Pharmaceutical composition for anticoagulant treatment and its application

Abstract

The present invention relates to a composition for anticoagulant treatment and its application, and particularly relates to a pharmaceutical composition containing (7aS,2’S)-2-oxo-clopidogrel and its application. When the solid preparation of pharmaceutical grade according to the present invention is orally administered to healthy adults before / after meals, it produces compound A and active metabolite H4 generated by the metabolism of clopidogrel sulfate, which is 12.5 times larger in specification, and is almost the same as C max , AUC (0-t) and AUC (0-∞) are obtained, ensuring the effectiveness and safety of the medicine.

Description

Technical Field

[0001] (Cross-reference) This application claims priority based on a Chinese patent application filed on June 17, 2022, with the invention title of "Pharmaceutical Composition for Anticoagulant Therapy and Its Applications" and application number CN202210688248.6, which is hereby incorporated herein by reference in its entirety.

[0002] The present invention relates to a composition for anticoagulant therapy and its applications, and particularly to a pharmaceutical composition containing (7aS,2’S)-2-oxo-clopidogrel and its applications.

Background Art

[0003] (7aS,2’S)-2-oxo-clopidogrel (Compound A represented by the following formula) is a metabolite of clopidogrel in the human body, and its chemical name is methyl (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-tetrahydrothieno[3,2-c]pyrid-5(4H)-yl)acetate.

Chemical Formula

[0004] Similar to clopidogrel, compound A is metabolically activated in the human body to the active metabolite H4, which can further inhibit platelet aggregation (Reference 1: Cai Liu, Yifan Zhang, Weili Chen, etc. Pharmacokinetics and pharmacokinetic / pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing. Phasci (2018), doi:10.10.1 / j.ejps.2018.10.011). Subsequently, it achieves the inhibitory effect on platelet aggregation by selectively inhibiting the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the activation of the secondary ADP-mediated glycoprotein GPIb / IIa complex. Clopidogrel is currently the first-choice drug for clinically preventing and treating heart, brain, and other arterial circulatory insufficiency diseases caused by platelet aggregation. However, there are significant individual differences in its drug efficacy, especially in Asians, that is, clopidogrel resistance (CPGR) has been observed. According to recent studies, CPGR is due to the differentiation of CYP2C19 enzyme activity in the individual liver. Specifically, clopidogrel is not normally metabolized in the liver of some patients, and the metabolites of compound A and its optical isomers are not produced or hardly produced. Therefore, it has been clarified that the metabolism of clopidogrel into the active ingredient is inhibited, and the anticoagulant effect cannot be exerted. On the other hand, by directly taking compound A, it may be possible to effectively avoid clopidogrel resistance. However, there has been no report on the biological equivalence between compound A and clopidogrel.

[0005] Compound A is an off-white solid powder with extremely low solubility, being very slightly soluble in water, slightly soluble in ethanol, sparingly soluble in methanol, almost insoluble in toluene, and very slightly soluble in acetone. Since it is classified as a low-solubility / high-membrane-permeability drug in the BCS (Biopharmaceutics Classification System), it becomes more difficult to achieve biological equivalence with clopidogrel. Also, such products, like clopidogrel, may cause bleeding and require careful control of the maximum blood concentration. If the blood drug concentration is too low, the therapeutic effect cannot be obtained, and if the blood drug concentration is too high, fatal safety problems such as bleeding may occur. Moreover, while clopidogrel requires two steps to be metabolized into the active ingredient H4 in the liver and there is clopidogrel resistance in some human bodies, compound A is metabolized in only one step. Therefore, it is very difficult to make the Tmax values of the two coincide and the Cmax values and AUC values biologically equivalent in all people.

[0006] Therefore, researching a pharmaceutical formulation of compound A that is biologically equivalent, sustainable, stable, and fully releaseable to the marketed clopidogrel tablets (Plavix (registered trademark), 75 mg) and ensuring the effectiveness and safety when using the pharmaceutical is an urgent problem to be solved clinically in this field.

Summary of the Invention

[0007] In view of the above circumstances, the purpose of the present invention is to provide a pharmaceutical composition containing compound A and its application, which are used for the treatment and / or prevention of anticoagulation-related diseases. This pharmaceutical composition containing compound A is sustainable, stable, and fully releases the active ingredient, exerts the medicinal effect, and can be used for the treatment and / or prevention of heart, brain, and other arterial circulation insufficiency diseases caused by platelet aggregation (including, but not limited to, ischemic stroke, heart attack, acute coronary syndrome, myocardial infarction, percutaneous coronary intervention, peripheral arterial disease, platelet aggregation inhibition, transient ischemic attack, etc.).

[0008] According to the present invention, there is provided the use of Compound A in the manufacture of a solid preparation for the treatment and / or prevention of anticoagulation-related diseases, wherein the solid preparation contains a therapeutically effective amount of Compound A which is (7aS,2’S)-2-oxo-clopidogrel represented by the following formula and has a particle size (D90) of 3 μm to 8 μm, and the average C of Compound A achieved at a single daily dose thereof max is 0.8 ng / ml to 1.2 ng / ml.

Chemical formula

[0009] In some embodiments, the therapeutically effective amount is in the range of 4 mg to 5.5 mg as a single daily dose, and preferably, the therapeutically effective amount is in the range of 4 mg to 5 mg as a single daily dose.

[0010] In some embodiments, the average C of Compound A achieved at the single daily dose max / C 12h is 8 to 12.

[0011] In some embodiments, the particle size (D90) of Compound A is 4 μm to 6 μm.

[0012] In some embodiments, the therapeutically effective amount is 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg or 5.5 mg as a single daily dose, and preferably 4 mg, 4.5 mg or 5 mg.

[0013] In some embodiments, the solid preparation in the use contains a binder.

[0014] In some embodiments, the binder is one or more selected from the group consisting of gum arabic, gelatin, sodium carboxymethyl cellulose, methyl cellulose, copovidone, povidone, and hydroxypropyl methyl cellulose.

[0015] In some embodiments, the solid preparation in the use further comprises a filler, a disintegrant, and a lubricant as pharmaceutically acceptable excipients.

[0016] In some embodiments, the filler includes, but is not limited to, one or more selected from the group consisting of mannitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, sucrose, dextrin, microcrystalline cellulose, lactose, starch, pre-gelatinized starch, powdered sugar, and dextrin.

[0017] In some embodiments, the disintegrant includes, but is not limited to, one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, potassium polyacrylate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and dried starch.

[0018] In some embodiments, the lubricant includes, but is not limited to, one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, silica, talc powder, polyethylene glycols, hydrogenated vegetable oil, and sodium dodecyl sulfate.

[0019] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average C of compound A achieved with the single daily dose max is within the range of 80% to 125% of 0.8 ng / ml.

[0020] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of compound A achieved with the single daily dose max is within the range of 80% to 125% of 0.9 ng / ml.

[0021] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of compound A achieved at said single daily dose max is within the range of 80% to 125% of 1.2 ng / ml.

[0022] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of compound A achieved at said single daily dose (0-48h) is within the range of 80% to 125% of 2.3 h*ng / ml.

[0023] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of compound A achieved at said single daily dose (0-48h) is within the range of 80% to 125% of 3.0 h*ng / ml.

[0024] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of compound A achieved at said single daily dose (0-48h) is within the range of 80% to 125% of 3.5 h*ng / ml.

[0025] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of compound A achieved at said single daily dose (0-t) is within the range of 80% to 125% of 2.3 h*ng / ml.

[0026] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of compound A achieved at said single daily dose (0-t) is within the range of 80% to 125% of 3.0 h*ng / ml.

[0027] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of compound A achieved at said single daily dose (0-t) is within the range of 80% to 125% of 3.5 h*ng / ml.

[0028] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-∞) is in the range of 80% to 125% of 2.7 h*ng / ml.

[0029] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-∞) is in the range of 80% to 125% of 3.5 h*ng / ml.

[0030] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-∞) is in the range of 80% to 125% of 4.2 h*ng / ml.

[0031] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average AUC of Compound A achieved with said single daily dose (0‐48h) is 2.3 to 3.5 h*ng / ml.

[0032] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average AUC of Compound A achieved with said single daily dose (0‐t) is 2.3 to 3.5 h*ng / ml.

[0033] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average AUC of Compound A achieved with said single daily dose (0‐∞) is 2.7 to 4.2 h*ng / ml.

[0034] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average AUC of the active metabolite H4 achieved with said single daily dose (0‐∞) is 13.5 to 19 h*ng / ml.

[0035] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average AUC of the active metabolite H4 achieved with said single daily dose (0‐t) is 13 to 18.5 h*ng / ml.

[0036] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average AUC of the active metabolite H4 achieved with said single daily dose (0‐12h) is 13 to 18.5 h*ng / ml.

[0037] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average C of the active metabolite H4 achieved with said single daily dose max is 12.5 to 17 ng / ml.

[0038] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-12h) is within the range of 80% to 125% of 13 h*ng / ml.

[0039] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-12h) is within the range of 80% to 125% of 14 h*ng / ml.

[0040] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose(0-12h) is within the range of 80% to 125% of 18.5 h*ng / ml.

[0041] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-t) is within the range of 80% to 125% of 13 h*ng / ml.

[0042] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-t) is within the range of 80% to 125% of 14 h*ng / ml.

[0043] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-t) is within the range of 80% to 125% of 18.5 h*ng / ml.

[0044] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-∞) is within the range of 80% to 125% of 13.5 h*ng / ml.

[0045] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-∞) is within the range of 80% to 125% of 15 h*ng / ml.

[0046] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-∞) is within the range of 80% to 125% of 19 h*ng / ml.

[0047] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average C of the active metabolite H4 achieved with said single daily dose max is within the range of 80% to 125% of 12.5 ng / ml.

[0048] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with said single daily dose max is within the range of 80% to 125% of 14 ng / ml.

[0049] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with said single daily dose max is within the range of 80% to 125% of 17 ng / ml.

[0050] According to the present invention, there is provided a pharmaceutical composition for the treatment and / or prevention of anticoagulation-related diseases, comprising a therapeutically effective amount of compound A and at least one pharmaceutically acceptable excipient, wherein the compound A is (7aS,2’S)-2-oxo-clopidogrel having a particle size (D90) of 3 μm to 8 μm and represented by the following formula, and the excipient includes a binder.

Chemical formula

[0051] In some embodiments, the therapeutically effective amount is in the range of 4 mg to 5.5 mg as a single daily dose, preferably, the therapeutically effective amount is in the range of 4 mg to 5 mg as a single daily dose.

[0052] In some embodiments, after the pharmaceutical composition is administered to a human subject at a therapeutically effective amount, the average C of compound A achieved with its single daily dose max is 0.8 ng / ml to 1.2 ng / ml.

[0053] In some embodiments, the binder includes, but is not limited to, one or more selected from the group consisting of gum arabic, gelatin, sodium carboxymethyl cellulose, methyl cellulose, copovidone, povidone, and hydroxypropyl methyl cellulose.

[0054] In some embodiments, the pharmaceutical composition further includes a filler, a disintegrant, and a lubricant as pharmaceutically acceptable excipients.

[0055] In some embodiments, the filler includes, but is not limited to, one or more selected from the group consisting of mannitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, sucrose, dextrin, microcrystalline cellulose, lactose, starch, pregelatinized starch, powdered sugar, and dextrin.

[0056] In some embodiments, the disintegrant includes, but is not limited to, one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, potassium polyacrylate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and dried starch.

[0057] In some embodiments, the lubricant includes, but is not limited to, one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, silica, talc powder, polyethylene glycols, hydrogenated vegetable oil, and sodium dodecyl sulfate.

[0058] In some embodiments, in the acetate buffer solution with a pH of 4.5, the dissolution amount measured by Method 2 of General Rule 0931 in the Chinese Pharmacopoeia 2020 Edition within 30 minutes is 70% or more.

[0059] In some embodiments, in an acetate buffer solution with a pH of 4.5, the dissolution amount of the pharmaceutical composition measured by Method 2 of General Rule 0931 of the Chinese Pharmacopoeia 2020 Edition within 60 minutes is 85% or more.

[0060] In some embodiments, after the pharmaceutical composition is administered to a human subject, the average AUC of Compound A achieved at the single daily dose of 4 mg to 5.5 mg (0‐48h) is 2.3 to 3.5 h*ng / ml.

[0061] In some embodiments, after the pharmaceutical composition is administered to a human subject, the average AUC of Compound A achieved at the single daily dose of 4 mg to 5.5 mg (0‐t) is 2.3 to 3.5 h*ng / ml.

[0062] In some embodiments, after the pharmaceutical composition is administered to a human subject, the average AUC of Compound A achieved at the single daily dose of 4 mg to 5.5 mg (0‐∞) is 2.7 to 4.2 h*ng / ml.

[0063] In some embodiments, after the pharmaceutical composition is administered to a human subject, the average C of Compound A achieved at the single daily dose of 4 mg to 5.5 mg max / C 12h is 8 to 12.

[0064] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after being administered to a human subject, the average AUC of the active metabolite H4 achieved at the single daily dose (0‐∞) is 13.5 to 19 h*ng / ml.

[0065] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after being administered to a human subject, the average AUC of the active metabolite H4 achieved at the single daily dose (0‐t) is 13 to 18.5 h*ng / ml.

[0066] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average AUC of the active metabolite H4 achieved with said single daily dose (0‐12h) is 13 to 18.5 h*ng / ml.

[0067] In some embodiments, the therapeutically effective amount is 4 mg to 5.5 mg as a single daily dose, and after administration to a human subject, the average C of the active metabolite H4 achieved with said single daily dose max is 12.5 to 17 ng / ml.

[0068] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average C of compound A achieved with said single daily dose max is within the range of 80% to 125% of 0.8 ng / ml.

[0069] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of compound A achieved with said single daily dose max is within the range of 80% to 125% of 0.9 ng / ml.

[0070] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of compound A achieved with said single daily dose max is within the range of 80% to 125% of 1.2 ng / ml.

[0071] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of compound A achieved with said single daily dose (0-48h) is within the range of 80% to 125% of 2.3 h*ng / ml.

[0072] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of compound A achieved with said single daily dose (0-48h) is within the range of 80% to 125% of 3.0 h*ng / ml.

[0073] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-48h) is in the range of 80% to 125% of 3.5 h*ng / ml.

[0074] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-t) is in the range of 80% to 125% of 2.3 h*ng / ml.

[0075] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-t) is in the range of 80% to 125% of 3.0 h*ng / ml.

[0076] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-t) is in the range of 80% to 125% of 3.5 h*ng / ml.

[0077] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-∞) is in the range of 80% to 125% of 2.7 h*ng / ml.

[0078] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-∞) is in the range of 80% to 125% of 3.5 h*ng / ml.

[0079] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with said single daily dose (0-∞)is within the range of 80% to 125% of 4.2 h*ng / ml.

[0080] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-12h) is within the range of 80% to 125% of 13 h*ng / ml.

[0081] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-12h) is within the range of 80% to 125% of 14 h*ng / ml.

[0082] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-12h) is within the range of 80% to 125% of 18.5 h*ng / ml.

[0083] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-t) is within the range of 80% to 125% of 13 h*ng / ml.

[0084] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-t) is within the range of 80% to 125% of 14 h*ng / ml.

[0085] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with said single daily dose (0-t) is within the range of 80% to 125% of 18.5 h*ng / ml.

[0086] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose (0-∞) is in the range of 80% to 125% of 13.5 h*ng / ml.

[0087] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose (0-∞) is in the range of 80% to 125% of 15 h*ng / ml.

[0088] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose (0-∞) is in the range of 80% to 125% of 19 h*ng / ml.

[0089] In some embodiments, the therapeutically effective amount is 4 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose max is in the range of 80% to 125% of 12.5 ng / ml.

[0090] In some embodiments, the therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose max is in the range of 80% to 125% of 14 ng / ml.

[0091] In some embodiments, the therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose max is in the range of 80% to 125% of 17 ng / ml.

[0092] Compound A is a metabolite of clopidogrel, but it has a different chemical structure from clopidogrel, a different material basis, and the main drug components of the formulated products are not the same. Therefore, the dosage of compound A will also be very different from that of clopidogrel. In addition, clopidogrel sulfate requires two steps to be metabolized in the liver as the active ingredient H4, and there is clopidogrel resistance in some human bodies, while compound A is metabolized in only one step. Therefore, it is very difficult to make the Tmax values of the two coincide and the Cmax value and AUC value biologically equivalent in all people.

[0093] From the metabolic pathway of clopidogrel (Reference 1 cited in the background art), it was theoretically calculated that the dosage at which compound A is equivalent to clopidogrel sulfate (75 mg) is about 11.25 mg (15% of the orally administered clopidogrel is metabolized into compound A). However, when a clinical trial was conducted, it was found that it was difficult to simultaneously achieve the coincidence of T max and C max , AUC (0-t) and AUC (0-∞) equivalence with this dosage of the compound. In particular, since compound A has the advantage of being metabolized in the body as a metabolic intermediate, it is even more difficult to make the T max values coincide. As a result of repeated studies on formulations and specifications with different particle sizes, the inventors surprisingly found that compound A with dosages of 4 mg, 5 mg, and 5.5 mg and the particle size (D90) controlled to 3 μm to 8 μm was biologically equivalent to clopidogrel sulfate (Plavix (registered trademark), 75 mg) in the human body. This dosage range has a difference of more than 10 times compared with clopidogrel sulfate (Plavix (registered trademark), 75 mg) and cannot be obtained from the prior art. In addition, the C max , AUC (0-t) and AUC (0-∞) of the active metabolite H4 produced in the human body from solid formulations containing compound A with different specifications are also different. In particular, the C max of H4 is low and it is difficult to achieve equivalence. By reducing the particle size to adjust the solubility, C max is increased and T maxcan be shortened, but at the same time, it is impossible to predict that the AUC (0-∞) will be biologically equivalent. In addition, it becomes even more difficult to control the C max / C 12h of Compound A to obtain the effect of sustained release.

[0094] In addition, the inventors have found that different formulation compositions have a great impact on dissolution. For example, when microcrystalline cellulose is added as a filler, the fluidity of the particles is improved by the microcrystalline cellulose, but after tableting, the dissolution rate of Compound A may decrease. Also, for example, the addition of different amounts of disintegrants does not significantly affect the dissolution rate of Compound A, but the improvement by different varieties and dosages of solubilizers is also very limited. Furthermore, for example, when the active ingredient is micronized, the dissolution rate of Compound A increases, but if the particle size is too small, burst release problems (the drug absorption is too fast and the bleeding risk increases) are likely to occur. Therefore, it has been difficult to adjust the Compound A-containing solid preparation to be sustainably, stably, and completely released by the conventional methods for solving the dissolution problems of poorly soluble drugs. In addition, during the research process, the inventors have shown that the absorption of Compound A is greatly affected by the presence or absence of food intake, and it is very difficult to make the C max before and after meals equivalent, which has been found to be a major challenge in the art. After repeated research on formulations and specifications, the inventors surprisingly found that by adding a binder during the preparation process of the solid preparation, it is possible to achieve complete biological equivalence with clopidogrel sulfate (Plavix (registered trademark), 75 mg) both before and after meals. As a result, this product can show complete biological equivalence and be stably and completely released.

[0095] Thus, in the Compound A-containing solid preparation of the present invention, there is a possibility of showing biological equivalence with clopidogrel sulfate (Plavix (registered trademark), 75 mg) both before and after meals only when adjusting the three-dimensional dynamic balance among the specifications, particle sizes, and formulation compositions of Compound A.

[0096] The AUC in the present invention(0~12h) 、 AUC (0~48h) 、 C 12h In terms such as "h" in "AUC", "C", etc., "h" is an English abbreviation for the time unit "hour", which is widely used in the art.

Advantages of the Invention

[0097] According to the present invention, for the first time, a solid preparation containing Compound A, which is safe and effective and used for the treatment and / or prevention of anticoagulation-related diseases, is provided. In this solid preparation, it shows complete biological equivalence with the commercially available drug clopidogrel sulfate (Plavix (registered trademark), 75 mg), and particularly has complete biological equivalence before and after meals. However, the dosage of Compound A, the active ingredient, is only 1 / 15 or less of that of the commercially available drug clopidogrel sulfate (Plavix (registered trademark), 75 mg). Moreover, for Compound A in this solid preparation, C max / C 12h does not exceed 12, T max does not exceed 1 h, and it has the advantages of fast drug release, being stable and capable of complete release, and having a better clinical effect. In addition, the preparation process of the solid preparation containing Compound A according to the present invention is simple and has a low production cost, so it is suitable for industrial production.

Modes for Carrying Out the Invention

[0098] Hereinafter, the technical solutions of the present invention will be described with reference to examples. It will be understood by those skilled in the art that the following examples are only used to explain the present invention and should not be construed as limiting the scope of the present invention. For specific technologies and conditions not specified in the examples, they are carried out according to the technologies or conditions described in the literature in the art or the product handling manuals. The reagents and equipment used are all commercially available ordinary products unless otherwise specified by the manufacturer.

[0099] (Example 1) Screening of Dosage and Particle Size

[0100] 1. Test preparations: The prescription information and manufacturing methods of the test preparations in Examples 1 to 10 are as shown in Table 1-1 below.

Table 1-1

[0101] Preparation method: (1) Weigh the raw materials according to the prescription amount. After adding each raw material (except hydrogenated castor oil), further add Compound A, and use a mixer to mix for 10 minutes at a rotation speed of 10 rpm, and use it for subsequent use. (2) Add the hydrogenated castor oil in the prescription amount, and use a mixer to mix for 2 hours at a rotation speed of 10 rpm, and use it for subsequent use. (3) Use a circular shallow concave punch to form the mixture into tablets, and set the hardness to 30 - 50 N.

[0102] 2. Administration method: Administer to healthy adults on an empty stomach Using the method of single-dose, single-site, single-dose, randomized, and non-blinded, 66 recruited healthy adult volunteers (more than 1 / 3 of them are female) were randomly divided into 11 groups (6 people in each group). The test formulation or the control formulation (Plavix (registered trademark), 75 mg) was randomly orally administered on an empty stomach. The PK parameters of Compound A in plasma were measured.

[0103] 3. Test results of Compound A:

Table 1-2

[0104] As shown in the above table, through the screening of dosage and particle size, when the dosage is too high (Example 4) or too low (Example 10), C of Compound A max cannot reach 80% - 125% of the control formulation (Plavix (registered trademark), 75 mg), the bioavailability is greatly different, and biological equivalence cannot be obtained. On the other hand, when the particle size is too low (Example 5), C of Compound A max is slightly higher, T max is too short, AUC (0-t) and AUC (0-∞) are both high and exceed 125% of the control formulation. Also, when the particle size is too high (Example 8), T maxwas too long, the time to onset of effect was long, and the AUCs were all less than 80% of the control formulation, resulting in a relatively low bioavailability and failure to achieve biological equivalence. In Examples 1 to 3, 6 to 7, and 9 where the dose was set at 4 mg to 5.5 mg and the particle size (D90) was controlled to be 3 μm to 8 μm, the C max and T max of Compound A, AUC (0-t) and AUC (0-∞) were all within the range of 80% to 125% of the corresponding parameters of the control formulation, indicating comparable bioavailability and demonstrating the desired biological equivalence. Furthermore, the inventors found that when there was no binder in the formulation (Example 9), each PK parameter of Compound A still showed a bioavailability comparable to that of the control formulation. However, compared with the examples using other binders, the T max of Compound A was slightly shorter, suggesting that the release rate of this product may be affected by the binder.

[0105] 4. Test results of the active metabolite H4:

Table 1-3

[0106] As shown in the above table, through screening of the dose and particle size, when the dose was too high (Example 4) or too low (Example 10), the C max of the active metabolite H4 far exceeded 80% to 125% of the control formulation (Plavix (registered trademark), 75 mg), resulting in a significant difference in bioavailability and failure to achieve biological equivalence. On the other hand, when the particle size was too high (Example 8), the C max of the active metabolite H4 was far lower than 80% of the control formulation, or when the particle size was too low (Example 5), there was a risk of an increase in C max , and it was impossible to achieve a bioavailability comparable to 80% to 125% of the control formulation, and biological equivalence was not realized. In the examples where the dose was set at 4 mg to 5.5 mg and the particle size (D90) was controlled to be 3 μm to 8 μm, the C max , T max , AUC (0-t) and AUC(0-∞) All were within the range of 80% to 125% of the corresponding parameters of the control formulation, with comparable bioavailability and the desired biological equivalence achieved. Furthermore, the inventors found that when there was no binder in the formulation (Example 9), each parameter of the active metabolite H4 still showed bioavailability equivalent to that of the control formulation. However, compared with the examples using other binders, the T max was slightly shorter, and the time to onset of effect was shorter. Therefore, it was speculated that the T max of the active metabolite H4 might also be affected by the binder.

[0107] (Example 2) Examination of Biological Equivalence in the Fasting State (Healthy Adults)

[0108] 1. Test formulations: Examples 2, 6, 7, and 9 in Example 2.

[0109] 2. Test method: In each example, a single-site, fasting oral administration, randomized, non-blinded, two-formulation, four-period crossover test was used, with a washout period of 7 days. In each example, 24 healthy subjects (more than 1 / 3 of whom were female) were recruited and randomly divided into two groups (12 subjects in each group). The test formulation or the control formulation (Plavix® 75 mg) was randomly orally administered on an empty stomach, and the compounds A and the mercaptan active metabolite H4 of clopidogrel in plasma were measured to evaluate the biological equivalence between the test formulation and the control formulation (Plavix®).

[0110] 3. Test results:

Table 2

[0111] Thus, as a result of examining the biological equivalence in the pre-meal (fasting) state, when the formulation prescription meets the dosage of 4 mg to 5.5 mg and the particle size (D90) of 3 μm to 8 μm, the C max , AUC (0-t) and AUC (0-∞)The geometric mean ratio of the test formulation to the corresponding parameters of the control formulation (Plavix® 75 mg) was within the range of 80% to 125%, and the 90% confidence interval was also within the range of 80% to 125%, indicating bioequivalence in the fasting state. It was also found that the presence or absence of a binder in the formulation did not affect the bioequivalence between the test formulation and the control formulation.

[0112] (Example 3) Examination of Bioequivalence after Meals

[0113] 1. Test formulations: Examples 2, 6, 7, 9.

[0114] 2. Test method: The same as in Example 2 above, except that the administration method was "oral administration after meals".

[0115] 3. Test results:

Table 3

[0116] Thus, as a result of examining the bioequivalence after meals, it was found that when the formulation did not contain a binder (Example 9), the bioequivalence after meals could not be satisfied, mainly because the C max of compound A and active metabolite H4 was not equivalent. On the other hand, when the formulation prescription met the dosage of 4 mg to 5.5 mg, the particle size (D90) of 3 μm to 8 μm, and the binder content (Examples 2, 6, 7), the C max , AUC (0-t) and AUC (0-∞)All of them reached within the range of 80% to 125% of the geometric mean ratio and 90% confidence interval of the corresponding parameters of the control preparation (Plavix (registered trademark), 75 mg), and it was found that they had postprandial bioequivalence. These findings were obtained accidentally, and moreover, this drug was able to overcome the demerit of being affected by food intake, providing a more scientific choice for the clinical use of pharmaceuticals. Also, from the overall perspective of the development process of this drug, although the impact on postprandial bioequivalence is significant, it was found that if postprandial equivalence is satisfied (using a binder), preprandial (fasting) bioequivalence can be expected.

[0117] (Example 4) Examination of Different Binders

[0118] 1. Test preparations: Examples 11 and 12. Here, the binder used in Example 11 was gum arabic (3.0 mg), and the binder used in Example 12 was povidone (4.1 mg), and the other formulations were the same as in Example 2.

[0119] 2. Postprandial bioequivalence: The test method was the same as in Example 3.

[0120] 3. Test method:

Table 4

[0121] As a result of examining the binder, it was found that formulations with gum arabic and povidone as binders could achieve bioequivalence in the same way as the formulation with hydroxypropyl methylcellulose as the binder. Therefore, it was speculated that the formulation based on the dosage and particle size range of the present invention is not affected by the type of binder.

[0122] (Example 5) Examination of Postprandial Bioequivalence of Capsules

[0123] 1. Test preparations: Examples 13 to 15. Here, the formulation information and preparation method are as follows.

Table 5-1

[0124] Preparation method of capsule agent: (1) Weigh the raw materials according to the prescription amount. After adding each raw material (except hydrogenated castor oil), further add Compound A, and use the mixture obtained by mixing with a mixer at a rotation speed of 10 rpm for 10 minutes for subsequent use. (2) Add the prescription amount of hydrogenated castor oil, and use the mixture obtained by mixing at a rotation speed of 10 rpm for 2 hours for subsequent use. (3) Encapsulation: Fill the above mixture into No. 3 hollow capsules to obtain a capsule agent.

[0125] 2. Bioequivalence test: It was the same as in Example 3.

[0126] 3. Test results:

Table 5-2

[0127] As a result of examining the bioequivalence of capsule agents with different specifications, when the capsule formulation prescription meets the dosage of 4 mg to 5.5 mg and the particle size (D90) of 3 μm to 8 μm (Examples 13, 14, 15), the C max , AUC (0-t) and AUC (0-∞) of Compound A and active metabolite H4 in the human body can all reach within the range of 80% to 125% of the geometric mean ratio and 90% confidence interval of the corresponding parameters of the control preparation (Plavix (registered trademark), 75 mg), indicating that it has postprandial bioequivalence.

[0128] (Example VI) Measurement of dissolution amount

[0129] 1. Test preparations: Example 2, Example 14.

[0130] 2. Dissolution method: Samples were collected and operated according to the dissolution and release determination method (Chinese Pharmacopoeia, 2020 Edition, Volume 4, General Rule 0931, Method 2), using 900 ml of hydrochloric acid solution with pH 1.2 or acetate buffer solution with pH 4.5 as the dissolution medium, and the rotation speed was 50 rpm / 1 minute. Solutions were collected at 5, 10, 15, 30, 45, 60, and 120 minutes. An appropriate amount of the filtrate was weighed, and the absorbance was measured at a wavelength of 220 nm according to the ultraviolet-visible spectrophotometry (General Rule 0401) to determine the dissolution amount per tablet.

[0131] 3. Dissolution results:

Table 6

[0132] In Examples 2 and 14 of the present invention, the dissolution amount at 30 minutes in the acetate buffer solution with pH 4.5 reached 70% or more, and the dissolution amount at 60 minutes reached 85% or more, and it was evaluated as complete release. Also, the dissolution amount at 10 minutes in the hydrochloric acid solution with pH 1.2 reached 99% or more, and it was evaluated that it could dissolve rapidly and completely.

[0133] It should be noted that the above description is only the optimal embodiment of the present invention. For those skilled in the art, various modifications can be made to these examples without departing from the technical principle of the present invention, and these corrections are also considered to be included in the protection scope of the present invention.

Claims

1. Use of Compound A in the manufacture of a solid preparation for the treatment and / or prevention of anticoagulation-related diseases, wherein 【Chemical 1】 The solid preparation has a particle diameter (D90) of 3 μm to 8 μm and contains a compound A which is (7aS,2'S)-2-oxo-clopidogrel represented by the above formula in a therapeutically effective amount, and the average C of compound A achieved with a single daily dose thereof ｍａｘ is 0.8 ng / ml to 1.2 ng / ml, and the use is characterized by this.

2. the therapeutically effective amount is in the range of 4 mg to 5.5 mg as a single daily dose, preferably, the therapeutically effective amount is in the range of 4 mg to 5 mg as a single daily dose, The use according to claim 1, characterized in that.

3. The average C of compound A achieved with the once-daily dose of 1 day ｍａｘ / C １２ｈ is 8 to 12, and the use according to claim 1 or 2, characterized in that

4. The use according to claim 1 or 2, characterized in that the solid preparation contains a binder.

5. The therapeutically effective amount is 4 mg as a single daily dose, and the average C of Compound A achieved with the single daily dose ｍａｘ is in the range of 80% to 125% of 0.8 ng / ml, The use according to claim 1 or 2, characterized in that.

6. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of compound A achieved with the single daily dose ｍａｘ is within the range of 80% to 125% of 0.9 ng / ml, The use according to claim 1 or 2, characterized in that.

7. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of compound A achieved with the single daily dose ｍａｘ is within the range of 80% to 125% of 1.2 ng / ml, The use according to claim 1 or 2, characterized in that.

8. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-４８ｈ） is in the range of 80% to 125% of 2.3 h*ng / ml, The use according to claim 1 or 2, characterized by this.

9. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-４８ｈ） is in the range of 80% to 125% of 3.0 h*ng / ml, and the use according to claim 1 or 2 is characterized by this.

10. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-４８ｈ） is within the range of 80% to 125% of 3.5 h*ng / ml, The use according to claim 1 or 2, characterized in that.

11. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-ｔ） is within the range of 80% to 125% of 2.3 h*ng / ml, The use according to claim 1 or 2, characterized by this.

12. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-ｔ） is within the range of 80% to 125% of 3.0 h*ng / ml, The use according to claim 1 or 2, characterized in that.

13. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-ｔ） is within the range of 80% to 125% of 3.5 h*ng / ml, and the use according to claim 1 or 2 is characterized by this.

14. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-∞） is within the range of 80% to 125% of 2.7 h*ng / ml, The use according to claim 1 or 2, characterized by this.

15. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 3.5 h*ng / ml, and the use according to claim 1 or 2 is characterized in that.

16. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 4.2 h*ng / ml, and the use according to claim 1 or 2 is characterized by this.

17. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-１２ｈ） is in the range of 80% to 125% of 13 h*ng / ml, The use according to claim 1 or 2, characterized in that.

18. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-１２ｈ） is in the range of 80% to 125% of 14 h*ng / ml, and the use according to claim 1 or 2 is characterized by this.

19. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-１２ｈ） is within the range of 80% to 125% of 18.5 h*ng / ml, and the use according to claim 1 or 2, characterized in that.

20. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-ｔ） is in the range of 80% to 125% of 13 h*ng / ml, The use according to claim 1 or 2, characterized by this.

21. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-ｔ） is in the range of 80% to 125% of 14 h*ng / ml, The use according to claim 1 or 2, characterized in that.

22. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-ｔ） is in the range of 80% to 125% of 18.5 h*ng / ml, The use according to claim 1 or 2, characterized by this.

23. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 13.5 h*ng / ml, The use according to claim 1 or 2, characterized by this.

24. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 15 h*ng / ml, and the use according to claim 1 or 2 is characterized in that.

25. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 19 h*ng / ml, and the use according to claim 1 or 2 is characterized by this.

26. The therapeutically effective amount is 4 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose ｍａｘ is in the range of 80% to 125% of 12.5 ng / ml, The use according to claim 1 or 2, characterized by this.

27. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose ｍａｘ is within the range of 80% to 125% of 14 ng / ml, and the use according to claim 1 or 2, characterized in that.

28. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose ｍａｘ is within the range of 80% to 125% of 17 ng / ml, and the use according to claim 1 or 2 is characterized in that.

29. A pharmaceutical composition for the treatment and / or prevention of anticoagulation-related diseases, comprising a therapeutically effective amount of Compound A and at least one pharmaceutically acceptable excipient, wherein [Chemical 2] the Compound A is (7aS,2'S)-2-oxo-clopidogrel represented by the above formula and having a particle size (D90) of 3 μm to 8 μm, and the excipient contains a binder, A pharmaceutical composition characterized by that.

30. The pharmaceutical composition according to claim 29, characterized in that the therapeutically effective amount is in the range of 4 mg to 5.5 mg as a single daily dose, preferably, the therapeutically effective amount is in the range of 4 mg to 5 mg as a single daily dose.

31. After the pharmaceutical composition is administered to a human subject in a therapeutically effective amount, the average C of compound A achieved at a single daily dose thereof ｍａｘ is 0.8 ng / ml to 1.2 ng / ml, and the pharmaceutical composition according to claim 29, characterized in that.

32. The pharmaceutical composition according to claim 29, characterized in that the binder is one or more selected from the group consisting of gum arabic, gelatin, sodium carboxymethyl cellulose, methyl cellulose, copovidone, povidone, and hydroxypropylmethyl cellulose.

33. The pharmaceutical composition according to any one of claims 29 to 31, further comprising a filler, a disintegrant, and a lubricant as pharmaceutically acceptable excipients.

34. the filler is one or more selected from the group consisting of mannitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, sucrose, dextrin, microcrystalline cellulose, lactose, starch, pregelatinized starch, powdered sugar, and dextrin, The disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, polyacrylic acid potassium, crospovidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and dried starch, The lubricant is one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, silica, talc powder, polyethylene glycols, hydrogenated vegetable oil, and sodium dodecyl sulfate, and the pharmaceutical composition according to claim 33 is characterized in that.

35. The pharmaceutical composition is characterized in that the dissolution amount in acetate buffer solution at pH 4.5 measured by Method 2 of General Rule 0931 of the Chinese Pharmacopoeia 2020 Edition for 30 minutes is 70% or more, and the pharmaceutical composition according to any one of claims 29 to 34.

36. The pharmaceutical composition is characterized in that the dissolution amount in acetate buffer solution at pH 4.5 measured by Method 2 of General Rule 0931 of the Chinese Pharmacopoeia 2020 Edition for 60 minutes is 85% or more, and the pharmaceutical composition according to any one of claims 29 to 34.

37. The average C of compound A achieved with the daily single dose ｍａｘ / C １２ｈ is 8 to 12, and the pharmaceutical composition according to any one of claims 29 to 34, characterized in that.

38. The therapeutically effective amount is 4 mg as a single daily dose, and the average C of compound A achieved with the single daily dose is within the range of 80% to 125% of 0.8 ng / ml. The pharmaceutical composition according to any one of claims 29 to 34, characterized in that. ｍａｘ is within the range of 80% to 125% of 0.8 ng / ml.

39. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of compound A achieved with the single daily dose ｍａｘ is within the range of 80% to 125% of 0.9 ng / ml, The use according to any one of claims 29 to 34, characterized in that.

40. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of compound A achieved with the single daily dose ｍａｘ is in the range of 80% to 125% of 1.2 ng / ml, The use according to any one of claims 29 to 34, characterized in that.

41. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-４８ｈ） is in the range of 80% to 125% of 2.3 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

42. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-４８ｈ） is within the range of 80% to 125% of 3.0 h*ng / ml, The use according to any one of claims 29 to 34, characterized by this.

43. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of compound A achieved with the single daily dose （０-４８ｈ） is in the range of 80% to 125% of 3.5 h*ng / ml, and the use according to any one of claims 29 to 34 is characterized in that.

44. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of compound A achieved with the single daily dose （０-ｔ） is in the range of 80% to 125% of 2.3 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

45. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of compound A achieved with the single daily dose （０-ｔ） is within the range of 80% to 125% of 3.0 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

46. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of compound A achieved with the single daily dose （０-ｔ） is within the range of 80% to 125% of 3.5 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

47. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of compound A achieved with the single daily dose （０-∞） is within the range of 80% to 125% of 2.7 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

48. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-∞） is within the range of 80% to 125% of 3.5 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

49. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of Compound A achieved with the single daily dose （０-∞） is within the range of 80% to 125% of 4.2 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

50. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-１２ｈ） is within the range of 80% to 125% of 13 h*ng / ml, The use according to any one of claims 29 to 34, characterized in that.

51. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-１２ｈ） is within the range of 80% to 125% of 14 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

52. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-１２ｈ） is in the range of 80% to 125% of 18.5 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

53. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-ｔ） is within the range of 80% to 125% of 13 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

54. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-ｔ） is within the range of 80% to 125% of 14 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

55. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-ｔ） is in the range of 80% to 125% of 18.5 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

56. The therapeutically effective amount is 4 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 13.5 h*ng / ml, Use according to any one of claims 29 to 34, characterized in that.

57. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 15 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

58. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average AUC of the active metabolite H4 achieved with the single daily dose （０-∞） is in the range of 80% to 125% of 19 h*ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

59. The therapeutically effective amount is 4 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose ｍａｘ is in the range of 80% to 125% of 12.5 ng / ml, The use according to any one of claims 29 to 34, characterized by this.

60. The therapeutically effective amount is 4.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose ｍａｘ is within the range of 80% to 125% of 14 ng / ml, The use according to any one of claims 29 to 34, characterized in that.

61. The therapeutically effective amount is 5.5 mg as a single daily dose, and the average C of the active metabolite H4 achieved with the single daily dose ｍａｘ is within the range of 80% to 125% of 17 ng / ml, and the use according to any one of claims 29 to 34, characterized in that.

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