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

Abstract

The present invention relates to a solid pharmaceutical dosage form for oral administration, comprising (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32, 5-dioxo-14-(trifluoromethyl)-32H-6-aza-3 (4, 1)-pyridine-1 (1)-[1, 2, 3] triazole-2 (1, 2), 7 (1)-dibenzaheptaphane-74-carboxamide (active ingredient (I)), and a pharmaceutically acceptable salt thereof. The active ingredient (I) is present in amorphous form and is released immediately from a solid pharmaceutical dosage form for oral administration, and to a method for the production thereof, to the use thereof as a medicament, and to the use thereof for the treatment and / or prophylaxis of diseases, in particular diseases, such as diseases. Use in particular for cardiovascular disorders, preferably thrombotic or thromboembolic disorders and oedema and ocular disorders

Description

[0001] This invention relates to solid pharmaceutical dosage forms for oral administration, comprising (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that the active ingredient (I) exists in an amorphous form and is immediately released from a solid pharmaceutical dosage form for oral administration, and also relates to its preparation method, 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.

[0002] Active ingredient (I), (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 2-Formamide, also known as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butyryl}amino)-2-fluorobenzamide, is known from WO 2017 / 005725 and has the following formula:

[0003]

[0004] The active ingredient (I) is used as a factor XIa inhibitor and, due to its specific mechanism of action, can be used, after oral administration, to treat and / or prevent conditions, preferably thrombotic or thromboembolic conditions and / or thrombotic or thromboembolic complications, particularly cardiovascular conditions (including coronary artery disease, angina pectoris, myocardial infarction, or in-stent thrombosis), as well as cerebrovascular artery conditions and other conditions that lead to transient ischemic attacks (TIAs), ischemic stroke (including cardiogenic and non-cardiogenic strokes), and / or peripheral artery conditions that lead to peripheral artery disease (including peripheral artery occlusion, acute limb ischemia, amputation, interventional procedures such as angioplasty, stent implantation, or re-occlusion and restenosis after surgery and bypass surgery), and / or in-stent thrombosis.

[0005] To develop a solid drug dosage form for oral administration, the active ingredient (I), (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide, used in amorphous form.

[0006] For diseases requiring long-term treatment or for long-term disease prevention, it is desirable to maintain the lowest possible frequency of drug administration and the smallest possible tablet size. This is not only more convenient for patients but also improves treatment reliability by reducing the disadvantages of irregular dosing (improving adherence). To improve adherence, especially in elderly patients, tablets should be as small as possible, i.e., have a high concentration of the active ingredient, particularly regarding higher dose strength.

[0007] During the research and development process, it was discovered that the amorphous form of the active ingredient (I) has poor solubility in water. Oral administration of poorly soluble active ingredients often presents problems, resulting in insufficient bioavailability of the active ingredient (I). Oral solid dosage forms (e.g., tablets) should provide near-immediate release of almost all of the active ingredient (I) and offer adequate dissolution properties. Solid dosage forms should also possess the excellent characteristics of being able to be manufactured on an industrial scale to meet the needs of a large number of patients, while employing sustainable manufacturing methods.

[0008] 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 readily revert to a crystalline form during storage. The mechanical properties and vapor adsorption characteristics of amorphous systems can differ significantly from those of crystalline materials, and amorphous drugs may be more chemically reactive. By definition, amorphous forms are metastable relative to crystalline materials, thus amorphous drugs readily revert to a crystalline form over time. Predicting the time range involved is obviously important but may be difficult to achieve. It has been shown that amorphous drugs may degrade faster than crystalline materials. [Craig et al., Thelevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze-dried systems. International Journal of Pharmaceutics 179(1999)179-207].

[0009] The problem related to the physical and chemical stability of amorphous drugs and systems is why amorphous methods are generally not adopted without stabilization measures.

[0010] In addition to creating lyophilized systems—in which the amorphous form of drugs (and excipients) can be stabilized—the creation of so-called amorphous solid dispersions (ASDs) is also well known as a stabilizing measure for original amorphous materials as well as formerly crystalline materials, and especially for oral dosage forms.

[0011] Even though these stabilized systems exhibit limitations in physical and chemical stability [Serajuddin published 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], developing amorphous drug formulations remains a challenging and significant undertaking (e.g., bioavailability, physical stability, chemical stability, and preparation). The challenges are even greater when developing amorphous drugs and processing them via direct tableting.

[0012] Currently, only a few attempts have been made to develop stable oral dosage forms containing amorphous drugs prepared by direct compression.

[0013] Sun et al. loaded amorphous active pharmaceutical ingredients / drugs onto mesoporous silica. Thus, a robust formulation with good content uniformity, manufacturability, physical stability, and dissolution rate was obtained. [Sun et al. published in: International Journal of Pharmaceutics. 539(1-2)(2018) 184-189].

[0014] DE 10 2010 005 124 A1 describes a solid oral dosage form prepared by direct tableting, comprising amorphous lecanidipine and a hydrogel agent (i.e., hydroxypropyl methylcellulose) added as a stabilizing excipient.

[0015] WO 2009 / 138224 discloses a pharmaceutical composition comprising drosperinone in a substantially amorphous form and a carrier selected from hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), or microcrystalline cellulose (MCC), wherein the drosperinone and the carrier are present in a co-milled state. The amorphous form of the drug can be stabilized by co-milling different drosperinone and carrier particles to form a two-phase system.

[0016] WO 2022 / 189278 describes an amorphous solid dispersion (ASD) and a solid drug dosage form for oral administration, comprising (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide.

[0017] The most relevant techniques for preparing stable amorphous drugs (in so-called amorphous solid dispersions (ASDs)) are based on two main distinct methods: solvent evaporation and melting. Some mechanical methods, such as ball milling or grinding, can also induce a degree of amorphization. [Breitenbach, European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107-117]. All these techniques share the commonality of being energy-intensive, costly, and / or posing ecological and hazard risks. Amorphous solid dispersions use specific carriers to amorphize and stabilize the drug in a solid state. Adding additional stabilizing excipients leads to increased tablet weight and size, which is known to negatively impact patient adherence. Furthermore, it is worth noting that amorphous materials in ASDs eventually revert to their crystalline form, albeit slowly. [Ma, Journal of Drug Delivery Science and Technology 50 (2019) 113-124]. Furthermore, when ASD is exposed to humid environments (e.g., stored under high humidity conditions), the presence of water significantly increases drug flowability and reduces the polymer's ability to inhibit recrystallization. Therefore, drug dosage forms containing ASD may require additional moisture-proofing measures, such as special coatings and / or the use of specialized product packaging materials that act as a moisture barrier or desiccant. For example, lopinavir and ritonavir are combined in fixed-dose tablets. Etravirin tablets are provided in a form coated with a polyvinyl alcohol polymer that protects the active ingredient from moisture, oxygen, and other environmental factors. It needs to be sold in bottled form, with each bottle containing three desiccant packets to keep the tablets dry.

[0018] Solid drug dosage forms prepared by tableting can optionally be rolled. Since many materials are not suitable for direct tableting, a granulation step is usually performed before tableting. Dry granulation of compacted materials after rolling is a common method for preparing granules besides wet granulation, and it is becoming increasingly important in the pharmaceutical industry. [Mosig published in: Powder Technology 266(2014)156-166].

[0019] This method is suitable for granulation of materials sensitive to moisture and heat. It is environmentally friendly, requires no solvent removal, and is easily scalable.

[0020] One major advantage is the continuous production of particles, which reduces costs.

[0021] However, compared with other granulation techniques, the resulting tablets have lower tensile strength. This is due to the limited binding potential, which is partially consumed in the first compression step. [Herting published in: International Journal of Pharmaceutics 338(2007)110-118].

[0022] Orally disintegrating tablets (ODTs) are a special type of tablet. They are attractive to many patient populations, such as the elderly who have difficulty swallowing these formulations, children, and patients with intellectual disabilities, uncooperative treatment, nausea, or those who need to restrict fluid intake / diet. Those who are traveling or have difficulty accessing water are also affected. To meet these medical needs, pharmaceutical engineers have developed a new oral dosage form called orally disintegrating tablets (ODTs), which typically disintegrate rapidly in saliva within seconds without the need for water. Drug dissolution and absorption, as well as clinical onset time and drug bioavailability, can be significantly higher than those observed with conventional dosage forms. [Hirani published in: Tropical Journal of Pharmaceutical Research, April 2009, 8(2), 161-172].

[0023] ODTs can be prepared using various methods, such as lyophilization, molding, and sublimation, using sugar filament systems or direct compression. Direct compression is convenient and cost-effective, but it is highly dependent on the active pharmaceutical ingredient (API) and the properties of the excipients used (e.g., flowability, compressibility, and compaction). Therefore, excipients with excellent compaction properties should be preferred. Excipients used in ODTs must be selected based on material properties (plastic, elastic, or brittle) and desired functions (e.g., well-defined particle size distribution, good flowability, enhanced compaction, or rapid disintegration). Mannitol is a commonly used excipient in fast-dissolving pharmaceutical formulations. However, when used as an untreated powder, poor flowability, cohesiveness, and insufficient compaction are limiting factors. Therefore, excipients co-processed with mannitol are an option. Co-processing refers to the interaction of two or more excipients at the subparticle level due to co-spray drying, co-spray agglomeration, or co-granulation, thereby improving functionality. [Published by Stoltenberg in: Eur. J. Pharm. Biopharm. 78 (2011) 662-669]. The co-processed mannitol used in this invention is sold under various trade names, for example... However, mannitol is known to induce amorphous drug crystallization even when stabilized in amorphous spray-dried dispersions. [Leane published in: Drug Dev Tech 18(2)(2013)359-366]. It has been shown in the literature that excipients such as mannitol can affect the polymorphic transformation during wet granulation, thus there is indeed a possibility that excipients can cause physical instability. Therefore, co-processed excipient systems containing mannitol (e.g., This can induce crystallization of amorphous drugs in drug formulations, especially when prepared without any stabilization measures.

[0024] Furthermore, literature indicates that tablet compression can cause phase separation, which is particularly important when it leads to the separation of the amorphous phase of amorphous drugs and ultimately instability, as described in [Ayenew published in: European Journal of Pharmaceutics and Biopharmaceutics 81(2012)207-213].

[0025] Some orally disintegrating formulations are hygroscopic and cannot maintain their physical integrity under normal temperature and humidity conditions. Therefore, they require moisture protection, which necessitates specialized product packaging. [Hirani, published in: Tropical Journal of Pharmaceutical Research, April 2009, 8(2), 161-172]. As mentioned above, hygroscopicity is a factor that increases the risk of amorphous drugs transforming into their crystalline form.

[0026] Therefore, the objective of this development project is to provide a solid drug dosage form for oral administration, comprising (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4-Formamide (active ingredient (I)), wherein the active ingredient (I) exists in an amorphous form, and this oral solid dosage form exhibits excellent dissolution properties and good bioavailability. The solid dosage form should also possess the excellent characteristic of being able to be prepared on an industrial scale. Furthermore, the amorphous form of the active ingredient (I) in the solid dosage form should be stable during long-term storage. Crystallization must be prevented under all circumstances, as crystallization of the active ingredient (I) leads to a decrease in dissolution rate and a reduction in the bioavailability of the active ingredient (I).

[0027] Surprisingly, a solid drug dosage form can be prepared without the use of water, organic solvents, or heating, in which the active ingredient (I) exists in an amorphous form and remains stable. This solid drug dosage form exhibits excellent dissolution properties and good bioavailability, as well as excellent tablet characteristics, thanks to its large-scale industrial preparation method, which can also be used for continuous preparation without individual batches if needed, while also being sustainable.

[0028] Surprisingly, in this invention, although it can be rolled, it still exhibits excellent tablet properties (including tablet hardness).

[0029] Surprisingly, the present invention describes a pharmaceutical dosage form prepared by a method not based on solvent evaporation or melting, wherein the amorphous drug contained therein is chemically and physically stable over a long period of time.

[0030] Surprisingly, the present invention describes a pharmaceutical dosage form provided as an orally disintegrating tablet (ODT) prepared by compression and containing mannitol, wherein the contained amorphous drug is chemically and physically stable over a long period of time.

[0031] Solid dosage forms for oral administration, comprising amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that the dosage form is

[0032] A) Roll-pressed granules, which are obtained by rolling and grinding a mixture of amorphous active ingredient (I) and excipients, or

[0033] B) Immediate-release tablets, wherein a mixture of amorphous active ingredient (I) and excipients is rolled and ground together with the excipients to obtain rolled granules, which are then compressed into immediate-release tablets, or

[0034] C) Immediate-release tablets, which are based on the direct compression of a mixture of amorphous active ingredient (I) and excipients into tablets, or

[0035] D) Oral dispersible tablets containing an amorphous form of active ingredient (I) and excipients.

[0036] Solid dosage forms for oral administration, comprising amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that the dosage form is

[0037] A) Roll-pressed granules, which are obtained by rolling and grinding a mixture of amorphous active ingredient (I) and excipients, or

[0038] B) Immediate-release tablets, wherein a mixture of amorphous active ingredient (I) and excipients is rolled and ground together with the excipients to obtain rolled granules, which are then compressed into immediate-release tablets, or

[0039] C) Immediate-release tablets, which are based on the direct compression of a mixture of amorphous active ingredient (I) and excipients into tablets, or

[0040] D) Oral dispersible tablets containing amorphous active ingredient (I) and excipients.

[0041] According to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0042] Solid drug dosage forms based on direct compression and their preparation methods are known.

[0043] The most common challenges in preparing solid drug dosage forms containing an amorphous active ingredient (I) are the required drug-to-excipient ratio to promote the desired release rate and bioavailability, and the selection of a suitable preparation method and scaling up to ensure the physical and chemical stability of the amorphous active ingredient (I) while enabling large-scale industrial production.

[0044] Furthermore, specific preparation methods that do not require the use of water, organic solvents, or heating can produce solid drug dosage forms for oral administration in the form of rolled granules or tablets (with good tablet hardness and low brittleness, enabling large-scale industrial tablet production), containing (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)). This solid dosage form is highly robust against changes in the preparation method during operation and technology transfer, and therefore the properties of this solid dosage form are not affected.

[0045] Surprisingly, it has been found that, according to the present invention, immediate-release tablets containing an amorphous form of active ingredient (I) prepared without the use of water or organic solvents or heating exhibit excellent dissolution properties and good bioavailability of active ingredient (I), as well as the excellent characteristics that allow for the industrial-scale preparation of solid drug dosage forms to meet the needs of a large number of patients, and that, if necessary, can be prepared continuously without separate batches, while using sustainable preparation methods.

[0046] This invention provides a method in which the active ingredient (I) is used in an amorphous form and mixed with other excipients. The mixture is then rolled. 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 can be used directly as granules or for preparing tablets. The tablets may optionally be coated.

[0047] The methods and excipients selected in this invention differ in some respects from those known to those skilled in the art and commonly used to prepare immediate-release tablets containing an amorphous active ingredient (I) without the use of water or organic solvents or heating.

[0048] 1) Solid drug dosage form

[0049] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-32 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) can be prepared without the use of water or organic solvents or heating.

[0050] The present invention also provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 - Formamide (active ingredient (I)) and other pharmaceutically acceptable excipients, which are prepared without the use of water or organic solvents or heating.

[0051] The present invention also provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 - Formamide (active ingredient (I)) and other pharmaceutically acceptable excipients (e.g., sweeteners, flavorings and colorants) can be prepared without the use of water or organic solvents or heating.

[0052] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4- Formamide (active ingredient (I)) is prepared without the use of water or organic solvents or heating, wherein, according to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0053] This invention provides a solid pharmaceutical dosage form A) for oral administration, comprising:

[0054] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0055] b) at least one disintegration promoter, and

[0056] c) At least one filler.

[0057] The present invention also provides a solid pharmaceutical dosage form A) for oral administration, comprising:

[0058] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0059] b) at least one disintegration promoter, and

[0060] c) At least one filler

[0061] According to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0062] This invention provides a solid pharmaceutical dosage form B) or C) for oral administration, comprising...

[0063] d) Amorphous (4S)-2 4 -Chloro-4-ethyl-73 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0064] e) At least one lubricant

[0065] f) at least one disintegration promoter, and

[0066] g) At least one filler.

[0067] The present invention also provides a solid pharmaceutical dosage form B) or C) for oral administration, comprising

[0068] d) Amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0069] e) At least one lubricant

[0070] f) at least one disintegration promoter, and

[0071] g) At least one filler,

[0072] According to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0073] This invention provides a solid pharmaceutical dosage form (D) for oral administration, comprising:

[0074] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0075] b) at least one lubricant, and

[0076] c) At least one filler or disintegration promoter.

[0077] This invention provides a solid pharmaceutical dosage form (D) for oral administration, comprising:

[0078] h) Amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0079] i) at least one lubricant, and

[0080] j) At least one filler or disintegration promoter.

[0081] According to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0082] This invention provides a solid pharmaceutical dosage form (D) for oral administration, comprising:

[0083] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0084] b) at least one lubricant, and

[0085] c) At least one filler or disintegration accelerator.

[0086] According to the disintegration method of the European Pharmacopoeia using a rigid basket device with a disc, the disintegration time is up to 3 minutes.

[0087] 1A) Roller-pressed granules (solid drug dosage form A)

[0088] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), which is roll-pressed granules obtained by rolling and grinding a mixture of amorphous active ingredient (I) and excipients.

[0089] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is a rolled particle obtained by rolling and grinding a mixture of amorphous active ingredient (I) and excipients without the use of water or organic solvents or heating.

[0090] This invention provides a solid drug dosage form for oral administration, which is a rolled granule containing...

[0091] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0092] b) at least one disintegration promoter, and

[0093] c) At least one filler.

[0094] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is a rolled granule containing...

[0095] a) Amorphous form of (4S)-2 in concentrations of 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0096] b) At least one disintegration promoter in a concentration of 2 mg to 100 mg, and

[0097] c) At least one filler with a content of 2 mg to 150 mg.

[0098] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is a rolled granule containing...

[0099] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0100] b) Croscarmellose sodium as a disintegration promoter, and

[0101] c) Microcrystalline cellulose and lactose as fillers.

[0102] Overall, the advantage of granulation by rolling is the improved flowability of the granules compared to the initial powder mixture. Literature indicates that tableting can cause stratification, which is particularly important when it leads to amorphous phase separation and ultimately instability of the amorphous drug form, as described by Ayenew (see above).

[0103] The advantage of this invention is that the mixture can be rolled without losing its excellent dissolution properties and good bioavailability of the active ingredient (I). Furthermore, tableting of the mixture reduces the risk of uneven distribution of the amorphous active ingredient (I) in solid drug dosage forms.

[0104] Surprisingly, the amorphous active ingredient (I) is long-term stable in rolled granules containing well-known standard excipients without the need for any stabilizers (e.g., polymers or gelling agents in the ASD matrix as described above).

[0105] To ensure excellent dissolution properties, the roller pressure [kN / cm] and gap [mm] must be strictly controlled during the rolling process. The roller pressure is preferably between 0.1 and 5.0 kN / cm, and the gap between 1.0 and 6.0 mm. Preferably, a smaller gap results in a lower roller pressure, and a larger gap results in a higher roller pressure. The most preferred roller pressure is 2 kN / cm and the gap is 3 mm.

[0106] Roll pressing is not a known method for stabilizing amorphous active ingredients. Therefore, surprisingly, roll pressing has been shown to be suitable for preparing solid drug dosage forms in which the amorphous active ingredient (I) is long-term stable.

[0107] 1B) Immediate-release tablets containing rolled granules (solid drug dosage form B)

[0108] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), which is an immediate-release tablet, wherein a mixture of amorphous active ingredient (I) and excipients is rolled and ground together with the excipients to obtain rolled particles, which are then compressed into immediate-release tablets.

[0109] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), which is an immediate-release tablet, wherein a mixture of amorphous active ingredient (I) and excipients is rolled and ground together with the excipients to obtain rolled particles, which are then compressed into immediate-release tablets, and its preparation does not require the use of water or organic solvents or heating.

[0110] This invention provides a solid pharmaceutical dosage form for oral administration, which is an immediate-release tablet containing rolled particles, comprising...

[0111] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0112] b) At least one lubricant

[0113] c) at least one disintegration promoter, and

[0114] d) At least one filler.

[0115] This invention also provides a solid pharmaceutical dosage form for oral administration, which is an immediate-release tablet containing rolled particles, comprising...

[0116] a) Amorphous form of (4S)-2 in concentrations of 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0117] b) At least one lubricant in a concentration of 0.5 mg to 7 mg.

[0118] c) at least one disintegration promoter in a concentration of 2 mg to 100 mg, and

[0119] d) At least one filler with a content of 2 mg to 150 mg.

[0120] This invention also provides a solid pharmaceutical dosage form for oral administration, which is an immediate-release tablet containing rolled particles, comprising...

[0121] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0122] b) Magnesium stearate as a lubricant.

[0123] c) Crosslinked carboxymethyl cellulose sodium as a disintegration promoter, and

[0124] d) Microcrystalline cellulose and lactose as fillers.

[0125] Overall, the advantage of granulation by rolling is the improved flowability of the granules compared to the initial powder mixture. Literature indicates that tableting can cause stratification, which is particularly important when it leads to amorphous phase separation and ultimately instability of the amorphous drug form, as described by Ayenew (see above).

[0126] It is clear from the literature that rolling solid drug dosage forms often suffer from reduced final tablet hardness or slower dissolution performance. The advantage of this invention is that the mixture can be rolled without sacrificing its excellent dissolution performance, good bioavailability of the active ingredient (I), and excellent tableting characteristics. The resulting tablets exhibit excellent tablet hardness. Furthermore, the tableting of the mixture reduces the risk of uneven distribution of amorphous active ingredient (I) in solid drug dosage forms.

[0127] Surprisingly, the amorphous form of the active ingredient (I) is long-term stable in the roll-formed granule-based tablet. The tablet contains only well-known standard excipients and no stabilizers (e.g., polymers or gelling agents in the ASD matrix as described above).

[0128] To ensure excellent dissolution properties, the roller pressure [kN / cm] and gap [mm] must be strictly controlled during the rolling process. The roller pressure is preferably between 0.1 and 5.0 kN / cm, and the gap between 1.0 and 6.0 mm. Preferably, a smaller gap results in a lower roller pressure, and a larger gap results in a higher roller pressure. The most preferred roller pressure is 2 kN / cm and the gap is 3 mm.

[0129] Rolling itself is not a known method for stabilizing amorphous active ingredients. Therefore, surprisingly, it has been shown that it is possible to prepare tablets based on rolled particles in which the amorphous active ingredient (I) is long-term stable.

[0130] 1C) Immediate-release tablets based on direct compression (solid drug dosage form C)

[0131] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), which is an immediate-release tablet, is based on the direct compression of a mixture of amorphous active ingredient (I) and excipients.

[0132] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), which is an immediate-release tablet, is based on the direct compression of a mixture of amorphous active ingredient (I) and excipients into tablets, and its preparation does not require the use of water or organic solvents or heating.

[0133] This invention provides a solid drug dosage form for oral administration, which is a direct-release tablet based on direct compression, comprising...

[0134] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3-Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0135] b) At least one lubricant

[0136] c) at least one disintegration promoter, and

[0137] d) At least one filler.

[0138] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is a direct-release tablet based on direct compression, comprising...

[0139] a) Amorphous form of (4S)-2 in concentrations of 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0140] b) At least one lubricant in a concentration of 0.5 mg to 7 mg.

[0141] c) at least one disintegration promoter in a concentration of 2 mg to 100 mg, and

[0142] d) At least one filler with a content of 2 mg to 150 mg.

[0143] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is a direct-release tablet based on direct compression, comprising...

[0144] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4-Formamide (active ingredient (I)),

[0145] b) Magnesium stearate as a lubricant.

[0146] c) Crosslinked carboxymethyl cellulose sodium as a disintegration promoter, and

[0147] d) Microcrystalline cellulose and lactose as fillers.

[0148] The advantages of this invention are that the amorphous active ingredient (I) is long-term stable in direct-compression-based immediate-release tablets without the need for any stabilizers (e.g., polymers or gelling agents in the ASD matrix as described above), while exhibiting excellent dissolution properties and good bioavailability of the active ingredient (I), as well as excellent tablet characteristics. The resulting tablets have excellent tablet hardness.

[0149] Surprisingly, this can be achieved by using well-known unstable excipients.

[0150] 1D) Oral dispersible tablets (solid drug dosage form D)

[0151] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), which is an oral dispersible tablet containing an amorphous form of active ingredient (I) and excipients.

[0152] This invention provides a solid pharmaceutical dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is an oral dispersible tablet containing an amorphous form of active ingredient (I) and excipients, which is prepared without the use of water or organic solvents or heating.

[0153] This invention provides a solid drug dosage form for oral administration, which is an orally dispersible tablet containing...

[0154] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0155] b) at least one lubricant, and

[0156] c) At least one filler or disintegration promoter.

[0157] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is an orally dispersible tablet containing...

[0158] a) Amorphous form of (4S)-2 in concentrations of 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0159] b) At least one lubricant in a concentration of 2 mg to 30 mg, and

[0160] c) At least one filler or disintegration accelerator in a concentration of 20 mg to 700 mg.

[0161] The present invention also provides a solid pharmaceutical dosage form for oral administration, which is an orally dispersible tablet containing...

[0162] a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)),

[0163] b) Magnesium stearate as a lubricant, and

[0164] c) Sugar alcohol mixtures as fillers or disintegration promoters.

[0165] Surprisingly, the advantage of this invention is that the amorphous active ingredient (I) can be formulated into oral dispersible tablets without any stabilization measures, while exhibiting excellent dissolution performance, good bioavailability of the active ingredient (I), and excellent disintegration performance.

[0166] Overview

[0167] For oral administration, rolled granules containing an amorphous active ingredient (I) can be formulated into solid or liquid dosage forms, such as tablets, sachets, capsules, sugar-coated pills, chewable tablets, effervescent tablets, dispersible tablets, lozenges, melts, or suspensions, and can be prepared according to methods known in the field of pharmaceutical composition preparation.

[0168] The drug dosage form of this invention is a tablet.

[0169] The drug dosage form of this invention is an immediate-release tablet.

[0170] The pharmaceutical dosage form of the present invention is a tablet, wherein a mixture of an amorphous active ingredient (I) and an excipient is rolled and ground together with the excipient to obtain rolled particles, which are then compressed into tablets, which are optionally coated, preferably coated.

[0171] The pharmaceutical dosage form of 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 excipients, and the tablet is optionally coated, preferably coated.

[0172] The pharmaceutical dosage form of the present invention is also an orally dispersible tablet, wherein the tablet is based on direct compression of a mixture of an amorphous active ingredient (I) and excipients.

[0173] (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 The amount of formamide (active ingredient (I)) in the tablet is 2 mg to 100 mg, preferably 5 mg to 50 mg, even more preferably 20 mg to 50 mg, and more preferably 50 mg.

[0174] Solid drug dosage forms, especially tablets, and rolled granules are expected to be stored stably for a longer period of time, preferably long-term stable.

[0175] Solid drug dosage forms, especially tablets, and rolled granules, can be stably stored for at least 3 months, preferably at least 6 months, even more preferably at least 12 months, even more preferably at least 24 months, even more preferably at least 30 months, and most preferably at least 48 months.

[0176] Long-term storage refers to storage for more than 24 months.

[0177] Stable storage means that the degradation rate of active ingredient (I) does not exceed 10%, preferably not more than 3%, and the active ingredient (I) is maintained in an amorphous form.

[0178] Storage conditions used to evaluate stability include, for example, a closed container at 25°C / 60% relative humidity, a closed 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 (pressure conditions).

[0179] Solid drug dosage forms containing active ingredient (I) exhibit surprisingly excellent stability even under pressure conditions (open storage at 40°C and 75% relative humidity for 6 months), allowing for non-protective packaging of drug dosage forms containing active ingredient (I) (e.g., blister packs or high-density polyethylene (HDPE) bottles without desiccants).

[0180] In the context of this invention, immediate-release tablets, particularly those that, according to the European Pharmacopoeia using device 2 (paddle method), release at least 85% of the active ingredient (I) into the release medium after 30 minutes. The stirrer speed is 75 rpm in 900 ml of release medium.

[0181] The release medium of this invention is an acetate buffer solution at pH 4.5 + 0.15% SDS. SDS is an abbreviation for sodium dodecyl sulfate, also known as sodium lauryl sulfate.

[0182] The pharmaceutical dosage form of this invention is also an orally dispersible tablet, characterized in that, according to the disintegration method of the European Pharmacopoeia using a rigid basket device with a disc, the disintegration time is at most 3 minutes. This device uses water as a medium, operates at 37±2°C, and according to the release method of the European Pharmacopoeia using device 2 (paddle method), at least 85% of the active ingredient (I) is released into the release medium after 30 minutes. The stirrer rotates at 75 rpm in 900 ml of release medium.

[0183] The release medium of this invention is an acetate buffer solution at pH 4.5 + 0.15% SDS. SDS is an abbreviation for sodium dodecyl sulfate, also known as sodium lauryl sulfate.

[0184] The present invention also relates to (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (I) is used in the preparation of the solid pharmaceutical dosage form for oral administration according to the present invention.

[0185] The active ingredient (I) exists in an amorphous form in the pharmaceutical dosage form of the present invention.

[0186] In the context of this invention, "excipient" includes fillers, lubricants, disintegration promoters, sweeteners, flavoring agents, and coloring agents. Therefore, those skilled in the art may classify similar or even identical substances as members of more than one of the above groups of substances. However, in the context of this invention, the functional description of substances intentionally uses specific substances to clarify their respective endowed properties.

[0187] The term "pharmaceutical acceptable" refers to excipients that, within reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and whose benefits / risks are commensurate with a reasonable ratio.

[0188] The fillers that can be used in the formulations of this invention are selected from the following: cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, such as monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrin, or... The preferred filler is microcrystalline cellulose or lactose or a combination thereof.

[0189] In the context of this invention, fillers can also be used as adhesives.

[0190] Available binders include cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or hydrated, such as monohydrate), glucose, maltose, sucrose, glucose, fructose, maltodextrin, or hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose 3cP). Hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose 3cP) is preferred as a binder.

[0191] Lubricants prevent components from adhering to, for example, the preparation equipment. Lubricants that can be used in the formulations of this invention are selected from the following: magnesium stearate, sodium stearate fumarate, stearic acid, glyceryl monostearate, glyceryl monobehenate, calcium behenate, hydrogenated vegetable fats or oils, polyethylene glycol, and talc. Preferred lubricants of this invention are those selected from magnesium stearate, stearic acid, and talc. A highly preferred lubricant is magnesium stearate.

[0192] Disintegration accelerators swell and dissolve upon contact with moisture. They can be used to break down dosage forms in the digestive tract, releasing the active ingredient. Disintegration accelerators suitable for the context of this invention are selected from: alginic acid, croscarmellose, corn starch, modified starch and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as calcium carboxymethyl cellulose (calcium carboxymethyl cellulose) and croscarmellose sodium (a cross-linked polymer of sodium carboxymethyl cellulose), or microcrystalline cellulose, or a combination of croscarmellose sodium and microcrystalline cellulose. Preferred disintegration accelerators are croscarmellose sodium or croscarmellose. A highly preferred disintegration accelerator is croscarmellose sodium.

[0193] Preferred sweeteners are pharmaceutically acceptable excipients having a sugar-like taste. Sweeteners suitable for the context of this invention are selected from those including sucralose, saccharin, sodium saccharin, potassium or calcium saccharin, acesulfame potassium, neotame, alitame, glycyrrhizin, or thaumatin, or sugars such as glucose, mannitol, fructose, sucrose, maltose, maltitol, galactose, sorbitol, or xylitol. In the context of this invention, sweeteners are added in amounts known to those skilled in the art.

[0194] In the context of this invention, a flavoring agent is a pharmaceutically acceptable excipient suitable for improving the taste of a pharmaceutical dosage form or giving it a pleasant taste to enhance its efficacy and increase its refinement. In the context of this invention, a flavoring agent is a natural flavoring substance obtained from plant or animal raw materials, a flavoring substance identical to that of nature obtained through synthesis or isolated by chemical methods, and which is chemically and sensorily identical to the flavoring substances naturally present in products intended for human consumption and artificial flavoring substances. In the context of this invention, flavoring agents are added in amounts known to those skilled in the art. Flavoring agents suitable for the context of this invention are selected from those including: synthetic / artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavoring), ethyl butyrate (pineapple), methyl aminobenzoate (grape); natural flavoring agents such as essential oils and oleoresins, herbs and spices; and flavoring agents identical to those of nature, which are flavoring substances obtained through synthesis or isolated by chemical methods and whose chemical composition is identical to that of natural analogs. In the context of this invention, flavoring agents are added in amounts known to those skilled in the art.

[0195] In the context of this invention, a colorant is a pharmaceutically acceptable excipient suitable for coloring or enhancing the color of an uncolored pharmaceutical dosage form to minimize batch-to-batch variability or to replace an existing color to enhance its efficacy and improve its refinement. It can be any dye, lake, or pigment such as indigo carmine, riboflavin, and titanium dioxide. In the context of this invention, the colorant is added in amounts known to those skilled in the art.

[0196] In the context of this invention, optional coating is achieved by adding conventional coating and film-forming agents familiar to those skilled in the art, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), ethyl cellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer (e.g., VA64 (BASF), shellac, copolymers of acrylic acid and / or methacrylates with trimethylammonium methyl acrylate, copolymers of dimethylaminomethacrylate and neutral methacrylates, polymers of methacrylic acid or methacrylates, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (such as polyethylene glycol 3350), glyceryl triacetate or triethyl citrate, and / or colorants / pigments, such as titanium dioxide, iron oxide (such as red iron oxide, yellow iron oxide), indigo or lakes of suitable colors, and / or anti-adhesion agents such as talc, and / or opacifiers such as titanium dioxide. Hydroxypropyl methylcellulose and polyethylene glycol are preferred as optional coating and film-forming agents according to the invention; iron oxide red is preferred as a colorant; and titanium dioxide is preferred as an opacifier. A preferred coating mixture may be about 60% by weight of hydroxypropyl methylcellulose, about 17.5% by weight of iron oxide yellow, about 0.25% by weight of iron oxide red and about 20% by weight of polyethylene glycol.

[0197] The mixture of coating substances described herein can also be used as a ready-to-use coating system, for example, under a trade name. Commercially available. Opadry It is a mixture of approximately 60% by weight hydroxypropyl methylcellulose, approximately 19.4% by weight titanium dioxide, approximately 0.6% by weight iron oxide red, and approximately 20% by weight polyethylene glycol. Preferably, it is marketed under a trade name. A readily available, ready-to-use coating system.

[0198] The coating is preferably from about 0.5% to 10% by weight of the coated tablet formulation, more preferably from 0.5% to 4.5% by weight of the coated tablet formulation, and even more preferably from about 1.5% to 4.5% by weight of the coated tablet formulation.

[0199] (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4Formamide (active ingredient (I)) and excipients are present in a solid dosage form at a ratio of active ingredient (I) to excipients of 1:0.5 to 1:20. Preferably, the ratio of active ingredient (I) to excipients is 1:0.5 to 1:10, more preferably 1:0.5 to 1:5, even more preferably 1:2, and very preferably 1:1.6. In particular, a ratio of active ingredient (I) to excipients of 1:1.6 allows for high drug loading and small tablet size.

[0200] 2) Preparation methods of solid drug dosage forms

[0201] This invention provides a method for preparing a solid drug dosage form for oral administration, wherein the solid drug dosage form comprises (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) can be prepared without the use of water or organic solvents or heating.

[0202] The present invention also provides a method for preparing a solid drug dosage form for oral administration, said solid drug dosage form comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) and other pharmaceutically acceptable excipients, which are prepared without the use of water or organic solvents or heating.

[0203] The present invention also provides a method for preparing a solid drug dosage form for oral administration, said solid drug dosage form comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-32 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 - Formamide (active ingredient (I)) and other pharmaceutically acceptable excipients (such as sweeteners, flavoring agents and coloring agents) can be prepared without the use of water or organic solvents or heating.

[0204] Surprisingly, this preparation method, which requires no water, organic solvents, or heating, makes (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 Formamide (active ingredient (I)) is stable in pharmaceutical dosage forms over a long period. Furthermore, no stabilization measures known to those skilled in the art are required. Compared to other formulations using, for example, amorphous solid dispersions, this preparation method, which eliminates the need for water, organic solvents, or heating, allows for the production of significantly smaller tablets, facilitating swallowing, and also enables companies to produce more tablets per batch. 2A) Preparation method of roller-pressed granules (solid drug dosage form) A))

[0205] This invention provides a method for preparing (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 A method for rolling granulation of α-formamide (active ingredient (I)), characterized in that...

[0206] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4-Formamide (active ingredient (I)) is first mixed with at least one filler and a portion of a disintegration accelerator.

[0207] ii) The resulting mixture is rolled and ground, and

[0208] iii) Mix the resulting particles with the remaining disintegration promoter.

[0209] The present invention also provides a method for preparing (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 A method for rolling granulation of α-formamide (active ingredient (I)), characterized in that...

[0210] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose and a portion of croscarmellose sodium.

[0211] ii) The resulting mixture is rolled and ground, and

[0212] iii) Mix the resulting particles with the remaining cross-linked sodium carboxymethyl cellulose.

[0213] Contains (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 Roll-pressed granules of formamide (active ingredient (I)) can be prepared by one of the methods described above.

[0214] (4S)-2 prepared by one of the above methods 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 Roll-pressed granules of formamide (active ingredient (I)).

[0215] Roller-pressed granules can be converted into pharmaceutical dosage forms, including, for example, tableting, filling into capsules (preferably hard gelatin capsules) or filling into pouches, in each case according to conventional methods familiar to those skilled in the art, and, where appropriate, the addition of other pharmaceutically suitable excipients.

[0216] 2B) Preparation method of immediate-release tablets containing rolled particles (solid drug dosage form B)

[0217] This invention provides a method for preparing a solid drug dosage form containing rolled particles for oral administration, the solid drug dosage form comprising amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0218] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with at least one filler and a portion of a disintegration accelerator.

[0219] ii) The resulting mixture is rolled and ground.

[0220] iii) Mix the resulting particles with the remaining disintegration accelerator.

[0221] iv) Add the lubricant to the mixture and mix again.

[0222] v) Compress the resulting mixture to obtain immediate-release tablets.

[0223] vi) Optionally, the tablets are coated to obtain the drug dosage form.

[0224] The present invention also provides a method for preparing a solid pharmaceutical dosage form containing rolled particles for oral administration, the solid pharmaceutical dosage form comprising amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0225] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose and a portion of croscarmellose sodium.

[0226] ii) The resulting mixture is rolled and ground.

[0227] iii) Mix the resulting particles with the remaining cross-linked sodium carboxymethyl cellulose.

[0228] iv) Add magnesium stearate to the mixture and mix again.

[0229] v) Compress the resulting mixture to obtain immediate-release tablets.

[0230] vi) Optionally, the tablets are coated to obtain the drug dosage form.

[0231] The present invention also provides a method for preparing a solid pharmaceutical dosage form containing rolled particles for oral administration, the solid pharmaceutical dosage form comprising amorphous (4S)-24 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0232] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose and a portion of croscarmellose sodium.

[0233] ii) The resulting mixture is rolled and ground.

[0234] iii) Mix the resulting particles with the remaining cross-linked sodium carboxymethyl cellulose.

[0235] iv) Add magnesium stearate to the mixture and mix again.

[0236] v) Compress the resulting mixture to obtain immediate-release tablets.

[0237] Optionally, the tablet may be coated to obtain the drug dosage form.

[0238] According to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0239] For oral administration, containing amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4Solid pharmaceutical dosage forms of α-formamide (active ingredient (I)) can be prepared by one of the methods described above.

[0240] For oral administration, containing amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 The solid pharmaceutical dosage form of α-formamide (active ingredient (I)) is prepared by one of the methods described above.

[0241] 2C) Preparation method of immediate-release tablets based on direct compression (solid drug dosage form C)

[0242] This invention provides a method for preparing a direct-compression-based immediate-release tablet for oral administration, the immediate-release tablet comprising amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0243] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with at least one filler and a portion of a disintegration accelerator.

[0244] ii) Add the lubricant to the mixture and mix again.

[0245] iii) The resulting mixture to be compressed is then compressed into tablets to obtain immediate-release tablets.

[0246] iv) Optionally, the immediate-release tablet may be coated.

[0247] The present invention also provides a method for preparing an immediate-release tablet based on direct compression for oral administration, the immediate-release tablet comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0248] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose and a portion of croscarmellose sodium.

[0249] ii) Add magnesium stearate to the mixture and mix again.

[0250] iii) The resulting mixture to be compressed is then compressed into tablets to obtain immediate-release tablets.

[0251] iv) Optionally, the immediate-release tablets may be coated.

[0252] The present invention also provides a method for preparing an immediate-release tablet based on direct compression for oral administration, the immediate-release tablet comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0253] i) The amorphous form of (4S)-2 4-Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose and a portion of croscarmellose sodium.

[0254] ii) Add magnesium stearate to the mixture and mix again.

[0255] iii) The resulting mixture to be compressed is then compressed into tablets to obtain immediate-release tablets.

[0256] iv) Optionally coat the immediate-release tablets

[0257] According to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0258] Immediate-release tablets based on direct compression for oral administration—containing amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) can be prepared by one of the methods described above.

[0259] Immediate-release tablets based on direct compression for oral administration—containing amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is prepared by one of the methods described above.

[0260] Preparation method of 2D) Oral dispersible tablets (solid drug dosage form D)

[0261] This invention provides a method for preparing an oral dispersible tablet for oral administration, the oral dispersible tablet comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0262] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with at least one filler or disintegration promoter.

[0263] ii) Add the lubricant to the mixture and mix again.

[0264] iii) Compress the obtained mixture to obtain oral dispersible tablets.

[0265] The present invention also provides a method for preparing an oral dispersible tablet for oral administration, the oral dispersible tablet comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0266] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-14 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with the sugar alcohol mixture.

[0267] ii) Add magnesium stearate to the mixture and mix again.

[0268] iii) Compress the obtained mixture to obtain oral dispersible tablets.

[0269] The present invention also provides a method for preparing an oral dispersible tablet for oral administration, the oral dispersible tablet comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0270] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with the sugar alcohol mixture.

[0271] ii) Add magnesium stearate to the mixture and mix again.

[0272] iii) The resulting mixture to be compressed is compressed into tablets to obtain orally dispersible tablets.

[0273] According to the release method of device 2 (paddle method) in the European Pharmacopoeia, at least 85% of the active ingredient (I) is released into the release medium after 30 minutes.

[0274] The present invention also provides a method for preparing an oral dispersible tablet for oral administration, the oral dispersible tablet comprising (4S)-2 in an amorphous form. 4-Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that

[0275] i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with the sugar alcohol mixture.

[0276] ii) Add magnesium stearate to the mixture and mix again.

[0277] iii) The resulting mixture is compressed into tablets to obtain orally dispersible tablets.

[0278] Among them, according to the European Pharmacopoeia, the disintegration method using a rigid basket device with a disc has a maximum disintegration time of 3 minutes.

[0279] 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 cropovidone.

[0280] For oral administration, containing amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 Oral dispersible tablets of α-formamide (active ingredient (I)) can be prepared by one of the methods described above.

[0281] Orally dispersible tablets for oral administration—containing amorphous (4S)-2 4-Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is prepared by one of the methods described above.

[0282] Drugs and Uses

[0283] The oral solid dosage form—containing the active ingredient (I) in an amorphous form and produced by a large-scale industrial method—has a high relative bioavailability in the human body, ranging from 85% to even 100%, preferably from 88% to even 100%.

[0284] The present invention also provides a medicine comprising the solid pharmaceutical dosage form of the present invention for oral administration, said solid pharmaceutical dosage form comprising the active ingredient (I).

[0285] The present invention also relates to the use of a solid pharmaceutical dosage form comprising the active ingredient (I) according to the present invention for oral administration in the preparation of a medicament for treating and / or preventing conditions, preferably thrombotic or thromboembolic conditions and / or thrombotic or thromboembolic complications, particularly cardiovascular conditions (including coronary artery disease, angina pectoris, myocardial infarction or in-stent thrombosis), as well as cerebrovascular artery conditions and other conditions leading to transient ischemic attacks (TIAs), ischemic stroke (including cardiac and non-cardiac strokes), and / or peripheral artery conditions leading to peripheral artery disease (including peripheral artery occlusion, acute limb ischemia, amputation, interventional procedures such as angioplasty, stent implantation or surgery and re-occlusion and restenosis after bypass surgery), and / or in-stent thrombosis.

[0286] The present invention also relates to the use of a solid pharmaceutical dosage form comprising the active ingredient (I) according to the present invention for oral administration for the prevention, secondary prevention and / or treatment of conditions, particularly myocardial infarction, ischemic stroke (including cardiac and non-cardiac stroke), acute limb ischemia, re-occlusion and restenosis after interventional procedures such as angioplasty, stent implantation or surgery and bypass surgery, and / or in-stent thrombosis.

[0287] The present invention will now be described in detail with reference to preferred embodiments; however, the invention is not limited to these embodiments. Unless otherwise stated, all amounts given refer to the dosage form in mg.

[0288] Experimental Section

[0289] abbreviation:

[0290] IR tablets: Fast-release tablets

[0291] SDS: Sodium lauryl sulfate, also known as sodium lauryl sulfate.

[0292] rh: relative humidity

[0293] Active ingredient (I) crystals refer to active ingredient (I) in crystal variant I.

[0294] ODT: Oral Dispersible Tablets

[0295] ASD matrix: Amorphous solid dispersion matrix

[0296] FeSSIV: Simulated intestinal fluid during feeding

[0297] FaSSIV: Simulated intestinal fluid in a fasting state

[0298] kN / cm: kilonewtons per centimeter

[0299] Dry granulation and roller pressing are used interchangeably.

[0300] 1. Preparation of active ingredients in amorphous form (I)

[0301] The active ingredient (I) is (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 2-Formamide, also known as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butyryl}amino)-2-fluorobenzamide, can be prepared in an amorphous form according to Examples 234 and 235 of WO 2017 / 005725.

[0302] 2. Release / Dissolution Method

[0303] According to the latest revision of the European Pharmacopoeia, 10th Edition, Topic 01 / 2016, oral solid dosage forms were tested using apparatus 2 (paddle method). The stirrer was set at 75 rpm in 900 mL of acetate buffer (pH 4.5) + 0.15% SDS. The release criterion was met if all six test samples released at least 85% of the active ingredient (I) into the release medium after a 30-minute study period.

[0304] 3. Preparation method of immediate-release tablets based on amorphous solid dispersions (comparative example)

[0305] Example 1

[0306] The pharmaceutical dosage form (tablet) of Example 1 was prepared by dissolving a solid dispersion matrix and active ingredient (I) in an organic solvent. During fluidized bed granulation, this solution was sprayed as the granulation solution onto an initially added disintegration accelerator (carrier). After drying and sieving, granules were obtained. The organic solvent could be ethanol, acetone, or a combination thereof. The resulting granules were mixed with the added disintegration accelerator. A lubricant was then added to the mixture and mixed again. The resulting mixture was compressed to obtain tablets. The tablets could then be coated with a pigment suspended in an aqueous solution—consisting of a coating agent and a film-forming agent. The amount of active ingredient (I) in the tablet was 50 mg.

[0307] 4. Preparation method of immediate-release tablets based on direct compression

[0308] Example 2

[0309] The pharmaceutical dosage form (tablet) of Example 2 was prepared by mixing the active ingredient (I) with microcrystalline cellulose, lactose, and croscarmellose sodium. A lubricant was then added to the mixture and it was mixed again. The resulting compressible mixture was then compressed to obtain tablets. The tablets were then coated with a pigment suspended in an aqueous solution consisting of a coating agent and a film-forming agent. The amount of active ingredient (I) in the tablet was 50 mg.

[0310] Example 4

[0311] The pharmaceutical dosage form (tablet) of Example 4 was prepared by mixing the active ingredient (I) with a sugar alcohol mixture. A lubricant was then added to the mixture and mixed again. The resulting mixture was compressed to obtain tablets. The tablets were then coated with a pigment suspended in an aqueous solution consisting of a coating agent and a film-forming agent. The amount of active ingredient (I) in the tablet was 50 mg.

[0312] 5. Preparation method of immediate-release tablets based on dry granulation and tableting

[0313] Example 3

[0314] The pharmaceutical dosage form (tablet) of Example 3 was prepared by mixing the active ingredient (I) with microcrystalline cellulose, lactose, and a portion of croscarmellose sodium. The mixture was then rolled and milled. The resulting particles were mixed with the remaining croscarmellose sodium. A lubricant was then added to the mixture and it was mixed again. The resulting mixture was compressed to form tablets. The tablets could then be coated with a pigment suspended in an aqueous solution consisting of a coating agent and a film-forming agent. The amount of active ingredient (I) in the tablet was 50 mg.

[0315] 6. Preparation method of roller-pressed granules

[0316] Example 5

[0317] The pharmaceutical dosage form (granules) of Example 5 was prepared by mixing the active ingredient (I) with microcrystalline cellulose, lactose, and croscarmellose sodium. The mixture was then rolled and milled to obtain rolled granules. The amount of active ingredient (I) in the rolled granules was 50 mg per 99 mg of the final granules.

[0318] 7. Dosage form composition, in mg / dosage form

[0319] Example 1 (Comparative Example): (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) immediate-release tablets, based on amorphous solid dispersion

[0320]

[0321] a) quantitatively remove solvent during preparation; b) optionally coat the tablets.

[0322] Example 2: (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) immediate-release tablets, based on direct compression

[0323]

[0324] a) Optionally coat the tablets

[0325] Example 3: (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) immediate-release tablets, based on dry granulation

[0326]

[0327]

[0328] a) Inside the granule; b) Outside the granule; c) Optionally, coating the tablet.

[0329] Example 4: (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) immediate-release tablets, based on direct compression

[0330]

[0331] a) These materials are also available under the trade name Pharmaburst, such as PharmaburstC1, Pharmaburst B1, and Pharmaburst B2 from SPIPharma. Pharmaburst contains spray-dried mannitol and sorbitol, and may also contain disintegrants such as crosspovidone.

[0332] The sugar alcohol mixture mentioned in Example 4 is a mixture containing mannitol and sorbitol, and may also contain a disintegrant such as crosspovidone.

[0333] Example 5: (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 Rolled granules of formamide (active ingredient (I))

[0334]

[0335]

[0336] 8. Bioavailability, dissolution, disintegration and outcomes

[0337] 8.1 Bioavailability

[0338] To study bioavailability, a drug formulation containing the active ingredient (I) was administered orally to animals. Blood samples were collected from the test animals. Pharmacokinetic parameters, such as area under the curve (AUC) and maximum concentration (Cmax), were determined after oral administration. The corresponding pharmacokinetic parameters after oral administration were further calculated. The main pharmacokinetic parameters, clearance (CL) and volume of distribution (Vss), were calculated as follows:

[0339]

[0340] 8.2 Dissolution

[0341] Dissolution results comparable to the amorphous solid dispersion of Example 1 were demonstrated by using preparation techniques such as direct compression (Example 2) or dry granulation (Example 5) followed by tablet compression (Example 3). All examples released at least 85% of the active ingredient (I) into the release medium after 30 minutes. Furthermore, both techniques (Examples 2 and 3) significantly reduced disintegration time from 13 minutes in Example 1 to 2 minutes in Examples 2 and 3. To improve patient compliance and thus enhance clinical efficacy, the tablet size was significantly reduced from the 12x6m oval shape of Example 1 to the 7mm circular shape of Examples 2 and 3 to facilitate swallowing.

[0342] Example 4 illustrates a formulation of an orally dispersible tablet. For this example, dissolution results comparable to those of the amorphous solid dispersion in Example 1 are shown. Example 4 releases at least 85% of the active ingredient (I) into the release medium after 30 minutes. The advantage of this technique is that no liquid is required for tablet administration. The tablet disintegrates directly in the mouth in less than one minute, thus facilitating tablet swallowing and patient compliance.

[0343] The preparations in Examples 2, 3, 4, and 5 require no water, organic solvents, or heating, and the active ingredient (I) exists in an amorphous and stable form. This demonstrates that the preparation method is suitable for large-scale industrial production while also being environmentally sustainable. Assuming a currently projected annual demand of approximately 50 tons of active ingredient (I), eliminating the organic solvents would save approximately 300 tons of organic solvents annually. Therefore, the newly developed formulations in Examples 2 through 5 significantly improve the sustainability of the products, with the energy-saving, heat-free method also contributing to this improvement.

[0344] 8.3 Disintegration Method

[0345] According to the latest revision of the European Pharmacopoeia, 10th edition, Topic 01 / 2020, oral solid dosage forms are tested in a rigid basket apparatus. Six samples are placed in test tubes within the basket apparatus, and a disc is added. The apparatus uses water as the medium and is operated at 37±2°C.

[0346] Table 1: Comparison of tablet characteristics in Examples 1 to 4

[0347]

[0348] 9. Solubility

[0349] The solubility of the active ingredient (I) in both amorphous and crystalline forms in different solvents was determined. The results are shown in Table 2.

[0350] Table 2: Solubility of active ingredients (I) in different solvents in amorphous and crystalline forms

[0351] <![CDATA[Solubility of crystal form 1) > <![CDATA[Amorphous form solubility 1) > FeSSIF V1 27.5 351.3 FaSSIV V1 8.6 79.5 water Insoluble <1

[0352] 1) After 24 hours, the result is expressed in mg / L at 25°C.

Claims

1. A solid dosage form for oral administration, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that, The dosage form is A) Roll-pressed granules, which are obtained by rolling and grinding a mixture of amorphous active ingredient (I) and excipients, or B) Immediate-release tablets, wherein a mixture of amorphous active ingredient (I) and excipients is rolled and ground together with the excipients to obtain rolled granules, which are then compressed into immediate-release tablets, or C) Immediate-release tablets, which are based on the direct compression of a mixture of amorphous active ingredient (I) and excipients into tablets, or D) Oral dispersible tablets containing an amorphous form of active ingredient (I) and excipients.

2. The solid drug dosage form A for oral administration according to claim 1, comprising: a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), b) at least one disintegration promoter, and c) At least one filler.

3. The solid drug dosage form B) or C) for oral administration according to claim 1, comprising: d) Amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), e) At least one lubricant f) at least one disintegration promoter, and g) At least one filler.

4. The solid dosage form (D) for oral administration according to claim 1, comprising: a) Amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), b) at least one lubricant, and c) At least one filler or disintegration promoter.

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

6. Solid dosage forms for oral administration, which are roller-pressed granules, containing... a) Amorphous form of (4S)-2 in concentrations of 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), b) At least one disintegration promoter in a concentration of 2 mg to 100 mg, and c) At least one filler with a content of 2 mg to 150 mg.

7. A solid dosage form for oral administration, which is an immediate-release tablet containing rolled granules, comprising... a) Amorphous form of (4S)-2 in concentrations of 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), b) At least one lubricant in a concentration of 0.5 mg to 7 mg. c) at least one disintegration promoter in a concentration of 2 mg to 100 mg, and d) At least one filler with a content of 2 mg to 150 mg.

8. A solid dosage form for oral administration, which is a direct-release tablet based on direct compression, comprising, a) Amorphous form of (4S)-2 in concentrations ranging from 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), b) At least one lubricant in a concentration of 0.5 mg to 7 mg. c) at least one disintegration promoter in a concentration of 2 mg to 100 mg, and d) At least one filler with a content of 2 mg to 150 mg.

9. A solid dosage form for oral administration, which is an orally dispersible tablet containing... a) Amorphous form of (4S)-2 in concentrations of 2 mg to 100 mg 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), b) At least one lubricant in a concentration of 2 mg to 30 mg, and c) At least one filler or disintegration accelerator in a concentration of 20 mg to 700 mg.

10. The solid pharmaceutical dosage form for oral administration according to claims 1 to 8, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) can be prepared without the use of water or organic solvents or heating.

11. Preparation of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 A method for rolling granulation of α-formamide (active ingredient (I)), characterized in that... i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 1,2-formamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose and partially cross-linked sodium carboxymethyl cellulose. ii) The resulting mixture is rolled and ground, and iii) Mix the resulting particles with the remaining cross-linked sodium carboxymethyl cellulose.

12. A method for preparing a solid pharmaceutical dosage form containing rolled particles for oral administration, the solid pharmaceutical dosage form comprising amorphous (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with microcrystalline cellulose, lactose and a portion of croscarmellose sodium. ii) The resulting mixture is rolled and ground. iii) Mix the resulting particles with the remaining cross-linked sodium carboxymethyl cellulose. iv) Add magnesium stearate to the mixture and mix again. v) Compress the resulting mixture to obtain immediate-release tablets. vi) Optionally, the tablets are coated to obtain the drug dosage form.

13. A method for preparing an immediate-release tablet based on direct compression for oral administration, the immediate-release tablet comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (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 resulting mixture to be compressed is then compressed into tablets to obtain immediate-release tablets. iv) Optionally, the immediate-release tablets may be coated.

14. A method for preparing an oral dispersible tablet for oral administration, the oral dispersible tablet comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)), characterized in that i) The amorphous form of (4S)-2 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)) is first mixed with the sugar alcohol mixture. ii) Add magnesium stearate to the mixture and mix again. iii) Compress the obtained mixture to obtain oral dispersible tablets.

15. A solid pharmaceutical dosage form for oral administration prepared by any one of the methods of claims 10 to 14, comprising (4S)-2 in an amorphous form. 4 -Chloro-4-ethyl-7 3 -Fluorine-3 5 -Methoxy-3 2 ,5-dioxo-1 4 -(trifluoromethyl)-3 2 H-6-aza-3(4,1)-pyridine-1(1)-[1,2,3]triazole-2(1,2),7(1)-dibenzoheptafen-7 4 -Formamide (active ingredient (I)).

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