfate, also known as sodium lauryl sulfate.

[0100] The pharmaceutical dosage form according to the present invention is also an orally disintegrating tablet characterized by disintegration in up to 3 minutes by the European Pharmacopoeia disintegration method using a hard basket rack apparatus with discs. The apparatus was operated at 37+ / -2°C using water as the medium, and at least 85% of the active ingredient (I) was released into the release medium after 30 minutes according to the European Pharmacopoeia release method using apparatus 2 (paddle). The rotation speed of the agitator was 75 rpm (revolutions per minute) in 900 ml of release medium.

[0101] According to the present invention, the release medium is acetate buffer pH 4.5 + 0.15% SDS. SDS is an abbreviation for sodium dodecyl sulfate, also known as sodium lauryl sulfate.

[0102] The present invention further provides for the preparation of an amorphous form of (4S)-2 for solid pharmaceutical dosage forms for oral administration according to the present invention. 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Regarding the use of carboxamide (I).

[0103] The active ingredient (I) is present in an amorphous form in the pharmaceutical dosage form according to the present invention.

[0104] In relation to the present invention, “excipients” are fillers, lubricants, disintegration accelerators, sweeteners, flavoring agents, and colorants. Therefore, it is possible for those skilled in the art to assign similar or even identical substances to two or more members of the above-mentioned group of substances. However, in relation to the present invention, specific substances are intentionally described in the functional descriptions of the substances to clarify the respective properties assigned to them.

[0105] The term "pharmaceutically acceptable" refers to an excipient that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and that has a reasonable benefit-to-risk ratio.

[0106] The fillers that can be used in the formulations according to the present invention are 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 hydrate, e.g., as monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrin, or Pharmaburst®. Preferred fillers are microcrystalline cellulose or lactose or a combination thereof or Pharmaburst®.

[0107] In relation to the present invention, a filler can also be used as a binder.

[0108] The 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 hydrate, e.g., as monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrin, or hypromellose (e.g., hypromellose 3cP). Hypromellose (e.g., hypromellose 3cP) is preferred as the binder.

[0109] Lubricants prevent components from adhering to, for example, manufacturing equipment. Lubricants that can be used in the formulations according to the present invention are selected from the list consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl monostearate, glyceryl monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylene glycol, and talc. Preferred lubricants according to the present invention are selected from the list consisting of magnesium stearate, stearic acid, and talc. Magnesium stearate is very preferred as a lubricant.

[0110] Disintegration accelerators swell and dissolve when wet. They can be used to break down the dosage form in the gastrointestinal tract and release the active ingredient. Suitable disintegration accelerators for the present invention are selected from a list consisting of alginic acid, cross-linked polyvinylpyrrolidone, starch derivatives such as corn starch, modified starch, and 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. Croscarmellose sodium or cross-linked polyvinylpyrrolidone are preferred as disintegration accelerators. Croscarmellose sodium is very preferred as a disintegration accelerator.

[0111] Preferred sweeteners are medically acceptable excipients that have a taste similar to sugar. Suitable sweeteners in relation to the present invention are selected from a list consisting of sucralose, saccharin, sodium saccharin, potassium saccharin or calcium saccharin, acesulfame potassium, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol. In relation to the present invention, the sweetener is added in amounts known to those skilled in the art.

[0112] In relation to the present invention, flavoring agents are pharmaceutically acceptable excipients suitable for improving or imparting a desirable taste to a pharmaceutical dosage form, complementing its effects, and enhancing its flavor. In relation to the present invention, flavoring agents include natural flavor substances obtained from plant or animal raw materials, natural identical flavor substances obtained by synthesis or isolated by chemical processes that are chemically and sensorily identical to naturally occurring flavor substances in products intended for human consumption, and artificial flavor substances. In relation to the present invention, flavoring agents are added in amounts known to those skilled in the art. In relation to the present invention, preferred flavoring agents are selected from a list consisting of synthetic / artificial flavoring agents such as amyl acetate (banana flavoring agent), benzaldehyde (cherry or almond flavoring agent), ethyl butyrate (pineapple), and methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural identical flavoring agents which are flavor substances obtained by synthesis or isolated by chemical processes and whose chemical composition is identical to their natural counterparts. In relation to the present invention, the flavoring agent is added in an amount known to those skilled in the art.

[0113] In relation to the present invention, the colorant is a pharmaceutically acceptable excipient suitable for coloring an uncolored pharmaceutical dosage form, or for enhancing its color, for minimizing batch-to-batch variation, or for replacing an existing color to complement its effect and improve its appearance. It may be any dye, lake, or pigment such as indigo carmine, riboflavin, and titanium dioxide. In relation to the present invention, the colorant is added in amounts known to those skilled in the art.

[0114] With regard to the present invention, any coating may be hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), ethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon® VA64, BASF), shellac, acrylic acid and / or methacrylic acid ester copolymer with trimethylammonium methyl acrylate, copolymer of dimethylaminomethacrylic acid and neutral methacrylic acid ester, polymer of methacrylic acid or methacrylic acid ester, or ethyl acrylate. The process is carried out by adding conventional coating agents and film-forming agents well known to those skilled in the art, such as to-methyl methacrylate copolymer, methyl methacrylate copolymer, propylene glycol, polyethylene glycol (e.g., polyethylene glycol 3350), glycerol triacetate or triethyl citrate, and / or colorants / pigments, such as titanium dioxide, iron oxides (e.g., red iron oxide, yellow iron oxide), indigotine or suitable dye lakes, and / or anti-tack agents such as talc, and / or opacifiers such as titanium dioxide. Preferably, hypromellose and polyethylene glycol are used as optional coating agents and film-forming agents according to the present invention, red iron oxide is preferred as a colorant, and titanium dioxide is preferred as an opacifier. A preferred mixture of coating materials may be about 60% by weight of hydroxypropyl methylcellulose, about 17.5% by weight of yellow iron oxide, about 0.25% by weight of red iron oxide, and about 20% by weight of polyethylene glycol.

[0115] The coating material mixtures described herein can also be used as ready-to-use coating systems, such as those commercially available under the trade name Opadry®. Opadry 14F94373® is a mixture of about 60% by weight hydroxypropyl methylcellulose, about 19.4% by weight titanium dioxide, about 0.6% by weight red iron oxide, and about 20% by weight polyethylene glycol. Ready-to-use coating systems available under the trade name Opadry® are preferred.

[0116] Preferably, the coating is about 0.5% to 10% by weight of the coated tablet formulation, preferably 0.5% to 4.5% by weight, and more preferably about 1.5% to 4.5% by weight of the coated tablet formulation.

[0117] (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) and excipients are present in the solid drug dosage form in a ratio of active ingredient (I) to excipients from 1:0.5 to 1:20. A ratio of active ingredient (I) to excipients from 1:0.5 to 1:10 is preferred, a ratio of active ingredient (I) to excipients from 1:0.5 to 1:5 is also preferred, a ratio of active ingredient (I) to excipients of 1:2 is more preferred, and a ratio of active ingredient (I) to excipients of 1:1.6 is very preferred. In particular, a ratio of active ingredient (I) to excipients of 1:1.6 allows for a high drug content and a small tablet size.

[0118] 2) Method for producing solid pharmaceutical dosage forms This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing a solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)) is provided, without using water, organic solvents, or heat.

[0119] The present invention also relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing an orally administered solid pharmaceutical dosage form containing carboxamide (active ingredient (I)) and further pharmaceutically acceptable excipients is provided, without using water, organic solvents, or heat.

[0120] The present invention also relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing an orally administered solid pharmaceutical dosage form comprising carboxamide (active ingredient (I)) and further pharmaceutically acceptable excipients such as sweeteners, flavoring agents, and coloring agents is provided, the method of which preparation is made without using water, organic solvents, or heat.

[0121] Surprisingly, the manufacturing method that does not use water, organic solvents, or heat is (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4- This enables carboxamide (active ingredient (I)) to remain stable for extended periods in pharmaceutical dosage forms. Furthermore, it eliminates the need for stabilization methods known to those skilled in the art. For example, compared to other formulations using amorphous solid dispersions, a manufacturing method that does not use water, organic solvents, or heat clearly allows for smaller tablet sizes, which on the one hand facilitates swallowing and on the other hand allows for a larger number of tablets per industrial batch.

[0122] 2A) Method for manufacturing roller-compressed granules (solid pharmaceutical dosage form A) This invention relates to (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for producing roller-compressed granules containing carboxamide (active ingredient (I)), i) (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with at least one filler and a portion of the disintegration accelerator, ii) The resulting mixture is roller-compressed, crushed, and iii) Mix the resulting granules with the remaining disintegration accelerator. The present invention provides a method characterized by the following features.

[0123] This invention relates to (4S)-2 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-32 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for producing roller-compressed granules containing carboxamide (active ingredient (I)), i) (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. ii) The resulting mixture is roller-compressed, crushed, and iii) Mix the resulting granules with the remaining croscarmellose sodium. The present invention provides a method characterized by the following features.

[0124] (4S)-2 can be manufactured by one of the above methods. 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Roller-compressed granules containing carboxamide (active ingredient (I)).

[0125] (4S)-2 is manufactured by one of the methods described above. 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-32 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Roller-compressed granules containing carboxamide (active ingredient (I)).

[0126] The roller-compressed granules can be converted into pharmaceutical dosage forms, for example, by tableting, filling into capsules, preferably hard gelatin capsules, or filling into sachets, in any case by following conventional methods well known to those skilled in the art, and, where appropriate, by adding further pharmaceutically suitable excipients.

[0127] 2B) Method for producing immediate-release tablets containing roller-compressed granules (solid pharmaceutical dosage form B) This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing a solid pharmaceutical dosage form containing roller-compressed granules for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with at least one filler and a portion of the disintegration accelerator, ii) The resulting mixture is compressed with rollers and crushed, iii) Mix the obtained granules with the remaining disintegration accelerator, iv) Add the lubricant to the mixture and mix again. v) The immediately compressible mixture obtained is compressed to obtain a rapid-release tablet. vi) The tablets are optionally coated to obtain a pharmaceutical dosage form. The present invention provides a method characterized by the following features.

[0128] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing a solid pharmaceutical dosage form containing roller-compressed granules for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. ii) The resulting mixture is compressed with rollers and crushed, iii) Mix the obtained granules with the remaining croscarmellose sodium, iv) Add magnesium stearate to the mixture and mix again, v) The immediately compressible mixture obtained is compressed to obtain a rapid-release tablet. vi) The tablets are optionally coated to obtain a pharmaceutical dosage form. The present invention provides a method characterized by the following features.

[0129] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing a solid pharmaceutical dosage form containing roller-compressed granules for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. ii) The resulting mixture is compressed with rollers and crushed, iii) Mix the obtained granules with the remaining croscarmellose sodium, iv) Add magnesium stearate to the mixture and mix again, v) The immediately compressible mixture obtained is compressed to obtain a rapid-release tablet. The tablets are optionally coated to obtain a pharmaceutical dosage form. Here, following the release method of the European Pharmacopoeia using device 2 (paddle), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes. The present invention provides a method characterized by the following features.

[0130] Amorphous form of (4S)-2 that can be manufactured by one of the above methods 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid dosage form for oral administration containing carboxamide (active ingredient (I)).

[0131] Amorphous form of (4S)-2 produced by one of the above methods 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A solid dosage form for oral administration containing carboxamide (active ingredient (I)).

[0132] 2C) Method for producing immediate-release tablets based on direct compression (Solid pharmaceutical dosage form C) This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing an immediate-release tablet for oral administration by direct compression, comprising carboxamide (active ingredient (I)), i) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -fluoro-35 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with at least one filler and a portion of the disintegration accelerator, ii) Add the lubricant to the mixture and mix again, iii) The immediately compressible mixture obtained is compressed to obtain immediate-release tablets. iv) Coat immediate-release tablets as desired. The present invention provides a method characterized by the following features.

[0133] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing an immediate-release tablet for oral administration by direct compression, comprising carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. ii) Add magnesium stearate to the mixture and mix again, iii) The immediately compressible mixture obtained is compressed to obtain immediate-release tablets. iv) Coat immediate-release tablets as desired. The present invention provides a method characterized by the following features.

[0134] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for preparing an immediate-release tablet for oral administration by direct compression, comprising carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. ii) Add magnesium stearate to the mixture and mix again, iii) The immediately compressible mixture obtained is compressed to obtain immediate-release tablets. iv) A rapid-release tablet is optionally coated, Here, following the release method of the European Pharmacopoeia using device 2 (paddle), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes. The present invention provides a method characterized by the following features.

[0135] Amorphous form of (4S)-2 that can be manufactured by one of the above methods 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A direct-compression, immediate-release tablet for oral administration containing carboxamide (active ingredient (I)).

[0136] Amorphous form of (4S)-2 produced by one of the above methods 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A direct-compression, immediate-release tablet for oral administration containing carboxamide (active ingredient (I)).

[0137] 2D) Method for manufacturing orally disintegrating tablets (solid drug dosage form D) This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for producing orally disintegrating tablets for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with at least one filler or disintegration accelerator, ii) Add the lubricant to the mixture and mix again, iii) Compress the readily compressible mixture obtained to obtain orally disintegrating tablets. The present invention provides a method characterized by the following features.

[0138] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for producing orally disintegrating tablets for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with a sugar alcohol mixture, ii) Add magnesium stearate to the mixture and mix again, iii) Compress the readily compressible mixture obtained to obtain orally disintegrating tablets. The present invention provides a method characterized by the following features.

[0139] This invention relates to the amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for producing orally disintegrating tablets for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with a sugar alcohol mixture, ii) Add magnesium stearate to the mixture and mix again, iii) The readily compressible mixture obtained is compressed to obtain orally disintegrating tablets. Here, following the release method of the European Pharmacopoeia using device 2 (paddle), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes. The present invention provides a method characterized by the following features.

[0140] This invention relates to the amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - A method for producing orally disintegrating tablets for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide (active ingredient (I)) is first mixed with a sugar alcohol mixture, ii) Add magnesium stearate to the mixture and mix again, iii) The readily compressible mixture obtained is compressed to obtain orally disintegrating tablets. Here, according to the European Pharmacopoeia disintegration method using a hard basket rack apparatus equipped with discs, the disintegration time is a maximum of 3 minutes. The present invention provides a method characterized by the following features.

[0141] The sugar alcohol mixture is a mixture containing mannitol. In addition to mannitol, the sugar alcohol mixture may also contain sorbitol and a disintegrant, such as crospovidone.

[0142] Amorphous form of (4S)-2 that can be manufactured by one of the above methods 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4- An orally disintegrating tablet for oral administration containing carboxamide (active ingredient (I)).

[0143] Amorphous form of (4S)-2 produced by one of the above methods 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - An orally disintegrating tablet for oral administration containing carboxamide (active ingredient (I)).

[0144] Pharmaceuticals and Use Administration of an oral solid dosage form containing an amorphous active ingredient (I) and manufactured by a large-scale industrial process results in high relative bioavailability in humans ranging from 85% to 100%, preferably from 88% to 100%.

[0145] The present invention further provides a pharmaceutical product comprising an oral solid pharmaceutical dosage form according to the present invention, which contains an active ingredient (I).

[0146] The present invention further relates to the use of an orally administered solid pharmaceutical dosage form according to the present invention comprising the active ingredient (I), and to the preparation of a medicament for the treatment and / or prevention of diseases, preferably thrombotic or thromboembolic diseases and / or thromboembolic complications, particularly cardiovascular diseases including coronary artery disease, angina pectoris, myocardial infarction or stent thrombosis, as well as diseases of the cerebrovascular arteries and other diseases leading to transient ischemic attacks (TIAs), ischemic strokes including cardiogenic and non-cardiogenic embolic strokes, and / or peripheral artery diseases including peripheral artery occlusion, acute limb ischemia, amputation, reocclusion and restenosis after interventions such as angioplasty, stent implantation or surgery and bypass, and / or stent thrombosis.

[0147] The present invention further relates to the use of an orally administered solid pharmaceutical dosage form according to the present invention, comprising active ingredient (I), for the prevention, secondary prevention, and / or treatment of diseases, particularly ischemic stroke including myocardial infarction, cardiogenic embolic and non-cardiogenic embolic stroke, acute limb ischemia, reocclusion and restenosis after interventions such as angioplasty, stent implantation or surgery and bypass, and / or stent thrombosis.

[0148] The present invention will be described in detail below with reference to preferred embodiments, but the present invention is not limited to these embodiments. Unless otherwise indicated, all amounts given refer to mg of the dosage form. [Examples]

[0149] Experiment Section Abbreviation: IR tablets: Immediate-release tablets SDS: Also known as sodium dodecyl sulfate or sodium lauryl sulfate.

[0150] rh: relative humidity The term "active component (I) crystal" refers to the active component (I) of crystal transformation I.

[0151] ODT: Orally disintegrating tablets ASD Matrix: Amorphous Solid Dispersion Matrix FeSSIV: Simulated intestinal fluid for feeding status FaSSIV: Fasting state simulated intestinal fluid kN / cm: Kilonewtons / centimeter Dry granulation is used as a synonym for roller compression.

[0152] 1. Preparation of amorphous active ingredient (I) The active ingredient (I) is (4S)-2, also known as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl]phenyl}-5-methoxy-2-oxopyridine-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide. 4 -Chloro-4-ethyl-7 3-fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 -Carboxamide, which can be prepared in amorphous form according to WO2017 / 005725, Examples 234 and 235.

[0153] 2. Release / dissolution method According to the final revision of the European Pharmacopoeia, 10th Edition, Monograph 01 / 2016, oral solid dosage forms are tested using Apparatus 2 (paddle). The agitator rotation speed is 75 rpm (revolutions per minute) in 900 ml of acetate buffer pH 4.5 + 0.15% SDS. The release criterion is met if all six test specimens release at least 85% of the active ingredient (I) into the release medium after a 30-minute investigation period.

[0154] 3. Method for producing immediate-release tablets based on amorphous solid dispersions (comparative example) Example 1 The pharmaceutical dosage form (tablet) of Example 1 is manufactured by dissolving a solid dispersion base and active ingredient (I) in an organic solvent. During the fluidized bed granulation process, this solution is sprayed as a granulation liquid onto the initial charge of the disintegration accelerator (carrier). After drying and sieving, granules are obtained. The organic solvent may be ethanol, acetone, or a combination thereof. The obtained granules are mixed together with the added disintegration accelerator. Then, a lubricant is added to the mixture and mixed again. The resulting readily compressible mixture is compressed to produce tablets. The tablets can then be coated with a pigment suspended in an aqueous solution consisting of a coating agent and a film-forming agent. In the tablets, the active ingredient (I) is present in an amount of 50 mg.

[0155] 4. Method for producing immediate-release tablets by direct compression Example 2 The pharmaceutical dosage form (tablet) of Example 2 is manufactured by mixing the active ingredient (I) with microcrystalline cellulose, lactose, and croscarmellose sodium. A lubricant is then added to the mixture and mixed again. The resulting readily compressible mixture is compressed to produce tablets. The tablets can then be coated with a pigment suspended in an aqueous solution consisting of a coating agent and a film-forming agent. In the tablets, the active ingredient (I) is present in an amount of 50 mg.

[0156] Example 4 The pharmaceutical dosage form (tablet) of Example 4 is prepared by mixing the active ingredient (I) with a sugar alcohol mixture. A lubricant is then added to the mixture and mixed again. The resulting readily compressible mixture is compressed to produce tablets. The tablets can then be coated with a pigment suspended in an aqueous solution consisting of a coating agent and a film-forming agent. In the tablets, the active ingredient (I) is present in an amount of 50 mg.

[0157] 5. Method for preparing immediate-release tablets based on dry granulation and compression. Example 3 The pharmaceutical dosage form (tablet) of Example 3 is manufactured by mixing the active ingredient (I) with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. The mixture is then roller-compressed and pulverized. The resulting granules are mixed with the remaining croscarmellose sodium. A lubricant is then added to the mixture and mixed again. The resulting readily compressible mixture is compressed to produce tablets. The tablets can then be coated with a pigment suspended in an aqueous solution consisting of a coating agent and a film-forming agent. In the tablets, the active ingredient (I) is present in an amount of 50 mg.

[0158] 6. Method for producing roller-compressed granules Example 5 The pharmaceutical dosage form (granules) of Example 5 is prepared by mixing the active ingredient (I) with microcrystalline cellulose, lactose, and croscarmellose sodium. The blend is then roller-compressed and pulverized to obtain roller-compressed granules. In the roller-compressed granules, the active ingredient (I) is present in an amount of 50 mg per 99 mg final granules.

[0159] Composition of the dosage form at 7 mg / dosage form Example 1 (Comparative Example) : (4S)-2 based on amorphous solid dispersion 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Immediate-release tablets of carboxamide (active ingredient (I)) [Table 1]

[0160] a) The solvent is quantitatively removed during the manufacturing process; b) The tablets may optionally be coated.

[0161] Example 2: (4S)-2 based on direct compression 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Immediate-release tablets of carboxamide (active ingredient (I)) [Table 2]

[0162] a) The tablets may be optionally coated.

[0163] Example 3: (4S)-2 based on dry granulation 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Immediate-release tablets of carboxamide (active ingredient (I)) [Table 3]

[0164] a) Inside the granules; b) Outside the granules; c) The tablets may be optionally coated.

[0165] Example 4: (4S)-2 based on direct compression 4 -Chloro-4-ethyl-7 3 -fluoro-3 5 -Methoxy-3 2 ,5-Dioxo-1 4 -(trifluoromethyl)-3 2 H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Immediate-release tablets of carboxamide (active ingredient (I)) [Table 4]

[0166] a) These materials are also available from SPI Pharma under the trade name Pharmaburst, e.g., Pharmaburst C1, Pharmaburst B1, and Pharmaburst B2. Pharmaburst contains spray-dried mannitol and sorbitol and may further contain disintegrants such as crospovidone.

[0167] The sugar alcohol mixture described in Example 4 is a mixture containing mannitol and sorbitol, and may further contain a disintegrant such as crospovidone.

[0168] Example 5: (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 4 - Roller-compressed granules of carboxamide (active ingredient (I)) [Table 5]

[0169] 8. Bioavailability, dissolution, disintegration and consequences 8.1 Bioavailability To investigate bioavailability, a pharmaceutical dosage form containing the active ingredient (I) is administered orally to animals. Blood samples are collected from the test animals. Pharmacokinetic parameters such as the area under the curve (AUC) and maximum concentration (Cmax) are determined after oral administration. Further corresponding pharmacokinetic parameters after oral administration are calculated. The primary pharmacokinetic parameters, clearance (CL) and volume of distribution (Vss), are calculated as follows:

[0170] [Table 6]

[0171] 8.2 Melting By using manufacturing techniques such as direct compression (Example 2) or dry granulation (Example 5) followed by tablet compression (Example 3), dissolution results comparable to the amorphous solid dispersion from Example 1 could be achieved. In all examples, at least 85% of the active ingredient (I) was released into the release medium after 30 minutes. In addition, both techniques (Examples 2 and 3) can significantly reduce the disintegration time from 13 minutes in Example 1 to 2 minutes in Examples 2 and 3. To increase patient compliance and thus improve the clinical efficacy of the treatment, the tablet size can be significantly reduced from a 12 × 6 mm oval in Example 1 to a 7 mm circular in Examples 2 and 3 to facilitate swallowing.

[0172] In Example 4, an orally disintegrating tablet formulation is shown. In this example, comparable dissolution results to the amorphous solid dispersion in Example 1 were achieved. Example 4 released at least 85% of the active ingredient (I) into the release medium after 30 minutes. This technique benefits from the fact that no fluid is required for tablet administration. The tablets disintegrate directly in the mouth in less than one minute, thus facilitating both tablet swallowing and patient compliance.

[0173] Examples 2, 3, 4, and 5 were prepared without the use of water, organic solvents, or heat, and the active ingredient (I) exists in an amorphous and stable form. This makes the process suitable for large-scale industrial applications while simultaneously demonstrating a sustainable manufacturing process for the global environment. By eliminating the use of organic solvents, assuming a currently projected annual requirement of approximately 50 tons of active ingredient (I), approximately 300 tons of organic solvents can be saved annually. Therefore, the newly developed formulations in Examples 2-5 clearly improve the sustainability aspects of the product, with the energy-saving process that does not use heat also contributing to this improvement.

[0174] 8.3 Method of Collapse According to the final revision of the European Pharmacopoeia, 10th Edition, Monograph 01 / 2020, oral solid dosage forms are tested using a rigid basket rack apparatus. Six test specimens are placed individually in tubes in the basket, and discs are added. The apparatus is operated using water as the medium at 37+ / -2°C.

[0175] Table 1: Comparison of tablet characteristics in Examples 1-4 [Table 7]

[0176] 9. Solubility The solubility of the active ingredient (I) in amorphous and crystalline forms was determined in different solvents. The results are shown in Table 2.

[0177] Table 2: Solubility of the active ingredient (I) in amorphous and crystalline forms in different solvents [Table 8]

Claims

1. Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - A solid pharmaceutical dosage form for oral administration containing carboxamide (active ingredient (I)), wherein the dosage form is A) Roller-compressed granules obtained by roller-compressing and grinding a mixture of an amorphous active ingredient (I) and an excipient, or B) A mixture of an amorphous active ingredient (I) and an excipient is roller-compressed to obtain roller-compressed granules, which are then compressed to form immediate-release tablets, or C) A rapid-release tablet based on the direct compression of a mixture of an amorphous active ingredient (I) and an excipient, or D) An orally disintegrating tablet containing an amorphous active ingredient (I) and an excipient. The solid pharmaceutical dosage form characterized by the above.

2. A) solid pharmaceutical dosage form for oral administration according to claim 1, a) (4S)-2 in amorphous form ４ -chloro-4-ethyl-7 ３ -fluoro-3 ５ -methoxy-3 ２ ,5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 ４ -carboxamide (active ingredient (I)), b) At least one disintegration accelerator, and c) At least one filler (Including the aforementioned solid drug dosage form A).

3. A solid pharmaceutical dosage form B) or C) for oral administration according to claim 1, d) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - Carboxamide (active ingredient (I)), e) At least one lubricant, f) At least one decay accelerator, and g) At least one filler Including the solid pharmaceutical dosage form B) or C).

4. A solid pharmaceutical dosage form D) for oral administration according to claim 1, a) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - Carboxamide (active ingredient (I)), b) At least one lubricant, and c) At least one filler or disintegration accelerator Including the aforementioned solid pharmaceutical dosage form D).

5. A solid pharmaceutical dosage form for oral administration according to any one of claims 1 to 4, characterized in that at least 85% of the active ingredient (I) is released into the release medium after 30 minutes, according to the release method of the European Pharmacopoeia using device 2 (paddle).

6. a) (4S)-2 in amorphous form in quantities ranging from 2 mg to 100 mg ４ -Chloro-4-ethyl-7 ３ -Fluoro-3 ５ - Methoxy-3 ２ , 5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - Carboxamide (active ingredient (I)), b) At least one disintegration accelerator in an amount ranging from 2 mg to 100 mg, and c) At least one filler in an amount ranging from 2 mg to 150 mg A solid pharmaceutical dosage form for oral administration, consisting of roller-compressed granules containing the above.

7. a) (4S)-2 in amorphous form in quantities ranging from 2 mg to 100 mg ４ -Chloro-4-ethyl-7 ３ -Fluoro-3 ５ - Methoxy-3 ２ , 5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - Carboxamide (active ingredient (I)), b) At least one lubricant in an amount ranging from 0.5 mg to 7 mg, c) At least one disintegration accelerator in an amount ranging from 2 mg to 100 mg, and d) At least one filler in an amount ranging from 2 mg to 150 mg A solid pharmaceutical dosage form for oral administration, which is an immediate-release tablet containing roller-compressed granules.

8. a) (4S)-2 in amorphous form in quantities ranging from 2 mg to 100 mg ４ -Chloro-4-ethyl-7 ３ -Fluoro-3 ５ - Methoxy-3 ２ , 5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - Carboxamide (active ingredient (I)), b) At least one lubricant in an amount ranging from 0.5 mg to 7 mg, c) At least one disintegration accelerator in an amount ranging from 2 mg to 100 mg, and d) At least one filler in an amount ranging from 2 mg to 150 mg A solid pharmaceutical dosage form for oral administration, which is a direct-compression, immediate-release tablet containing [the specified ingredient].

9. a) (4S)-2 in amorphous form in quantities ranging from 2 mg to 100 mg ４ -Chloro-4-ethyl-7 ３ -Fluoro-3 ５ - Methoxy-3 ２ , 5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - Carboxamide (active ingredient (I)), b) At least one lubricant in an amount ranging from 2 mg to 30 mg, and c) At least one filler or disintegration accelerator in an amount ranging from 20 mg to 700 mg. A solid pharmaceutical dosage form for oral administration, which is an orally disintegrating tablet containing [ingredient name].

10. (4S)-2 in amorphous form according to any one of claims 1 to 8, prepared without the use of water, organic solvents, or heat. ４ -Chloro-4-ethyl-7 ３ -Fluoro-3 ５ - Methoxy-3 ２ , 5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - A solid dosage form for oral administration containing carboxamide (active ingredient (I)).

11. (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - A method for preparing roller-compressed granules containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ -Carboxamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. ii) The obtained mixture is roller-compressed, crushed, and iii) Mix the obtained granules with the remaining croscarmellose sodium. The method characterized by the above.

12. Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - A method for preparing a solid pharmaceutical dosage form containing carboxamide (active ingredient (I)) in the form of roller-compressed granules for oral administration, i) (4S)-2 in amorphous form ４ -chloro-4-ethyl-7 ３ -fluoro-3 ５ -methoxy-3 ２ ,5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 ４ -carboxamide (active ingredient (I)) is first mixed together with a part of microcrystalline cellulose, lactose and croscarmellose sodium, ii) The resulting mixture is rolled and crushed, iii) Mix the obtained granules with the remaining croscarmellose sodium, iv) Add magnesium stearate to the mixture and mix again, v) The immediately compressible mixture obtained is compressed to obtain a rapid-release tablet. vi) Obtain a pharmaceutical dosage form by optionally coating the tablets. The method characterized by the above.

13. The amorphous form of (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(4,1)-pyridina-1(1)-[1,2,3]triazola-2(1,2),7(1)-dibenzenaheptafan-7 ４ -carboxamide (active ingredient (I)), a method for preparing an immediate-release tablet based on direct compression for oral administration, comprising i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ -Carboxamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. ii) Add magnesium stearate to the mixture and mix again, iii) The immediately compressible mixture obtained is compressed to obtain a rapid-release tablet. iv) Coat immediate-release tablets as desired. The method characterized by the above.

14. Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - A method for preparing orally disintegrating tablets for oral administration containing carboxamide (active ingredient (I)), i) Amorphous form of (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(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ -Carboxamide (active ingredient (I)) is first mixed with a sugar alcohol mixture, ii) Add magnesium stearate to the mixture and mix again, iii) Compress the readily compressible mixture obtained to obtain orally disintegrating tablets. The method characterized by the above.

15. Amorphous form of (4S)-2 produced by the method described in any one of claims 10 to 14 ４ -Chloro-4-ethyl-7 ３ -Fluoro-3 ５ - Methoxy-3 ２ , 5-dioxo-1 ４ -(trifluoromethyl)-3 ２ H-6-Aza-3(4,1)-Pyridina-1(1)-[1,2,3]Triazola-2(1,2),7(1)-Dibenzenaheptaphan-7 ４ - A solid dosage form for oral administration containing carboxamide (active ingredient (I)).

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