Oral dispersible pharmaceutical dosage form of edoxaban

Abstract

The present invention relates to an orodispersible pharmaceutical dosage form of edoxaban having improved overall properties, its preparation process, and its use as an anticoagulant.

Description

[Technical field]

[0001] Related Applications This application is related to Indian Provisional Patent Application No. IN202121053646, filed on November 22, 2021, which is incorporated herein in its entirety.

[0002] The present invention relates to an orodispersible pharmaceutical dosage form of edoxaban having improved overall properties, its preparation process, and its use as an anticoagulant. [Background technology]

[0003] Edoxaban is represented by the structural formula (I) and its chemical name is (N'-(5-chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide).

[0004] [ka]

[0005] In Europe, edoxaban (Lixiana®) was approved by the European Medicines Agency (EMA) in June 2015, and in the United States, the Food and Drug Administration (FDA) approved edoxaban (Savaysa®) in January 2015. Edoxaban is indicated in both the EU and the United States for (i) the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors such as congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke or transient ischemic attack (TIA), and (ii) the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults, and the prevention of recurrent DVT and PE. Lixiana® / Savaysa® is commercially available in both Europe and the United States as immediate release film-coated tablets in strengths of 15, 30 and 60 mg (based on edoxaban free base). The pharma- ceutically acceptable salt of edoxaban used in Lixiana® / Savaysa® is edoxaban tosylate monohydrate.

[0006] Edoxaban immediate release film-coated tablets are the only commercially available dosage form in Europe (Lixiana®) and the United States (Savaysa®). These conventional tablets must be swallowed - that is, the patient being treated must be able to perform the action of swallowing correctly. However, swallowing may prove difficult for some categories of patients, such as elderly or pediatric patients, or patients who barely cooperate with medical personnel due to the progression of a disabling disease. In these clinical situations, where patients have difficulty swallowing, it would be prudent to replace the tablets swallowed with water with other oral dosage forms that would be easier to swallow.

[0007] A particular solid pharmaceutical dosage form that disintegrates rapidly is an orodispersible tablet (also called an orally disintegrating tablet (ODT) or fast disintegrating tablet), which does not require water and can therefore be consumed in situations where the patient requires an easy to administer dosage form. Orodispersible tablets are an improved dosage form compared to conventional tablets, as they do not require swallowing and are in line with the current fast-paced modern lifestyle. Furthermore, orodispersible tablets are particularly suitable for patients suffering from dysphagia, where the closure of the glottis and the simultaneous contraction of the laryngeal muscles do not adequately propel conventional tablets, which must be swallowed.

[0008] In this regard, the prior art discloses orodispersible pharmaceutical compositions containing edoxaban. However, they suffer from serious drawbacks, such as long overall process and high cost, because they are manufactured by wet granulation process, which requires several processing steps and long manufacturing time. Furthermore, orodispersible edoxaban compositions known from the prior art made by wet granulation technique tend to result in a finished drug formulation with variability in terms of dissolution rate of edoxaban. Another limitation of known orodispersible edoxaban compositions is their stability, since edoxaban is subjected to moisture conditions (water or other solvents) during the wet granulation process or high temperature required to dry the obtained edoxaban granules. Such harsh conditions result in stability problems of the manufactured orodispersible edoxaban compositions.

[0009] For example, EP 3549585 discloses an orally disintegrating tablet comprising edoxaban, an organic acid, a water-soluble polymer at 0.1-2.0% w / w based on the total weight of the disintegrating tablet, and a disintegrant. All of the examples disclosed therein, with suitable physicochemical properties such as disintegration time and hardness, were prepared by compressing two different types of granules obtained after two separate wet granulation processes, i.e., in the first step, edoxaban-containing granules (called "drug-containing granules") were obtained by wet granulating a mixture containing the active ingredient and other excipients employing an aqueous solution containing 0.1-2.0% w / w of a water-soluble polymer as a granulating agent, and the second step consisted of wet granulating the pharma- ceutically acceptable excipients to obtain the second type of granules (called "rapidly disintegrating granules"). The final step consisted of mixing both the edoxaban-containing granules and the rapidly disintegrating granules with additional excipients and compressing to obtain orally disintegrating tablets.

[0010] EP 3815686 discloses an edoxaban granule preparation manufactured by two separate and independent granulation processes that produce two different types of granules. Specifically, the first type of granules, which are edoxaban-containing granules (referred to as "drug-containing granules"), is obtained by wet granulation of a mixture of edoxaban and other excipients. In a subsequent separate step, the second type of granules (referred to as "drug-free granules") is obtained by wet granulation of a mixture of xylitol or sorbitol and carmellose sodium, employing either an aqueous solution containing carmellose sodium as a granulating agent or water alone.

[0011] In Japan, edoxaban (Lixiana®) was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in April 2011. Edoxaban is approved in Japan for the same mentioned indications as in Europe and the United States. In addition, edoxaban is approved in Japan for the prevention of venous thromboembolism (VTE) in patients who have undergone any of the following orthopedic surgeries of the lower extremities: total knee replacement, total hip replacement, and hip fracture surgery.

[0012] In addition to being available in the form of a conventional film-coated tablet, edoxaban (Lixiana®) is also commercially available as an orally disintegrating tablet in 15, 30 and 60 mg strengths (based on edoxaban free base). ODTs are distinguished from conventional sublingual tablets, buccal tablets and lozenges by their fast disintegration time in the oral cavity, generally less than about 60 seconds. In fact, the FDA Center for Drug Evaluation and Research (CDER) defines an orodispersible tablet as "a solid dosage form containing a medicinal substance that disintegrates rapidly, usually within a few seconds, when placed on the tongue." Thus, in the field of developing / manufacturing orodispersible tablets, it is generally accepted that such tablets should disintegrate in less than one minute when placed in the mouth - otherwise, a longer disintegration time would make the orodispersible tablet less appealing, as the patient's taste buds on the tongue and other receptors in the oral cavity would be widely exposed to direct contact with the active ingredient. Furthermore, for patients who are mobile or have limited access to water, taking an orodispersible tablet that does not disintegrate rapidly (i.e., in less than one minute) can be uncomfortable. In this regard, it has been observed that Lixiana® orally disintegrating tablets of 60 mg strength commercially available in Japan take more than 60 seconds to completely disintegrate, which may lead to lower acceptability of said orodispersible dosage form and ultimately affect adherence to treatment and poor clinical patterns.

[0013] Edoxaban is a Class 4 substance according to the Biopharmaceutical Classification (BCS), with low water solubility and low permeability. Edoxaban exhibits high solubility in strongly acidic aqueous solutions, but its solubility decreases in neutral pH aqueous solutions. Lixiana® film-coated tablets and orally disintegrating tablets release edoxaban in an immediate release manner. In particular, it has been determined that both commercially available forms of Lixiana® (conventional tablets and orodispersible tablets) release 85% or more of edoxaban within 15 minutes at pH=1.2.

[0014] It should be noted that when developing a new orodispersible pharmaceutical dosage form, it is a standard requirement by regulatory authorities to demonstrate strict bioequivalence criteria of said newly developed orodispersible pharmaceutical dosage form to a reference product, a conventional film-coated tablet. For example, in Europe, according to the bioequivalence guideline (CPMP / EWP / QWP / 1401 / 98 Rev.l / Corr., 2010), the bioequivalence of a newly developed orodispersible tablet must be evaluated in human studies if it cannot be demonstrated that the active ingredient is not absorbed in the oral cavity. Thus, said bioequivalence requirement poses a great challenge to the development of a new orodispersible tablet. Summary of the Invention [Problem to be solved by the invention]

[0015] Therefore, in view of the prior art, there is a need to provide an edoxaban orodispersible pharmaceutical dosage form with overall improved properties. In this regard, there is room for improvement in the prior art to provide an edoxaban orodispersible composition that can be obtained by a fast, simple and low-cost process while simultaneously improving disintegration time, stability, friability and hardness. Furthermore, from a regulatory point of view, there is a need to provide an edoxaban orodispersible pharmaceutical dosage form that exhibits a reliable and suitable dissolution profile of edoxaban to provide bioequivalence with Lixiana® immediate release film-coated tablets. [Means for solving the problem]

[0016] The inventors of the present invention have been able to design a new orodispersible pharmaceutical dosage form comprising edoxaban (or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt of said edoxaban), a binder in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, which can be obtained by a direct compression process of a dry powder mixture comprising edoxaban (or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban), a binder, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0017] By producing the orodispersible pharmaceutical dosage form of the present invention by direct compression process, the production of a complete batch of edoxaban orodispersible tablets is performed within a few hours, thus allowing the complete production in one shift at the manufacturing site. This represents an improvement over the wet granulation manufacturing process known in the art, which requires more than a standard 8-hour shift at the manufacturing site. In other words, the time taken to produce a complete batch of edoxaban orodispersible tablets according to the present invention (i.e., by direct compression process) is less than half the time required to produce a complete batch of edoxaban orodispersible tablets according to EP 3549585. Thus, the direct compression process of the present invention provides an improvement in production time, leading to a reduction in economic and energetic production costs.

[0018] Still further, the inventors have surprisingly found that the orodispersible pharmaceutical dosage form of the present invention, obtained by direct compression, comprising edoxaban (or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 15.0% w / w relative to the total weight of the dosage form, a disintegrant and one or more further pharma- ceutically acceptable excipients, also has overall improved technical properties, as summarized below.

[0019] Despite the teaching away comments from EP 3549585, which discloses that if the content of water-soluble polymer (i.e., a type of binder) is too high - i.e., more than 3.0% w / w based on the total weight of the edoxaban orodispersible dosage form - the final tablet takes too much time to suspend and is therefore not suitable as an orally disintegrating tablet, the present inventors have unexpectedly found that the orodispersible pharmaceutical dosage form of the present invention, which contains a high amount of binder (i.e., 3.5% to 15.0% w / w based on the total weight of the dosage form), actually disintegrates satisfactorily quickly, in particular in less than 2 minutes, in particular in less than 1.5 minutes, more particularly in less than 1 minute, and even more particularly in less than 55 seconds. In particular, the dosage form of the present invention disintegrates within a time range of 2 minutes to 5 seconds, preferably within a time range of 1 minute 40 seconds to 10 seconds, more preferably within a time range of 1 minute 30 seconds to 15 seconds, and even more preferably within a time range of 1 minute 15 seconds to 20 seconds.

[0020] This disintegration time takes more than one and a half minutes to completely disintegrate and represents an improvement over the commercially available Lixiana® orodisintegrating tablets of 60 mg strength, which are produced by compressing two different types of granules ("edoxaban-containing granules" and "rapidly disintegrating granules") after two separate and separate wet granulation processes. Such improved disintegration time demonstrates that the edoxaban orodispersible dosage form of the present invention is a suitable dosage form to replace conventional Lixiana® film-coated tablets in the treatment of (i) prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors, and / or (ii) treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults; and / or (iii) prevention of venous thromboembolism (VTE) in patients who have undergone any of the following orthopedic surgeries of the lower extremities: total knee replacement, total hip replacement, and hip fracture surgery.

[0021] The edoxaban orodispersible pharmaceutical dosage form of the present invention has sufficient hardness and low friability, which are important advantages for withstanding physical shocks along the manufacturing process as well as for storage and handling and transportation. Furthermore, the edoxaban orodispersible pharmaceutical dosage form of the present invention has improved stability with respect to commercially available Lixiana® orodispersible tablets and Lixiana® film-coated tablets. By preparing the orodispersible form of the present invention via a direct compression process in the presence of a binder, a disintegrant and one or more additional pharma- ceutically acceptable excipients in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, the formation of degradation products can surprisingly be prevented over time. In particular, the edoxaban orodispersible composition of the present invention complies with the strict standards of impurity limit specifications required by European or Japanese regulatory authorities.

[0022] Moreover, the edoxaban orodispersible pharmaceutical dosage form of the present invention allows to provide a reliable and suitable dissolution profile of edoxaban, and therefore releases edoxaban in a manner sufficiently equivalent to be bioequivalent to Lixiana® immediate release film-coated tablets. In this regard, the edoxaban orodispersible composition of the present invention rapidly releases at least 85% or more of edoxaban within 15 minutes at pH=1.2. By having such a dissolution profile, and thus being sufficiently equivalent to the currently marketed Lixiana® conventional tablets, the edoxaban orodispersible dosage form of the present invention avoids the risk of being either suprabioequivalent or infrabioequivalent, which may affect the toxicity and / or efficacy of said orodispersible dosage form. Thus, the orodispersible pharmaceutical dosage form of the present invention constitutes a valuable therapeutic tool in the field of anticoagulant pharmaceuticals.

[0023] Advantageously, the inventors have also unexpectedly found that the preferred presence of two different pharma- ceutical acceptable disintegrants in the orodispersible pharmaceutical dosage form of the present invention provides a synergistic effect in terms of disintegration time, as well as in terms of hardness and friability.In other words, the interaction of the two different pharma-ceutical acceptable disintegrants in the orodispersible tablet of the present invention achieves improved disintegration time, hardness, friability and stability while providing a suitable dissolution profile of edoxaban.

[0024] Accordingly, a first aspect of the present invention relates to an orodispersible pharmaceutical dosage form comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 15.0% w / w relative to the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0025] A second aspect of the present invention relates to a direct compression process for preparing the orodispersible pharmaceutical dosage form of the first aspect of the present invention, comprising the steps of: (i) mixing edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof with a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients; (ii) blending the mixture of step (i); (iii) adding one or more lubricants to the mixture of step (ii); (iv) blending the mixture of step (iii); and (v) compressing the dry powder mixture of step (iv) to form the orodispersible pharmaceutical dosage form.

[0026] A third aspect of the invention relates to the orodispersible dosage form of the first aspect of the invention for use in: a) (i) the prevention of stroke and systemic embolism in adult patients with Non-valvular Atrial Fibrillation (NVAF) with one or more risk factors such as congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke or transient ischemic attack (TIA); and / or b) the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults, and the prevention of recurrent DVT and PE; and / or c) the prevention of venous thromboembolism (VTE) in patients who have undergone any of the following orthopaedic surgical procedures of the lower extremities: total knee replacement, total hip replacement and hip fracture surgery. [Brief description of the drawings]

[0027] [Figure 1] Figure 1 shows the dissolution profiles of (i) Lixiana® (60 mg strength) film coated tablets, (ii) Lixiana® (60 mg strength) commercially available orally disintegrating tablets in Japan, (iii) Comparative Formulation 1, (iv) Formulations 2, 3 and 4. The dissolution profiles were measured according to the following dissolution method: (i) USP Apparatus II (paddle); (ii) Speed ​​= 50 rpm; (iii) pH = 1.2; (iv) Volume = 900 mL; (v) Temperature = 37°C; (vi) N = 6. Percentage of dissolution (%D) is expressed in % w / w; Time (t) is expressed in minutes (min). [Diagram 2] Figure 1 shows the dissolution profiles of (i) Comparative Formulation 6, (ii) Formulations 5, 7, 8, 9 and 10. The dissolution profiles were measured according to the following dissolution method: (i) USP Apparatus II (paddle); (ii) Speed ​​= 50 rpm; (iii) pH = 1.2; (iv) Volume = 900 mL; (v) Temperature = 37°C; (vi) N = 6. Percentage of dissolution (%D) is expressed in % w / w; Time (t) is expressed in minutes (min). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] As used herein, the term "active ingredient" or "API" refers to a pharma- ceutically active molecule (e.g., edoxaban) that induces a desired pharmacological or physiological effect, as well as its pharma- ceutically acceptable, therapeutically active salts, hydrates, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, analogs, and the like. Terms such as "active," "active agent," "active pharmaceutical ingredient," "active substance," "drug substance," "active drug," and the like may be used synonymously for "active ingredient."

[0029] The term "edoxaban" as used herein corresponds to the International Nonproprietary Name (INN) of (N'-(5-chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide), as well as pharmaceutically acceptable salts and / or hydrates thereof. Pharmaceutically acceptable salts of edoxaban and their hydrates include any of a wide range of inorganic and organic acids. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid, and acid addition salts with organic acids such as p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, citric acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, tartaric acid, maleic acid, malic acid, fumaric acid, and mandelic acid.Preferred salts and their hydrates for the purpose of the present invention are edoxaban p-toluenesulfonate (also called edoxaban tosilate), edoxaban p-toluenesulfonate monohydrate (also called edoxaban tosilate monohydrate), edoxaban methanesulfonate, and edoxaban benzenesulfonate.Of these, the most preferred salt for the purpose of the present invention is edoxaban p-toluenesulfonate monohydrate (also called edoxaban tosilate monohydrate).

[0030] The term "orodispersible pharmaceutical dosage form" as used herein encompasses various pharmaceutical forms such as inter alia orodispersible tablets, orodispersible minitablets, orodispersible powders, etc. The preferred orodispersible pharmaceutical dosage form for the purposes of the present invention is the orodispersible tablet.

[0031] The term "orodispersible tablet" as used herein is defined according to the European Pharmacopoeia, Edition 10.0, page 939, as an uncoated tablet intended to be placed in the mouth where it disperses rapidly before being swallowed, more precisely an orodispersible tablet disintegrates within 3 minutes in a disintegration test. According to this definition, the term orodispersible tablet is intended to be synonymous with solid oral dosage forms called inter alia orodispersible tablets, orally disintegrating tablets, orally disintegrating tablets, fast disintegrating tablets, fast dissolving tablets, orodissolving tablets.

[0032] The term "disintegration test" as used herein is defined according to the European Pharmacopoeia (ed. 10.0, p. 323), test A, water at pH=7, 37° C. and 30 cycles per minute. The term "complete disintegration" as used herein is defined according to the European Pharmacopoeia, ed. 10.0, p. 323. Disintegration as defined herein does not mean complete dissolution of the dosage form or its active pharmaceutical ingredient.

[0033] The term "disintegrate" as used herein is defined as the act of causing a solid dosage form to go from a solid state to a completely disintegrated state.

[0034] Thus, in the context of the present invention, an orodispersible pharmaceutical dosage form, including an orodispersible tablet, is preferably defined as a pharmaceutical dosage form that disintegrates or disperses in the mouth without being able to form CO2 upon contact with an aqueous solution, such as saliva. In other words, an orodispersible pharmaceutical dosage form, particularly an orodispersible tablet, according to the present invention does not contain a CO2-forming agent and does not generate CO2 upon contact with water, either before administration or upon contact with an acidic aqueous solution, such as gastric juice. For the avoidance of doubt, an orodispersible pharmaceutical dosage form, particularly an orodispersible tablet, according to the present invention preferably does not include an effervescent or effervescent-like composition.

[0035] The term "dissolution profile" as used herein refers to the dissolution of edoxaban over time from the dosage form of the present invention. Hereinafter, the dissolution profile is measured by the weight of dissolved edoxaban (as free base) per the initial weight of edoxaban in the dosage form (calculated based on the weight of edoxaban free base) and expressed as a weight percentage (% w / w). Unless otherwise stated, hereinafter, the dissolution profile is measured under two different pH conditions: a) pH=1.2; and b) pH=6.8. The dissolution profile measured at pH=1.2 is determined using USP Apparatus II (paddles) by placing the dosage form in 900 mL (for 60 mg and 30 mg edoxaban strengths) and 500 mL (for 15 mg edoxaban strength) at 37°C, stirring at 50 revolutions per minute, and N=6. Dissolution profiles measured at pH=6.8 are determined using USP Apparatus II (paddles) by placing the dosage forms in 900 mL (for 60 mg and 30 mg edoxaban strengths) and 500 mL (for 15 mg edoxaban strength) at 37°C, stirring at 50 rpm and N=6.

[0036] As used herein, the term "edoxaban immediate release" or "edoxaban released in an immediate release manner" refers to dissolution of at least 85% of edoxaban as the free base, expressed as a percentage by weight per initial weight of edoxaban in the dosage form (calculated based on the weight of edoxaban free base) within 15 minutes at pH=1.2, measured as described in the paragraph above.

[0037] The term "friability" as used herein refers to the tendency of a tablet to chip, crumble, or break during handling. Testing for friability is performed according to the guidelines in the European Pharmacopoeia, Edition 10.0, pages 336-337. A maximum mass loss of 1.0% or less is considered acceptable for most products.

[0038] The term "Pharmaceutically acceptable excipient" (also called "excipient") refers to a substance that is formulated with the active pharmaceutical ingredient of a drug product and includes all types of pharma- ceutically acceptable compounds commonly used in pharmaceutical compositions, especially in orodispersible tablets. The term "pharmaceutically acceptable excipient" includes diluents, binders, disintegrants, lubricants, organic acids, sweeteners, glidants, colorants and flavoring agents, and mixtures thereof.

[0039] The term "diluent" as used herein is defined as a pharma- ceutically acceptable excipient that is used as diluent in pharmaceutical compositions.The term "diluent" includes one or more combinations selected from the group consisting of mannitol, maltol, sorbitol, maltitol, xylitol, isomalt, erythritol, lactose, starch and its derivatives, such as pregelatinized starch, cellulose and its derivatives, particularly microcrystalline cellulose, and calcium phosphate.

[0040] Starch, corn starch and pregelatinized starch are generally considered as diluents, but they may also have some disintegrant-like properties and / or some binder-like properties. Therefore, they may be considered as multifunctional excipients. However, in the context of the present invention, starch, corn starch and pregelatinized starch are defined exclusively as diluents. In other words, in the context of the present invention, the terms "binder" and "disintegrant" do not include starch, corn starch or pregelatinized starch.

[0041] The term "binder" as used herein is defined as a pharma- ceutically acceptable excipient that holds ingredients together in a pharmaceutical composition. Binders are agents used to increase the cohesiveness of powder particles or granules during compression to obtain a pharmaceutical form with a defined hardness. Binders ensure that tablets and granules can be formed with the required mechanical strength.

[0042] However, in the context of the present invention, a binder is defined as an agent used solely to increase the cohesive strength of powder particles. In other words, considering that the orodispersible pharmaceutical dosage form of the present invention can be obtained only by direct compression process (without any granulation process), the term "binder" does not include agents used to prepare a binder solution for manufacturing granules.

[0043] Furthermore, in the context of the present invention, the term "binder" shall not be understood as a "coating agent", since a coating agent serves the purpose of coating a pharmaceutical dosage form (e.g., a tablet), but a binder as used herein in the present invention is a pharma- ceutically acceptable excipient that holds powder particles together in a pharmaceutical composition. In other words, the term "binder" in the context of the present invention does not encompass agents used as coating agents or in the coating process.

[0044] Binders in the context of the present invention are divided into two classes: a) "natural binders" and b) "cellulosic polymers".

[0045] The term "natural binder" as used herein is defined as a pharma- ceutically acceptable excipient which is a natural polymeric binder or a salt thereof, preferably selected from the group of alginic acid, sodium alginate, gelatin, guar gum, gum arabic, candelilla wax, carnauba wax, and mixtures thereof.

[0046] The term "cellulosic" or "cellulosic polymer" as used herein is defined as a material made from, related to, or a chemical derivative of cellulose. Examples of "cellulosic polymers" are hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and mixtures thereof. Preferred cellulosic polymers for the purposes of the present invention are selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose. Most preferred are hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0047] The term "disintegrant" as used herein is defined as a pharma- ceutically acceptable excipient used as a disintegrant in pharmaceutical compositions. The term "disintegrant" includes one or more combinations selected from the group of crospovidone, croscarmellose sodium, carmellose calcium, carmellose, calcium silicate and sodium starch glycolate, and mixtures thereof. For the avoidance of doubt, in the context of the present invention, the term "disintegrant" preferably does not include the "cellulosic polymer" defined in the above paragraph - since said "cellulosic polymer" is a binder (i.e., not a "disintegrant"). In other words, in the context of the present invention, the term "disintegrant" preferably does not include hydroxypropyl methylcellulose or hydroxypropyl cellulose.

[0048] The term "lubricant" as used herein is defined as a pharma- ceutically acceptable excipient used as a lubricant in pharmaceutical compositions.The term "lubricant" includes one or more combinations selected from the group of talc, sodium benzoate, sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, stearic acid and glyceryl monostearate; more specifically, such lubricant is selected from the group of sodium stearyl fumarate and magnesium stearate.

[0049] The term "organic acid" as used herein is defined as a pharma- ceutically acceptable excipient that is an organic compound that is acidic and can be used in pharmaceutical compositions. Acidic means that the pH in an aqueous solution is less than 7. Organic acids include carboxylic acids, sulfonic acids, and enols, or their salts. The term "organic acid" includes one or more combinations selected from the group of adipic acid, aspartic acid, ascorbic acid, alginic acid, benzoic acid, citric acid, anhydrous citric acid, glutamic acid, succinic acid, tartaric acid, sorbic acid, lactic acid, fumaric acid, maleic acid, malonic acid, malic acid, oxalic acid, galactaric acid, gluconic acid, and glucuronic acid; more specifically, such organic acids are selected from the group of citric acid, anhydrous citric acid, tartaric acid, and fumaric acid.

[0050] The term "sweetening agent" as used herein is defined as a pharma- ceutically acceptable excipient used as a sweetening agent in pharmaceutical compositions. The term "sweetening agent" includes one or more combinations selected from the group consisting of aspartame, acesulfame potassium (acesulfame K), sodium saccharinate, neohesperidin dihydrochalcone, sucralose, sucrose, fructose, monoammonium glycyrrhizinate, and mixtures thereof.

[0051] The term "glidant" as used herein is defined as a pharma- ceutically acceptable excipient used as a glidant in pharmaceutical compositions. The term "glidant" includes one or more combinations selected from the group consisting of colloidal silicon dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, and mixtures thereof.

[0052] The term "coloring agent" as used herein is defined as a pharma- ceutically acceptable excipient used as a coloring agent in pharmaceutical compositions.The term "coloring agent" includes one or more combinations selected from the group consisting of food yellow No. 5, food red No. 2 and food blue No. 2; food lake dye, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene, riboflavin and mixtures thereof; more specifically, such coloring agents are selected from the group consisting of yellow ferric oxide, ferric oxide and titanium oxide.

[0053] The term "flavoring agent" as used herein is defined as a pharma- ceutically acceptable excipient used as flavoring agent in pharmaceutical compositions.The term "flavoring agent" includes one or more combinations selected from the group of cherry, raspberry, apricot, pear, strawberry, bitter masker, pineapple, lemon, honey, mint garden, orange, peppermint, menthol, blackcurrant, banana, red fruit, wild berry and caramel flavor; more specifically, such flavoring agent is selected from the group of cherry, apricot, mint and honey flavor.

[0054] As mentioned above, one aspect of the present invention relates to an orodispersible pharmaceutical dosage form comprising edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, wherein the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0055] According to the present invention, the amount of binder present in the orodispersible pharmaceutical dosage form may vary between 3.5% and 15.0% w / w relative to the total weight of the dosage form, preferably between 3.5% and 12.0% w / w relative to the total weight of the dosage form, preferably between 4.00% and 11.50% w / w relative to the total weight of the dosage form, more preferably between 4.5% and 10.0% w / w relative to the total weight of the dosage form, even more preferably between 4.5% and 8.0% or 4.5% and 6.0% w / w relative to the total weight of the dosage form. The orodispersible pharmaceutical dosage forms of the present invention may comprise 3.50%, 4.00%, 4.50%, 5.00%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00% w / w of binder based on the total weight of the dosage form.

[0056] According to the present invention, the amount of edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof per orodispersible dosage form may vary from 15 to 60 mg, based on the weight of edoxaban free base.

[0057] According to the present invention, the weight to weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, may range between 1.00:0.21 to 1.00:1.35, preferably 1.00:0.24 to 1.00:1.05, and more preferably 1.00:0.31 to 1.00:0.70. The orodispersible pharmaceutical dosage forms of the present invention are 1.00:0.21;1.00:0.24;1.00:0.25;1.00:0.30;1.00:0.31;1.00:0.35;1.00:0.40;1.00:0.45;1.00:0.50;1.00:0.55,1.00:0.60;1.00:0.65;1.00:0.70;1.00:0.75;1.00:0. 1.00:1.80; 1.00:0.85; 1.00:0.90; 1.00:0.95; 1.00:1.00; 1.00:1.05; 1.00:1.10; 1.00:1.15; 1.00:1.20; 1.00:1.25; 1.00:1.30; 1.00:1.35.

[0058] According to the present invention, the total amount of one or more disintegrants present in the orodispersible pharmaceutical dosage form may range between 5.0% and 20.0% w / w by total weight of the dosage form, or between 7.5% and 17.5% w / w by total weight of the dosage form, or between 7.5% and 12.5% ​​w / w by total weight of the dosage form, or between 12.5% ​​and 17.5% w / w by total weight of the dosage form. The orodispersible pharmaceutical dosage forms of the present invention may comprise 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.5%, 20.0% w / w of one or more disintegrants based on the total weight of the dosage form.

[0059] According to the present invention, the orodispersible pharmaceutical dosage form may comprise a first disintegrant and a second disintegrant different from the first disintegrant. According to the present invention, the weight to weight ratio of the first disintegrant to the second disintegrant may be in the range of 3.00:1.00 to 1.00:1.00, preferably 2.50:1.00 to 1.00:1.00, more preferably 2.00:1.00 to 1.00:1.00, even more preferably 1.50:1.00 to 1.00:1.00. The orodispersible pharmaceutical dosage form of the present invention may comprise a weight to weight ratio of the first disintegrant to the second disintegrant of 3.00:1.00; 2.90:1.00; 2.80:1.00; 2.70:1.00; 2.60:1.00; 2.50:1.00; 2.40:1.00; 2.30:1.00; 2.20:1.00; 2.10:1.00; 2.00:1.00; 1.90:1.00; 1.80:1.00; 1.70:1.00; 1.60:1.00; 1.50:1.00; 1.40:1.00; 1.30:1.00; 1.20:1.00; 1.10:1.00; 1.00:1.00.

[0060] According to the present invention, the orally dispersible pharmaceutical dosage form may comprise an organic acid in an amount of 0.1% to 20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w relative to the total weight of the dosage form.

[0061] More preferably, the orally dispersible pharmaceutical dosage form of the present invention comprises 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0% or 11.5% by weight of the total dosage form. It may contain 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0% w / w organic acid.

[0062] The organic acid used in the orally dispersible pharmaceutical dosage form according to the present invention is not particularly limited, but examples thereof include adipic acid, aspartic acid, ascorbic acid, alginic acid, benzoic acid, citric acid, anhydrous citric acid, glutamic acid, succinic acid, tartaric acid, sorbic acid, lactic acid, fumaric acid, maleic acid, malonic acid, malic acid, oxalic acid, galactaric acid, gluconic acid, and glucuronic acid; more preferably, examples thereof include citric acid, anhydrous citric acid, tartaric acid, and fumaric acid.

[0063] According to the present invention, the percentage to percentage ratio of organic acid to one or more disintegrants may range from 1.00:1.875 to 1.00:17.50, preferably from 1.00:3.125 to 1.00:17.50, more preferably from 1.00:4.375 to 1.00:17.50. The orally dispersible pharmaceutical dosage form of the present invention is 1.00:1.875;1.00:2.00;1.00:2.50;1.00:3.00;1.00:3.125;1.00:3.50;1.00:4.00;1.00:4.375;1.00:4.50;1.00:5.00;1.00:5.50;1.00:6.00;1.00:6.50;1.00:7.00;1.00:7.50;1.00:8.00;1.00:8.50;1.00:9.00;1.00:9.50;1.00 1.00:16.00;1.00:16.50;1.00:17.00;1.00:17.50 in a percentage to percentage ratio of organic acid to one or more disintegrants.

[0064] In one embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0065] In a particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0066] In a particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.00% to 11.50% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0067] In a particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0068] In a particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0069] In a particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0070] In a particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 4.00%-11.50% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0071] In a particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharma- ceutically acceptable excipients, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients.

[0072] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0073] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the binder, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0074] In a more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.00%-11.50% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0075] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0076] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0077] In a more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0078] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0079] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0080] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0081] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0082] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0083] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0084] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0085] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0086] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0087] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0088] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0089] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0090] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a binder in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0091] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0092] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0093] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0094] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulose-based polymer in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0095] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulose-based polymer in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0096] In a more specific embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulose-based polymer in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0097] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0098] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0099] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0100] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.24 to 1.00:1.05, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0101] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.24 to 1.00:1.05, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0102] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.24 to 1.00:1.05, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0103] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.31 to 1.00:0.70, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0104] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.31 to 1.00:0.70, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0105] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulosic polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.31 to 1.00:0.70, and the cellulosic polymer is a hydroxypropyl cellulose. and wherein the orodispersible pharmaceutical dosage form is obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0106] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0107] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0108] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.21-1.00:1.35, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0109] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0110] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0111] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.24-1.00:1.05, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0112] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0113] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 3.5%-12.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0114] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg based on the weight of edoxaban free base, a cellulosic polymer in an amount of 4.5%-10.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the weight of edoxaban free base, is 1.00:0.31-1.00:0.70, The cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0115] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, one or more disintegrants in a total amount of 5.0% to 20.0% w / w based on the total weight of the dosage form, preferably 7.5% to 17.5% w / w based on the total weight of the dosage form, and one or more further pharma- ceutically acceptable excipients. and a weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdered mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma-ceutically acceptable salt thereof, a binder, one or more disintegrants, and one or more further pharma- ceutically acceptable excipients.

[0116] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.00% to 11.50% w / w based on the total weight of the dosage form, one or more disintegrants in a total amount of 5.0% to 20.0% w / w based on the total weight of the dosage form, preferably 7.5% to 17.5% w / w based on the total weight of the dosage form, and one or more further pharma- ceutically acceptable excipients. wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdered mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma-ceutically acceptable salt of said edoxaban, a binder, one or more disintegrants, and one or more further pharma- ceutically acceptable excipients.

[0117] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a first disintegrant and a second further disintegrant different from the first disintegrant, wherein the total amount of both the first disintegrant and the second disintegrant is 5.0% to 20.0% w / w based on the total weight of the dosage form, preferably 7.5% to 17.5% w / w based on the total weight of the dosage form. and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdered mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt thereof, a binder, a first disintegrant, a second disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0118] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.00% to 11.50% w / w based on the total weight of the dosage form, a first disintegrant and a second further disintegrant different from the first disintegrant, wherein the total amount of both the first disintegrant and the second disintegrant is 5.0% to 20.0% w / w based on the total weight of the dosage form, preferably 7.5% to 17.5% w / w based on the total weight of the dosage form. and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdered mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a binder, a first disintegrant, a second disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0119] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5%-15.0% w / w based on the total weight of the dosage form, a first disintegrant and a second further disintegrant different from the first disintegrant, wherein the total amount of both the first disintegrant and the second disintegrant is 5.0%-20.0% w / w based on the total weight of the dosage form, preferably 7.5%-17.5% w / w based on the total weight of the dosage form, and a weight to weight ratio of the first disintegrant to the second disintegrant is 3.00:1.00-1.00: a first disintegrant and a second disintegrant having a weight-to-weight ratio of edoxaban to binder of 1.00:0.21 to 1.00:1.35, calculated based on the weight of edoxaban free base, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdered mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma-ceutically acceptable salt thereof, a binder, a first disintegrant, a second disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0120] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.00%-11.50% w / w based on the total weight of the dosage form, a first disintegrant and a second further disintegrant different from the first disintegrant, wherein the total amount of both the first disintegrant and the second disintegrant is 5.0%-20.0% w / w based on the total weight of the dosage form, preferably 7.5%-17.5% w / w based on the total weight of the dosage form, and a weight to weight ratio of the first disintegrant to the second disintegrant is 3.00:1.00-1.00. :1.00, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to binder, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdered mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma-ceutical acceptable salt of said edoxaban, a binder, a first disintegrant, a second disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0121] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a first disintegrant and a second further disintegrant different from the first disintegrant, wherein the total amount of both the first disintegrant and the second disintegrant is 5.0% to 20.0% w / w based on the total weight of the dosage form, preferably 7.5% to 17.5% w / w based on the total weight of the dosage form, and wherein the weight to weight ratio of the first disintegrant to the second disintegrant is 3.00:1.00 to 1.00:1.0 ... the weight to weight ratio of the first disintegrant to the second disintegrant is 3.00:1.00 to 1.00:1.00, and the weight to weight ratio of the first disintegrant to the second disintegrant is 3.00:1.00 to a first disintegrant and a second disintegrant selected from the group consisting of cellulose, carmellose, calcium silicate and sodium starch glycolate, and one or more further pharma- ceutical acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the binder, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma-ceutical acceptable salt thereof, a binder, a first disintegrant, a second disintegrant, and one or more further pharma- ceutical acceptable excipients.

[0122] In an even more particular embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a binder in an amount of 4.00% to 11.50% w / w based on the total weight of the dosage form, a first disintegrant and a second further disintegrant different from the first disintegrant, wherein the total amount of both the first disintegrant and the second disintegrant is 5.0% to 20.0% w / w based on the total weight of the dosage form, preferably 7.5% to 17.5% w / w based on the total weight of the dosage form, the weight to weight ratio of the first disintegrant to the second disintegrant is 3.00:1.00 to 1.00:1.00, and ... a first disintegrant and a second disintegrant selected from the group consisting of calcium carbonate, carmellose, calcium silicate and sodium starch glycolate, and one or more further pharma- ceutically acceptable excipients, wherein the weight-to-weight ratio of edoxaban to the binder, calculated based on the weight of edoxaban free base, is 1.00:0.21 to 1.00:1.35, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powder mixture comprising edoxaban or a pharma-ceutically acceptable salt thereof, a hydrate of said edoxaban or a hydrate of a pharma-ceutically acceptable salt of said edoxaban, a binder, a first disintegrant, a second disintegrant, and one or more further pharma-ceutically acceptable excipients.

[0123] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutical acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutical acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 8.0% w / w based on the total weight of the dosage form. and wherein the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.21 to 1.00:1.35, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0124] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutically acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 8.0% w / w based on the total weight of the dosage form. and wherein the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.21 to 1.00:1.35, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0125] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutical acceptable salt thereof, a cellulose-based polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutical acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 1.5%. and wherein the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.21 to 1.00:1.35, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0126] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutical acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutical acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 8.0% w / w based on the total weight of the dosage form. and the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.24 to 1.00:1.05, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0127] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutically acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 8.0% w / w based on the total weight of the dosage form. and the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.24 to 1.00:1.05, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0128] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutical acceptable salt thereof, a cellulose-based polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutical acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 1.5%. and the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.24 to 1.00:1.05, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0129] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutical acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutical acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 8.0% w / w based on the total weight of the dosage form. and wherein the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.31 to 1.00:0.70, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0130] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, a cellulose-based polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutically acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 8.0% w / w based on the total weight of the dosage form. and wherein the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.31 to 1.00:0.70, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0131] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutical acceptable salt thereof, a cellulose-based polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the dosage form, a disintegrant, an organic acid in an amount of 0.1% to 20.0% w / w based on the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w based on the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w based on the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w based on the total weight of the dosage form, and one or more further pharma- ceutical acceptable excipients, and the edoxaban selenite content calculated based on the weight of edoxaban free base is 1.0% to 1.5%. and wherein the weight-to-weight ratio of the cellulose-based polymer to the cellulose-based polymer is 1.00:0.31 to 1.00:0.70, and the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutical acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutical acceptable salt of said edoxaban, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0132] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 3.5%-15.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.21 to 1.00:1.35, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0133] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 3.5%-12.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.21 to 1.00:1.35, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0134] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 4.5%-10.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.21 to 1.00:1.35, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0135] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 3.5%-15.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.24 to 1.00:1.05, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0136] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 3.5%-12.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.24 to 1.00:1.05, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0137] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 4.5%-10.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.24 to 1.00:1.05, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0138] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 3.5%-15.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.31 to 1.00:0.70, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0139] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 3.5%-12.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.31 to 1.00:0.70, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0140] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof in an amount per dosage form of 15-60 mg, based on the weight of edoxaban free base; a cellulosic polymer in an amount of 4.5%-10.0% w / w relative to the total weight of the dosage form; a disintegrant; an organic acid in an amount of 0.1%-20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5%-15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75%-10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0%-8.0% w / w relative to the total weight of the dosage form; and one or more further pharma- ceutically acceptable excipients, based on the weight of edoxaban free base. and the weight-to-weight ratio of edoxaban to the cellulosic polymer, calculated based on the above, is 1.00:0.31 to 1.00:0.70, and the cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible pharmaceutical dosage form can be obtained by a direct compression process of a dry powdery mixture comprising edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof, a cellulosic polymer, a disintegrant, an organic acid, and one or more further pharma- ceutical acceptable excipients.

[0141] In a preferred embodiment, the edoxaban or a pharma- ceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof, is edoxaban contained in the orally dispersible pharmaceutical dosage form of the present invention, which is edoxaban p-toluenesulfonate monohydrate (also referred to as edoxaban tosylate monohydrate).

[0142] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention comprises edoxaban tosylate monohydrate in the form of particles having a D(v,90) of less than or equal to 50.0 μm as measured by laser light scattering.

[0143] The term "edoxaban tosilate monohydrate particles having D(v,x)" as used herein is defined as meaning that X% of the volume of the edoxaban tosilate monohydrate particles has a diameter equal to or less than the specified diameter. For example, the term "edoxaban tosilate monohydrate particles having D(v,90) equal to or less than 50.0 μm" means that 90% of the volume of the edoxaban tosilate monohydrate particles has a diameter equal to or less than 50.0 μm. The particle size distribution (PSD) of edoxaban tosilate monohydrate particles referred to herein refers to the particle size distribution determined using techniques available in the art, such as laser light scattering techniques (e.g., by using a Malvern device). Alternatively, a person skilled in the art can use other equivalent devices to measure the particle size distribution (PSD) of edoxaban tosilate monohydrate particles.

[0144] Active pharmaceutical ingredients (APIs) with D(v,90) values ​​below 50.0 μm generally impart poor flowability to said APIs. Furthermore, lower D(v,90) values ​​are more difficult to handle on an industrial scale, especially in terms of ease of operation and worker health and safety. Another disadvantage of APIs with low D(v,90) values ​​is the undesirable effect of segregation of the active ingredient to other pharma- ceutically acceptable excipients of the product along the manufacturing process, as well as low values ​​of homogeneous content of the finished drug product. Furthermore, APIs with low D(v,90) values ​​may suffer from increased susceptibility to oxidation due to increased surface area.

[0145] However, in a more preferred embodiment of the present invention, the inventors have also surprisingly found that an orodispersible dosage form according to the present invention, obtained by direct compression, comprising edoxaban tosylate monohydrate in the form of particles having a D(v,90) of 50.0 μm or less as measured by laser light scattering, a binder in an amount of 3.5% to 15.0% w / w relative to the total weight of the dosage form, a disintegrant, and one or more further pharma- ceutically acceptable excipients, has excellent flowability and content uniformity while being easy to operate on an industrial scale (i.e. improving worker safety). Moreover, no segregation problems were observed on an industrial scale.

[0146] In a preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet.

[0147] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a binder in an amount of 3.5% to 15.0% w / w, based on the total weight of the orodispersible tablet, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the orodispersible tablet is obtainable by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0148] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a binder in an amount of 3.5% to 12.0% w / w, based on the total weight of the orodispersible tablet, a disintegrant, and one or more further pharma- ceutically acceptable excipients, the orodispersible tablet being obtainable by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0149] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a binder in an amount of 4.00% to 11.50% w / w, based on the total weight of the orodispersible tablet, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the orodispersible tablet is obtainable by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0150] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a binder in an amount of 4.5% to 10.0% w / w based on the total weight of the orodispersible tablet, a disintegrant, and one or more further pharma- ceutically acceptable excipients, the orodispersible tablet being obtainable by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0151] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the orodispersible tablet, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible tablet can be obtained by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0152] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the orodispersible tablet, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible tablet can be obtained by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0153] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the orodispersible tablet, a disintegrant, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the orodispersible tablet can be obtained by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer, a disintegrant, and one or more further pharma- ceutically acceptable excipients.

[0154] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer in an amount of 3.5% to 15.0% w / w based on the total weight of the orodispersible tablet, a disintegrant, an organic acid in an amount of 4.0% w / w based on the total weight of the orodispersible tablet, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the organic acid is citric acid or anhydrous citric acid or tartaric acid, and the orodispersible tablet can be obtained by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutically acceptable excipients.

[0155] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer in an amount of 3.5% to 12.0% w / w based on the total weight of the orodispersible tablet, a disintegrant, an organic acid in an amount of 4.0% w / w based on the total weight of the orodispersible tablet, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the organic acid is citric acid or anhydrous citric acid or tartaric acid, and the orodispersible tablet can be obtained by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutically acceptable excipients.

[0156] In a more preferred embodiment, the orodispersible pharmaceutical dosage form of the present invention is an orodispersible tablet comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer in an amount of 4.5% to 10.0% w / w based on the total weight of the orodispersible tablet, a disintegrant, an organic acid in an amount of 4.0% w / w based on the total weight of the orodispersible tablet, and one or more further pharma- ceutically acceptable excipients, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and the organic acid is citric acid or anhydrous citric acid or tartaric acid, and the orodispersible tablet can be obtained by a direct compression process of a dry powder mixture comprising edoxaban p-toluenesulfonate monohydrate, a cellulose-based polymer, a disintegrant, an organic acid, and one or more further pharma- ceutically acceptable excipients.

[0157] As mentioned above, the second aspect of the present invention relates to a direct compression process for preparing the orodispersible dosage form of the first aspect of the present invention, comprising the steps of: (i) mixing edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof with a binder, a disintegrant, and one or more further pharma- ceutically acceptable excipients; (ii) blending the mixture of step (i); (iii) adding one or more lubricants to the mixture of step (ii); (iv) blending the mixture of step (iii); and (v) compressing the dry powder mixture of step (iv) to form the orodispersible pharmaceutical dosage form.

[0158] In one embodiment, a method for preparing an orodispersible pharmaceutical dosage form of the present invention comprises the steps of: (i) mixing edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of said pharma- ceutically acceptable salt thereof with a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients; (ii) blending the mixture of step (i); (iii) adding one or more lubricants to the mixture of step (ii); (iv) blending the mixture of step (iii); and (v) compressing the dry powder mixture of step (iv) to form an orodispersible pharmaceutical dosage form.

[0159] In one embodiment, a method for preparing an orodispersible pharmaceutical dosage form of the present invention comprising the steps of: (i) mixing edoxaban or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt thereof with a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients; (ii) blending the mixture of step (i); (iii) adding one or more lubricants to the mixture of step (ii); (iv) blending the mixture of step (iii); and (v) compressing the dry powder mixture of step (iv) to form an orodispersible tablet provides an orodispersible tablet.

[0160] In a particular embodiment, a method for preparing an orodispersible pharmaceutical dosage form of the present invention comprising the steps of: (i) mixing edoxaban p-toluenesulfonate monohydrate with a binder, a disintegrant, and one or more additional pharma- ceutically acceptable excipients; (ii) blending the mixture of step (i); (iii) adding one or more lubricants to the mixture of step (ii); (iv) blending the mixture of step (iii); and (v) compressing the dry powder mixture of step (iv) to form an orodispersible tablet provides an orodispersible tablet.

[0161] All the embodiments disclosed above for the orodispersible pharmaceutical dosage form of the present invention also apply to the preparation method.

[0162] Throughout the specification and claims, the word "comprise" and variations of this word are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word "comprise" encompasses the case of "consisting of." Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of this specification or may be learned by practice of the present invention. The following examples and drawings are provided by way of illustration and are not intended to be limiting of the present invention. Reference signs placed within parentheses in connection with the drawings and in the claims are intended only to enhance comprehension of the claims and should not be construed as limiting the scope of the claims. Furthermore, the present invention covers all possible combinations of the specific and preferred embodiments described herein. EXAMPLES

[0163] Physicochemical characterization of Lixiana® orally disintegrating tablets commercially available in Japan A sample of Lixiana® orally disintegrating tablets commercially available in Japan in 60 mg strength was purchased and further characterized: Description: Non-coated tablet - oval with score line Strength: 60mg (based on edoxaban free base) ·Average weight: 362.76mg ·Diameter: 13.406mm Thickness: 4.78mm ·Hardness: 96.3N Collapse time: 1 minute 45 seconds (i.e. 105 seconds)

[0164] Disintegration times were obtained according to test A of the European Pharmacopoeia (ed. 10.0, p. 323) at pH=7 in water, 37° C. and 30 cycles per minute.

[0165] Thus, as can be observed, the disintegration times of currently marketed Lixiana® orally disintegrating tablets are far from the gold standard in the field, i.e. disintegration times of about 60 seconds or less. In fact, the observed disintegration times are almost twice the generally accepted maximum of about 60 seconds.

[0166] Example 1: General method for preparing the orodispersible tablets of the present invention Edoxaban (or a pharma- ceutically acceptable salt thereof or a hydrate of said edoxaban or a hydrate of a pharma- ceutically acceptable salt of said edoxaban), a binder and one or more disintegrants are weighed, sieved through a 1 mm mesh and further added to a suitable bin blender (Servo-lift bowl). The following additional excipients may be optionally added to the mixture present in the bin blender: diluent, organic acid, sweetener, glidant, colorant and flavoring agent. The mixture is blended at 34 rpm for 10-25 minutes. Then, a lubricant is weighed, sieved through a 1 mm mesh and further added to the blended mixture. The resulting mixture is blended at 34 rpm for 5 minutes. The resulting dry powder mixture is compressed in a rotary press into the desired orodispersible tablets of the present invention. A general composition is shown in Table 1 below.

[0167] [Table 1]

[0168] Example 2: Orodispersible tablet composition according to the invention Formulations 2-5 - as representative examples according to the present invention - are shown in Tables 2-3. The formulations 2-5 were similarly prepared according to the manufacturing method described in Example 1. The orodispersible tablets of formulations 2-5 contained edoxaban p-toluenesulfonate monohydrate (i.e., edoxaban tosylate monohydrate) as the active pharmaceutical ingredient. Comparative formulation 1 (containing 2% w / w binder) and comparative formulation 6 (containing 20% ​​w / w binder) are also shown in Tables 2-3 below.

[0169] [Table 2]

[0170] [Table 3]

[0171] Example 3. Characterization of orodispersible tablets according to the invention: disintegration test, hardness, thickness, friability test Formulations 2-5 (according to the invention) and comparative formulations 1 and 6, described in Tables 2-3, were tested for disintegration time according to Test A of the European Pharmacopoeia (ed. 10.0, p. 323) at pH=7 in water, 37° C. and 30 cycles per minute. The results are shown in Table 4.

[0172] Formulations 2-5 (according to the invention) and comparative formulations 1 and 6 were also subjected to a friability test according to the guidelines of the European Pharmacopoeia, edition 10.0, pages 336-337. The results are shown in Table 4. Formulations 2-5 (according to the invention) and comparative formulations 1 and 6 were also characterized by their hardness and thickness.

[0173] [Table 4]

[0174] As shown in Table 4, all orodispersible tablets (according to the present invention) of Formulations 2-5 met the requirements to be orodispersible tablets according to the definition given by the European Pharmacopoeia, Edition 10.0, p. 939. Furthermore, all disintegrated in about 60 seconds or less - and are therefore considered to be fast / rapid orodispersible tablets. Comparative Formulation 6 can be formally defined as an orodispersible tablet according to the definition given by the European Pharmacopoeia, but required nearly 2 minutes to completely disintegrate.

[0175] Furthermore, all orodispersible tablets of formulations 2 to 5 (according to the invention) met the requirement of having a friability of less than 1% according to the European Pharmacopoeia guidelines.

[0176] Example 4. Dissolution profile of orodispersible tablets according to the invention The dissolution profiles of formulations 2-5 (according to the invention), comparative formulations 1 and 6, commercially available Lixiana® film-coated tablets (60 mg strength) and Japanese commercially available orally disintegrating tablets Lixiana® (60 mg strength) were measured according to the following dissolution method: (i) USP Apparatus II (paddle); (ii) speed = 50 rpm; (iii) pH = 1.2; (iv) volume = 900 mL; (v) temperature = 37°C; (vi) N = 6. The results are shown in Tables 5-6.

[0177] [Table 5]

[0178] [Table 6]

[0179] The dissolution profiles show that the orodispersible pharmaceutical dosage forms of the present invention (Formulations 2-5) rapidly release at least 85% or more of edoxaban within 15 minutes at pH=1.2. When the binder is present in small amounts (i.e., 2% w / w in Comparative Formulation 1) or in too large amounts (20% w / w in Comparative Formulation 6), edoxaban is not immediately released (i.e., less than 85% dissolved within 15 minutes at pH=1.2).

[0180] By having such a dissolution profile, and therefore being sufficiently comparable to the currently marketed Lixiana® conventional tablets, the edoxaban orodispersible dosage forms of the present invention (Formulations 2-5) avoid the risk of either over- or under-bioequivalence, which may affect the toxicity and / or efficacy of said orodispersible dosage forms.

[0181] Example 5: Further orodispersible tablet compositions according to the invention Further orodispersible tablets in Tables 7-8 were similarly prepared according to the manufacturing method described in Example 1.

[0182] [Table 7]

[0183] [Table 8]

[0184] Example 6. Characterization of further orodispersible tablets according to the invention: disintegration test, hardness, thickness, friability test Formulations 7-10 (according to the invention) described in Tables 7-8 were tested for disintegration time according to Test A of the European Pharmacopoeia (ed. 10.0, p. 323) at pH=7 in water, 37° C. and 30 cycles per minute. The results are shown in Table 9.

[0185] Formulations 7-10 were also subjected to friability testing according to the guidelines of the European Pharmacopoeia, edition 10.0, pages 336-337. The results are shown in Table 9. Formulations 7-10 were also characterized by their hardness and thickness.

[0186] [Table 9]

[0187] As shown in Table 9, all orodispersible tablets of formulations 7-10 (according to the present invention) met the requirement to be orodispersible tablets as per the definition given by the European Pharmacopoeia, Edition 10.0, page 939. Furthermore, all disintegrated in about 60 seconds or less - and therefore are considered to be fast / rapid orodispersible tablets.

[0188] Furthermore, all orodispersible tablets of formulations 7 to 10 (according to the invention) met the requirement of having a friability of less than 1% according to the European Pharmacopoeia guidelines.

[0189] Example 7. Dissolution profiles of further orodispersible tablets according to the invention The dissolution profiles of formulations 7-10 (according to the present invention) were measured according to the following dissolution method: (i) USP Apparatus II (paddle); (ii) Speed ​​= 50 rpm; (iii) pH = 1.2; (iv) Volume = 900 mL; (v) Temperature = 37°C; (vi) N = 6. The results are shown in Table 10.

[0190] [Table 10]

[0191] The dissolution profiles show that the orodispersible pharmaceutical dosage forms of the present invention (Formulations 7 to 10) rapidly release at least 85% or more of edoxaban within 15 minutes at pH=1.2.

[0192] By having such a dissolution profile, and therefore being sufficiently comparable to the currently marketed Lixiana® conventional tablets, the edoxaban orodispersible dosage forms of the present invention (Formulations 7-10) avoid the risk of either over- or under-bioequivalence, which may affect the toxicity and / or efficacy of said orodispersible dosage forms.

[0193] Example 8: Forced degradation test of the formulation of the present invention As representative formulations according to the present invention, formulations 4 and 10 were subjected to forced degradation tests under different temperature and relative humidity (RH) conditions. For comparison purposes, samples of Lixiana® orally disintegrating tablets (ODT) and Lixiana® film-coated tablets (FCT), which are commercially available in Japan, were also analyzed. The forced degradation tests were conducted under the following conditions: (a) accelerated conditions at 40°C / 75% RH; (b) thermal degradation at 50°C. The following impurities were quantified (see Table 11): (i) the amount of 2-(((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)amino)-2-oxoacetic acid (also called "oxoacetic acid impurity"), which is the main degradation impurity of edoxaban by hydrolysis; (ii) the amount of the main unknown impurity; (iii) the amount of total impurities. All values ​​are expressed as % w / w.

[0194] [Table 11]

[0195] As shown in Table 11, representative formulations according to the present invention (Formulations 4 and 10) prepared by a direct compression process are more stable under forced disintegration conditions than the commercially available Lixiana® orally disintegrating tablets and Lixiana® film-coated tablets. In particular, the total impurities present in Formulations 4 and 10 are half the amount present in the commercially available products manufactured by wet granulation.

[0196] Example 9: Stability of formulations of the present invention Formulation 11 has the same quantitative composition as Formulation 10, except that the mint flavor (5% w / w, 21 mg) is replaced with apricot flavor (5% w / w, 21 mg) (see Table 8). Formulation 11 was prepared similarly to Formulation 10.

[0197] Formulation 11 was subjected to stability testing at 25° C. and 60% relative humidity (RH) and analyzed at 1, 2, and 3 months. For comparison purposes, a sample of Lixiana® film-coated tablets (FCT) was also analyzed under the same conditions. The following impurities were quantified (see Table 12): (i) the amount of 2-(((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)amino)-2-oxoacetic acid (also referred to as "oxoacetic acid impurity"), which is the main degradation impurity of edoxaban by hydrolysis; (ii) the amount of the main unknown impurity; (iii) the amount of total impurities. All values ​​are expressed as % w / w.

[0198] [Table 12]

[0199] As shown in Table 12, Formulation 11 prepared by direct compression process is more stable under stability testing at 25° C. and 60% RH than commercially available Lixiana® film-coated tablets. Notably, the main unknown impurities and total number of impurities at 2 and 3 months of analysis were significantly lower in Formulation 11 according to the invention than in the commercially available product manufactured by wet granulation.

[0200] Example 10: Comparison of manufacturing time between the orodispersible formulation prepared according to the present invention and the orodispersible formulation of the prior art The manufacturing time required to obtain formulation 10, as a representative formulation according to the present invention, was compared with the manufacturing time required to obtain the formulation disclosed in [Examples 1-2] of EP 3549585 (see Table 13).

[0201] Formulation 10 having the quantitative formula (Table 8) described in Example 5 was prepared according to the method described in Example 1--all the following ingredients were weighed separately, sieved through 1 mm mesh and further added into a bin blender (Servo-lift bowl): edoxaban tosilate monohydrate 404.00 g, D-mannitol 645.30 g, starch 315.00 g, crospovidone 210.00 g, hydroxypropyl methylcellulose (HPMC) 120.00 g, croscarmellose sodium 157.50 g, aspartame 15.40 g, citric acid 84.00 g, colloidal silicon dioxide 10.50, yellow ferric oxide 1.80 g and mint flavor 150.00 g. It took 60 minutes to weigh, sieve and add all the ingredients. The resulting mixture was blended for 15 minutes. Then 31.50 g of magnesium stearate was weighed, sieved through 1 mm mesh and further added to the blended mixture. This took 5 minutes. The resulting mixture containing magnesium stearate was blended for 5 minutes. The resulting dry powdered mixture was compressed in a rotary press into the desired orodispersible tablets of the present invention. It took 180 minutes to compress into tablets.

[0202] The formulation disclosed in [Example 1-2] of EP 3549585 was prepared according to the method described therein (i.e., obtaining two different types of granules after two separate wet granulation processes). All ingredients were weighed and added to the granulator dryer device, which took 60 minutes. Granulation to obtain drug-containing granules (i.e., edoxaban-containing granules) took 60 minutes, and drying took another 60 minutes. Then, all ingredients were weighed and added to the device for the second granulation, which took 60 minutes. Granulation to obtain fast disintegrating granules took 60 minutes, and drying took another 60 minutes. The drug-containing granules and the fast disintegrating granules were mixed and blended for 15 minutes. Then, magnesium stearate was weighed, sieved through a 1 mm mesh, and further added to the blended mixture, which took 5 minutes. The resulting mixture containing magnesium stearate was blended for 5 minutes. The resulting dry powder mixture was compressed into orodispersible tablets in a rotary press, which took 180 minutes.

[0203] [Table 13]

[0204] As shown in Table 13, the time taken to manufacture a complete batch of edoxaban orodispersible tablets according to the present invention (i.e., by a direct compression process) is less than half the time required to manufacture a complete batch of edoxaban orodispersible tablets according to EP 3549585. Thus, the direct compression process of the present invention provides improved production time, leading to reduced economic and energetic production costs.

[0205] Citation List European Patent No. 3549585 European Patent No. 3815686 European Pharmacopoeia, Edition 10.0, page 939 European Pharmacopoeia, Edition 10.0, page 323 European Pharmacopoeia, Edition 10.0, pages 336-337 Bioequivalence Guidelines (CPMP / EWP / QWP / 1401 / 98 Rev.1 / Corr., 2010)

Claims

1. 1. An orodispersible pharmaceutical dosage form comprising edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharmaceutically acceptable salt of said edoxaban, a binder in an amount of 3.5% to 15.0% w / w based on the total weight of the dosage form, a disintegrant, and one or more additional pharmaceutically acceptable excipients, An orodispersible pharmaceutical dosage form obtainable by a direct compression process of a dry powder mixture comprising edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharmaceutically acceptable salt thereof, said binder, said disintegrant, and said one or more additional pharmaceutically acceptable excipients.

2. the orodispersible pharmaceutical dosage form disintegrates in less than 3 minutes, particularly less than 2 minutes, more particularly less than 1 minute, 2. The orodispersible pharmaceutical dosage form according to claim 1, wherein the disintegration test was carried out using European Pharmacopoeia Disintegration Apparatus A by placing the dosage form in water at pH=7 at 37°C and 30 cycles per minute.

3. 2. The orodispersible pharmaceutical dosage form according to claim 1, wherein the binder is present in an amount of 3.5% to 12.0% w / w relative to the total weight of the dosage form, preferably in an amount of 4.00% to 11.50% w / w relative to the total weight of the dosage form, more preferably in an amount of 4.5% to 10.0% w / w relative to the total weight of the dosage form.

4. 2. The orodispersible pharmaceutical dosage form according to claim 1, wherein the amount of edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharmaceutically acceptable salt of said edoxaban per dosage form is 15 to 60 mg based on the weight of edoxaban free base.

5. 2. The orodispersible pharmaceutical dosage form according to claim 1, wherein the weight-to-weight ratio of edoxaban to the binder, calculated based on the weight of edoxaban free base, is from 1.00:0.21 to 1.00:1.35, preferably from 1.00:0.24 to 1.00:1.05, and more preferably from 1.00:0.31 to 1.00:0.

70.

6. 2. The orodispersible pharmaceutical dosage form of claim 1, wherein the binder is a cellulose-based polymer.

7. 7. The orodispersible pharmaceutical dosage form according to claim 6, wherein the cellulose-based polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, preferably selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose.

8. 2. The orodispersible pharmaceutical dosage form according to claim 1, comprising one or more disintegrants in a total amount of from 5.0% to 20.0% w / w relative to the total weight of the dosage form, preferably from 7.5% to 17.5% w / w relative to the total weight of the dosage form.

9. 9. The orodispersible pharmaceutical dosage form of claim 8, comprising a first disintegrant and further comprising a second disintegrant different from the first disintegrant.

10. 10. The orodispersible pharmaceutical dosage form according to claim 9, wherein the weight to weight ratio of said first disintegrant to said second disintegrant is from 3.00:1.00 to 1.00:1.00, preferably from 2.50:1.00 to 1.00:1.00, more preferably from 2.00:1.00 to 1.00:1.00, and even more preferably from 1.50:1.00 to 1.00:1.

00.

11. 2. The orodispersible pharmaceutical dosage form of claim 1, wherein the one or more disintegrants are selected from the group consisting of crospovidone, croscarmellose sodium, carmellose calcium, carmellose, calcium silicate, and sodium starch glycolate, and mixtures thereof.

12. 2. The orodispersible pharmaceutical dosage form according to claim 1, further comprising an organic acid in an amount of 0.1% to 20.0% w / w relative to the total weight of the dosage form, preferably in an amount of 0.5% to 15.0% w / w relative to the total weight of the dosage form, more preferably in an amount of 0.75% to 10.0% w / w relative to the total weight of the dosage form, and even more preferably in an amount of 1.0% to 8.0% w / w relative to the total weight of the dosage form.

13. 13. The orodispersible pharmaceutical dosage form according to claim 12, comprising an organic acid selected from the group consisting of adipic acid, aspartic acid, ascorbic acid, alginic acid, benzoic acid, citric acid, anhydrous citric acid, glutamic acid, succinic acid, tartaric acid, sorbic acid, lactic acid, fumaric acid, maleic acid, malonic acid, malic acid, oxalic acid, galactaric acid, gluconic acid, and glucuronic acid, preferably selected from citric acid, anhydrous citric acid, tartaric acid and fumaric acid.

14. 13. An orodispersible pharmaceutical dosage form according to claim 12, wherein said organic acid is citric acid or anhydrous citric acid or tartaric acid, and said organic acid is present in an amount of 4.0% w / w relative to the total weight of the dosage form.

15. 2. The orodispersible pharmaceutical dosage form according to claim 1, wherein the percentage to percentage ratio of organic acid to the one or more disintegrants is from 1.00:1.875 to 1.00:17.50, preferably from 1.00:3.125 to 1.00:17.50, more preferably from 1.00:4.375 to 1.00:17.

50.

16. The direct compression process (i) mixing edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharmaceutically acceptable salt of said edoxaban, with said binder, said disintegrant, and said one or more additional pharmaceutically acceptable excipients; (ii) blending the mixture of step (i); (iii) adding one or more lubricants to the mixture of step (ii); (iv) blending the mixture of step (iii); (v) compressing the dry powder mixture of step (iv) to form an orodispersible pharmaceutical dosage form; 2. The orodispersible pharmaceutical dosage form of claim 1, comprising:

17. 2. The orodispersible pharmaceutical dosage form according to claim 1, wherein the edoxaban or the pharmaceutically acceptable salt thereof, or the hydrate of the edoxaban or the hydrate of the pharmaceutically acceptable salt of the edoxaban is selected from the group consisting of edoxaban tosilate, edoxaban tosilate monohydrate, edoxaban methanesulfonate, and edoxaban benzenesulfonate, and is preferably edoxaban tosilate monohydrate.

18. 18. The orodispersible pharmaceutical dosage form of claim 17, wherein the edoxaban tosilate monohydrate is present in the form of particles having a D(v,90) of 50.0 μm or less as measured by laser light scattering.

19. 2. The orodispersible pharmaceutical dosage form of claim 1, which is an orodispersible tablet.

20. 10. The orodispersible pharmaceutical dosage form of claim 1 for use in the treatment of: (i) the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) who have one or more risk factors such as congestive heart failure, high blood pressure, age 75 years or older, diabetes, previous stroke or transient ischemic attack (TIA); and / or b) the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrent DVT and PE in adults; and / or c) the prevention of venous thromboembolism (VTE) in patients who have undergone any of the following orthopedic surgeries of the lower extremities: total knee replacement, total hip replacement, and hip fracture surgery.

21. A method for preparing an orodispersible pharmaceutical dosage form as defined in any one of claims 1 to 19, comprising the steps of: (i) mixing edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of said edoxaban or a hydrate of a pharmaceutically acceptable salt of said edoxaban, with said binder, said disintegrant, and said one or more additional pharmaceutically acceptable excipients; (ii) blending the mixture of step (i); (iii) adding one or more lubricants to the mixture of step (ii); (iv) blending the mixture of step (iii); (v) compressing the dry powder mixture of step (iv) to form an orodispersible pharmaceutical dosage form; A method comprising:

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