Pharmaceutical composition for treating cerebral infarction

Abstract

The present invention provides a safe and effective therapy and pharmaceutical composition for treating cerebral infarction, which uses SMTP-7 (compound I) or a salt thereof. The pharmaceutical composition contains SMTP-7 (compound I) or a pharmacologically acceptable salt thereof, and is administered at a dose of 1 to 6 mg / kg as SMTP-7 (compound I) or a salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Japanese Patent Application No. 2021-079820, filed on May 10, 2021, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention relates to a pharmaceutical composition for treating cerebral infarction, which contains a specific dose of SMTP-7 as an active ingredient. [Background technology]

[0003] Cerebral infarction is one of the leading causes of death in developed countries. Even if a patient's life is saved, there is a high possibility that they will be left with residual disabilities such as paralysis. Cerebral infarction is effectively treated by reopening the blocked area. However, the return of blood flow to the area damaged by cerebral infarction can cause hemorrhagic cerebral infarction, which can worsen life and functional prognosis.

[0004] Thrombolytic therapy, which involves intravenous administration of a thrombolytic agent, rt-PA, and physical thrombectomy by endovascular surgery are known as treatments for reopening blocked blood vessels during the acute phase of cerebral infarction. Currently, rt-PA, which is used as the first-line drug, can be administered to patients 4.5 hours after the onset of symptoms. This drug shows a strong thrombolytic effect, but is highly likely to cause hemorrhagic side effects. There are strict restrictions other than the timing of administration. The proportion of patients who can be administered rt-PA is less than 10% of all cerebral infarction patients. Even when rt-PA can be administered, a few percent of patients develop severe intracranial hemorrhagic side effects, and in some cases the condition may worsen.

[0005] Intravascular surgery can only be performed in limited facilities, and the condition for surgical treatment is major artery occlusion. 80 to 90 percent of patients do not meet the condition and are outside the scope of application. There is a high possibility of bleeding over time due to reperfusion abnormality, similar to patients who have received rt-PA treatment. In that case, if a drug that has not only a thrombolytic effect but also an effect of suppressing intracranial bleeding is developed, the number of applicable subjects can be increased and side effects can be reduced. The drug of the present invention will be an innovative cerebral infarction treatment agent.

[0006] SMTP (Stachybotrys Microspora triprenylphenol) compounds, which have a triprenylphenol skeleton and refer to a group of compounds produced by filamentous fungi, are known to exhibit thrombolytic and angiogenesis inhibitory effects (Patent Documents 1-3). SMTP compounds induce structural changes in plasminogen, and as a result, promote thrombolysis. Therefore, it is possible to avoid the induction of excessive plasmin production, and the risk of developing hemorrhagic side effects is reduced (Non-Patent Document 1). Furthermore, SMTP compounds inhibit soluble epoxy hydrolase (sEH), thereby producing anti-inflammatory activity (Non-Patent Document 2) and antioxidant activity, resulting in a cerebral protective effect. The present inventors have already confirmed, as a result of experiments using animal models, that one of the SMTP compounds, SMTP-7, is effective in treating cerebral infarction (Patent Document 4). Summary of the Invention

[0007] It is an object of the present invention to provide a safe and effective therapy and pharmaceutical composition using SMTP-7 (Compound I) or a salt thereof in patients with cerebral infarction.

[0008] The present inventors conducted a clinical trial in which SMTP-7 (Compound I) was administered to healthy subjects and cerebral infarction patients, and as a result, the present inventors found a safe and effective dose of SMTP-7 for cerebral infarction patients.

[0009] The present invention is based on the results of the above clinical trials and relates to the following items [1] to

[50] . [1] A pharmaceutical composition for treating cerebral infarction, comprising compound I represented by the following formula (I) or a salt thereof, which is administered to a subject at a dose of 1 to 6 mg / kg as compound I: [ka]

[0010] [2] The pharmaceutical composition according to [1], wherein compound I is administered to a subject at a dose of 1 mg / kg.

[0011] [3] The pharmaceutical composition according to [1], wherein compound I is administered to a subject at a dose of 3 mg / kg.

[0012] [4] The pharmaceutical composition according to [1], wherein compound I is administered to a subject at a dose of 6 mg / kg.

[0013] [5] The pharmaceutical composition according to any one of [1] to [4], which is administered to a subject within 12 hours after the onset of cerebral infarction.

[0014] [6] The pharmaceutical composition according to any one of [1] to [4], which is administered to a subject 3 to 12 hours after the onset of cerebral infarction.

[0015] [7] The pharmaceutical composition according to any one of [1] to [4], which is administered to a subject 4.5 to 12 hours after the onset of cerebral infarction.

[0016] [8] The pharmaceutical composition according to any one of [1] to [7], which is administered to a subject at risk of causing bleeding.

[0017] [9] The pharmaceutical composition according to [8], wherein the bleeding is intracranial or extracranial bleeding, and the intracranial hemorrhage is, for example, symptomatic intracranial hemorrhage or intracranial hemorrhage resulting in a worsening of the NIHSS score by 4 or more points.

[0018]

[10] The pharmaceutical composition according to any one of [1] to [9], which is administered to a subject suffering from cerebral infarction accompanied by vascular occlusion, including partial occlusion.

[0019]

[11] The pharmaceutical composition according to any one of [1] to

[10] , wherein the composition is administered intravenously.

[0020]

[12] The pharmaceutical composition according to any one of [1] to

[11] , which is administered once a day, preferably in a single dose.

[0021]

[13] The pharmaceutical composition according to any one of [1] to

[12] , which is administered as a bolus followed by continuous administration.

[0022]

[14] The pharmaceutical composition according to

[13] , which is administered intravenously over 1 minute and then infused intravenously over 30 minutes.

[0023]

[15] The pharmaceutical composition according to any one of [1] to

[14] , which can be administered to a subject for whom administration of a thrombolytic agent or physical thrombectomy is difficult or impossible.

[0024]

[16] The pharmaceutical composition described in

[15] , wherein the thrombolytic agent is tissue plasminogen activator.

[0025]

[17] The pharmaceutical composition according to any one of [1] to

[16] , wherein the cerebral infarction is atherothrombotic / embolic cerebral infarction, cardiogenic cerebral infarction, or lacunar cerebral infarction.

[0026]

[18] The pharmaceutical composition according to any one of [1] to

[17] , wherein a single dose of Compound I or a salt thereof is contained in a sealed container together with a pharmacologically acceptable carrier.

[0027]

[19] The pharmaceutical composition according to any one of [1] to

[18] , wherein 20 mg to 1000 mg of compound I or a salt thereof is contained in a sealed container together with a pharmacologically acceptable carrier.

[0028]

[20] A pharmaceutical composition comprising compound I or a salt thereof, which is administered to a subject within 12 hours after the onset of cerebral infarction.

[0029]

[21] The pharmaceutical composition described in

[20] , which is administered to a subject 3 to 12 hours after the onset of cerebral infarction.

[0030]

[22] The pharmaceutical composition described in

[20] , which is administered to a subject 4.5 to 12 hours after the onset of cerebral infarction.

[0031]

[23] The pharmaceutical composition according to any one of

[20] to

[22] , wherein compound I is administered to a subject at a dose of 1 to 6 mg / kg.

[0032]

[24] The pharmaceutical composition according to any one of

[20] to

[22] , wherein compound I is administered to a subject at a dose of 1 mg / kg.

[0033]

[25] The pharmaceutical composition according to any one of

[20] to

[22] , wherein compound I is administered to a subject at a dose of 3 mg / kg.

[0034]

[26] The pharmaceutical composition according to any one of

[20] to

[22] , wherein compound I is administered to a subject at a dose of 6 mg / kg.

[0035]

[27] The pharmaceutical composition according to any one of

[20] to

[26] , which is administered to a subject at risk of causing bleeding.

[0036]

[28] The pharmaceutical composition according to

[27] , wherein the bleeding is intracranial or extracranial bleeding, and the intracranial hemorrhage is, for example, symptomatic intracranial hemorrhage or intracranial hemorrhage resulting in a worsening of the NIHSS score by 4 or more points.

[0037]

[29] The pharmaceutical composition according to any one of

[20] to

[28] , which is administered to a subject suffering from cerebral infarction accompanied by vascular occlusion, including partial occlusion.

[0038]

[30] The pharmaceutical composition according to any one of

[20] to

[29] , which is administered intravenously.

[0039]

[31] The pharmaceutical composition according to any one of

[20] to

[30] , which is administered once a day, preferably in a single dose.

[0040]

[32] The pharmaceutical composition according to any one of

[20] to

[31] , which is administered as a bolus followed by continuous administration.

[0041]

[33] The pharmaceutical composition according to

[32] , which is administered intravenously over 1 minute and then infused intravenously over 30 minutes.

[0042]

[34] The pharmaceutical composition according to any one of

[20] to

[33] , which can be administered to a subject for whom administration of a thrombolytic agent or physical thrombectomy is difficult or impossible.

[0043]

[35] The pharmaceutical composition described in

[34] , wherein the thrombolytic agent is tissue plasminogen activator.

[0044]

[36] The pharmaceutical composition according to any one of

[20] to

[35] , wherein the cerebral infarction is atherothrombotic / embolic cerebral infarction, cardiogenic cerebral infarction, or lacunar cerebral infarction.

[0045]

[37] A pharmaceutical composition for treating cerebral infarction, comprising compound I or a salt thereof, the composition reopening occluded blood vessels in cerebral infarction (the composition is an agent for reopening occluded blood vessels).

[0046]

[38] A pharmaceutical composition for treating cerebral infarction, comprising compound I or a salt thereof, the pharmaceutical composition being administered to a subject at risk of causing bleeding.

[0047]

[39] A pharmaceutical composition for reducing a risk of causing bleeding in cerebral infarction, comprising compound I or a salt thereof.

[0048]

[40] A pharmaceutical composition for treating cerebral infarction, comprising compound I or a salt thereof, the pharmaceutical composition improving independent living after cerebral infarction.

[0049]

[41] The pharmaceutical composition according to

[40] , wherein the indicator of improvement in independent living is a result of 0 to 1 on the mRS (modified Rankin Scale) 90 days after administration.

[0050]

[42] The pharmaceutical composition according to

[40] , wherein the indicator of improvement in independent living is a result of 0 to 2 on the mRS (modified Rankin Scale) 90 days after administration.

[0051]

[43] A pharmaceutical composition for treating cerebral infarction, comprising compound I or a salt thereof, said pharmaceutical composition having an effect of dissolving thrombus in a patient suffering from cerebral infarction.

[0052]

[44] A pharmaceutical composition for treating cerebral infarction, comprising Compound I or a salt thereof, the pharmaceutical composition having a low risk of hemorrhagic side effects, for example, a low risk of hemorrhagic side effects compared to conventional drugs for treating cerebral infarction (e.g., tPA).

[0053]

[45] The pharmaceutical composition described in

[44] , wherein the hemorrhagic side effect is symptomatic intracranial hemorrhage.

[0054]

[46] The pharmaceutical composition according to any one of [1] to

[45] , comprising either or both of a basic additive and an amphiphilic additive.

[0055]

[47] The pharmaceutical composition according to

[46] , wherein the basic additive is one or more selected from the group consisting of amino sugars, alkanolamines, and trometamol salts, preferably one or more selected from the group consisting of meglumine, triethanolamine, and trometamol hydrochloride, and the amphiphilic additive is one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol, polysorbate, polyethylene glycol, ursodeoxycholic acid, sorbitan fatty acid ester, and sodium deoxycholate, preferably one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate.

[0056]

[48] ​​The pharmaceutical composition according to any one of [1] to

[47] , wherein compound I is SMTP-7 represented by formula (II). [ka]

[0057]

[49] The pharmaceutical composition according to any one of [1] to

[48] , wherein the cerebral infarction is an ischemic stroke.

[0058]

[50] The pharmaceutical composition described in

[49] , wherein the ischemic stroke is acute ischemic stroke.

[0059] The pharmaceutical compositions described in

[37] to

[45] may have one or more of the characteristics defined by [1] to

[19] .

[0060] According to another aspect, the present invention provides the following [1] to

[43] .

[0061] [1] A method for treating cerebral infarction, comprising administering to a subject compound I represented by the following formula (I) or a salt thereof, wherein compound I or a salt thereof is administered at a dose of 1 to 6 mg / kg as compound I: [ka]

[0062] [2] The method according to [2], wherein compound I or a salt thereof is administered to the subject at a dose of 1 mg / kg.

[0063] [3] The method according to [2], wherein compound I or a salt thereof is administered to the subject at a dose of 3 mg / kg.

[0064] [4] The method according to [2], wherein compound I or a salt thereof is administered to the subject at a dose of 6 mg / kg.

[0065] [5] The method according to any one of [1] to [4], wherein the subject has had a cerebral infarction within 12 hours of onset.

[0066] [6] The method according to any one of [1] to [4], wherein the subject is a subject 3 to 12 hours after the onset of cerebral infarction.

[0067] [7] The method according to any one of [1] to [4], wherein the subject is a subject 4.5 to 12 hours after the onset of cerebral infarction.

[0068] [8] The method according to any one of [1] to [7], wherein the subject is a subject at risk of developing bleeding.

[0069] [9] The method according to [8], wherein the bleeding is intracranial or extracranial bleeding, and the intracranial bleeding is, for example, symptomatic intracranial bleeding or intracranial bleeding resulting in a worsening of the NIHSS score by 4 or more points.

[0070]

[10] The method according to any one of [1] to [9], wherein the subject includes a subject having a vascular occlusion, including partial occlusion.

[0071]

[11] The method according to any one of [1] to

[10] , wherein compound I or a salt thereof is administered intravenously.

[0072]

[12] The method according to any one of [1] to

[11] , wherein compound I or a salt thereof is administered once a day, preferably in a single dose.

[0073]

[13] The method according to any one of [1] to

[12] , wherein Compound I or a salt thereof is administered as a bolus followed by continuous administration.

[0074]

[14] The pharmaceutical composition according to

[13] , wherein compound I or a salt thereof is administered intravenously over 1 minute, followed by intravenous infusion over 30 minutes.

[0075]

[15] The method according to any one of [1] to

[14] , wherein the subject includes a subject for whom administration of a thrombolytic agent or physical thrombectomy is difficult or impossible.

[0076]

[16] The method according to

[15] , wherein the thrombolytic agent is tissue plasminogen activator.

[0077]

[17] The method according to any one of [1] to

[16] , wherein the cerebral infarction is atherothrombotic / embolic cerebral infarction, cardiogenic cerebral infarction, or lacunar cerebral infarction.

[0078]

[18] A method for treating cerebral infarction, comprising administering compound I or a salt thereof to a subject, wherein the subject has experienced an onset of cerebral infarction within 12 hours.

[0079]

[19] The method according to

[18] , wherein the subject is a subject 3 to 12 hours after the onset of cerebral infarction.

[0080]

[20] The method according to

[18] , wherein the subject is a subject 4.5 to 12 hours after the onset of cerebral infarction.

[0081]

[21] The method according to any one of

[18] to

[20] , wherein compound I or a salt thereof is administered to the subject at a dose of 1 to 6 mg / kg as compound I.

[0082]

[22] The method according to any one of

[18] to

[20] , wherein compound I or a salt thereof is administered to the subject at a dose of 1 mg / kg as compound I.

[0083]

[23] The method according to any one of

[18] to

[20] , wherein compound I or a salt thereof is administered to the subject at a dose of 3 mg / kg as compound I.

[0084]

[24] The method according to any one of

[18] to

[20] , wherein compound I or a salt thereof is administered to the subject at a dose of 6 mg / kg as compound I.

[0085]

[25] The method according to any one of

[18] to

[24] , wherein the subject is a subject at risk of developing bleeding.

[0086]

[26] The method according to

[25] , wherein the bleeding is intracranial or extracranial bleeding, and the intracranial bleeding is, for example, symptomatic intracranial bleeding or intracranial bleeding resulting in a worsening of the NIHSS score by 4 or more points.

[0087]

[27] The method according to any one of

[18] to

[26] , wherein the subject has a vascular occlusion, including partial occlusion.

[0088]

[28] The method according to any one of

[18] to

[27] , wherein compound I or a salt thereof is administered intravenously.

[0089]

[29] The method according to any one of

[18] to

[28] , wherein compound I or a salt thereof is administered once a day, preferably in a single dose.

[0090]

[30] The method according to any one of

[18] to

[29] , wherein compound I or a salt thereof is administered as a bolus followed by continuous administration.

[0091]

[31] The method according to

[30] , wherein compound I or a salt thereof is administered intravenously over 1 minute, followed by infusion over 30 minutes.

[0092]

[32] The method according to any one of

[18] to

[31] , wherein the subject includes a subject for whom administration of a thrombolytic agent or physical thrombectomy is difficult or impossible.

[0093]

[33] The method according to

[32] , wherein the thrombolytic agent is tissue plasminogen activator.

[0094]

[34] The method according to any one of

[18] to

[33] , wherein the cerebral infarction is atherothrombotic / embolic cerebral infarction, cardiogenic cerebral infarction, or lacunar cerebral infarction.

[0095]

[35] A method for recanalizing an obstructed blood vessel, comprising administering compound I or a salt thereof to a subject.

[0096]

[36] A method for treating cerebral infarction, comprising administering compound I or a salt thereof to a subject, wherein the subject is at risk of hemorrhagic stroke.

[0097]

[37] A method for reducing a hemorrhagic risk in cerebral infarction, comprising administering compound I or a salt thereof to a subject.

[0098]

[38] A method for improving independent living after cerebral infarction, comprising administering compound I or a salt thereof to a subject. Alternatively, a method for treating cerebral infarction, comprising administering compound I or a salt thereof to a subject, wherein the method improves independent living after cerebral infarction.

[0099]

[39] The indicator of improvement in independent living is a modified Rankin Scale (mRS) score of 0 to 1 on the 90th day after administration, as described in

[38] .

[0100]

[40] The indicator of improvement in independent living is a modified Rankin Scale (mRS) score of 0 to 2 on the 90th day after administration, as described in

[38] .

[0101]

[41] A method for dissolving a thromboembolism in a patient with cerebral infarction, comprising administering compound I or a salt thereof. Alternatively, a method for treating cerebral infarction, comprising administering compound I or a salt thereof, wherein a thrombus in a patient with cerebral infarction is dissolved.

[0102]

[42] A method for treating cerebral infarction, comprising administering to a subject Compound I or a salt thereof, the method having a low risk of hemorrhagic side effects, for example, a low risk of hemorrhagic side effects compared to conventional drugs for cerebral infarction (e.g., tPA).

[0103]

[43] The method according to

[42] , wherein the hemorrhagic side effect is symptomatic intracranial hemorrhage.

[0104] The methods according to

[35] -

[43] may have one or more of the features defined by [1]-

[17] .

[0105] According to the present invention, cerebral infarction can be safely and effectively treated using SMTP-7. In particular, cerebral infarction patients who cannot be treated with conventional thrombolytic agents can be treated with a new drug therapy. [Brief description of the drawings]

[0106] [Figure 1] 1 shows a flowchart of a placebo-controlled, randomized, double-blind study in healthy subjects (Phase I study). [Diagram 2] 1 shows comparative plasma TMS-007 pharmacokinetic parameters in rats, monkeys, and humans. [Diagram 3] Pharmacokinetic parameters (plasma TMS-007 concentration, Cmax, AUC) in monkeys and humans are shown. [Figure 4] Pharmacokinetic parameters in humans (healthy subjects) are shown. [Diagram 5] Details of subjects in a single-dose study (Phase II study) in patients with cerebral infarction are shown below. [Figure 6] Details of the analysis population in the single-dose study in patients with cerebral infarction (Phase II study) are shown below. [Figure 7]The original mRS scores on day 90 after administration between the placebo group and the FAS group (TMS-007 1 mg administration group) are shown. [Figure 8] The original mRS scores on day 90 after administration between the placebo group and the FAS group (TMS-007 3 mg administration group) are shown. [Figure 9] The original mRS scores at 90 days after administration between the placebo group and the FAS group (TMS-007 6 mg group) are shown. [Figure 10] The original mRS scores on day 90 after administration between the placebo group and the FAS group (TMS-007 combination group) are shown. [Figure 11] Box plots of plasma drug concentrations in different dose groups 31 minutes after the start of administration of the investigational drug, i.e., in the PK analysis population, are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] In this specification, when a numerical range is expressed as A to B, the numerical values ​​before and after the "to" are included as the lower limit and upper limit, respectively.

[0108] In this specification, when the amount of a component of a composition is described, if multiple substances corresponding to that component are present in the composition, the amount refers to the total amount of those substances present in the composition, unless otherwise specified.

[0109] In the present specification, when a group (atomic group) is described, unless the description of "substituted" or "unsubstituted" is found, it is intended to include both a group having a substituent and a group having no substituent. For example, an "alkyl group" includes not only an alkyl group having no substituent (an unsubstituted alkyl group) but also an alkyl group having a substituent (a substituted alkyl group).

[0110] In this specification, the term "step" includes not only independent steps, but also indistinguishable steps, even if they cannot be clearly distinguished from other steps, as long as the intended task is achieved by the step.

[0111] In this specification, "mass %" and "weight %" are used interchangeably, and "parts by mass" and "parts by weight" are used interchangeably. In this specification, the terms "weight average molecular weight (Mw)" and "number average molecular weight (Mn)" refer to molecular weights separated by a gel permeation chromatography (GPC) apparatus using a column of TSKgel GMHxL, TSKgel G4000HxL, or TSKgel G2000HxL (all of which are trade names of Tohso Corporation) and a solvent of THF (tetrahydrofuran), and detected by a differential refractometer through calculation based on polystyrene used as a standard substance, unless otherwise specified.

[0112] 1. Pharmaceutical Compositions (1) Active ingredient The pharmaceutical composition of the present invention contains compound I represented by formula (I), and specifically contains SMTP-7 represented by formula (II) as an active ingredient. [ka] Chemical Name:2,5-bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-oxo-3,6,7,8-tetrahydro-1H-9-oxa-2-azacyclopenta[a]naphthalen-2-yl]-pentanoic acid Molecular formula:C 51 H 68 N2O 10 Molecular weight: 869.09 [ka] Chemical name: (S)-2,5-bis((2S,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid Molecular formula:C 51H 68 N2O 10 Molecular weight: 868.49

[0113] Compound I can be in the form of a pharma- ceutically acceptable salt. Inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, or citric acid, organic acids such as formic acid, fumaric acid, malic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, or p-toluenesulfonic acid, alkali metals and alkaline earth metals such as sodium, potassium, calcium, or magnesium, basic amines, and basic amino acids are suitable for forming salts of Compound I.

[0114] Examples of suitable salts of Compound I include the sodium, potassium, calcium, and magnesium salts, with the sodium and potassium salts being preferred, and the sodium salt being most preferred.

[0115] Compound I may be chemically synthesized or may be obtained by purification from a culture of a filamentous fungus such as Stachybotrys microspore. Methods for producing Compound I are described, for example, in JP 2004-224737 A, JP 2004-224738 A, and WO 2007 / 111203 A.

[0116] Compound I can be an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers. Such enantiomer, diastereomer, mixture of enantiomers, or mixture of diastereomers can be obtained by chemical synthesis or by purification from the culture of filamentous fungi. When compound I is obtained from filamentous fungi, it can be obtained mainly by adding L-ornithine to the culture medium of filamentous fungi.

[0117] Compound I has thrombolytic, anti-inflammatory and antioxidant effects, and as a result, Compound I exerts cytoprotective and neuroprotective effects in addition to thrombolytic effects, and thus exerts preventive or therapeutic effects against ischemic disorders such as cerebral infarction.

[0118] (2) Composition / dosage form In the pharmaceutical composition of the present invention, the content of Compound I relative to the total mass of the pharmaceutical composition is preferably 1% by mass to 80% by mass, more preferably 5% by mass to 60% by mass, and even more preferably 5% by mass to 50% by mass.

[0119] The pharmaceutical composition of the present invention is an intravenous preparation (injection). The intravenous preparation includes a sterile aqueous solution or a non-aqueous solvent, a suspension, or an emulsion. Examples of aqueous solvents include distilled water for injection and saline. Examples of non-aqueous solvents include alcohols such as ethanol. The pharmaceutical composition of the present invention may further contain a pharma- ceutically acceptable carrier such as an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a dissolving agent.

[0120] Preferably, the pharmaceutical composition of the present invention contains a basic excipient and / or an amphiphilic excipient.

[0121] Examples of basic additives include alkanolamines such as triethanolamine, monoethanolamine, diisopropanolamine, and triisopropanolamine; trometamol (trihydroxymethylaminomethane) or a salt thereof; amino acids such as glycine; and amino sugars such as meglumine. Among these, at least one selected from the group consisting of amino sugars, alkanolamines, and trometamol salts is preferably contained, at least one selected from the group consisting of meglumine, triethanolamine, and trometamol hydrochloride is more preferably contained, at least one of meglumine and trometamol hydrochloride is even more preferably contained, and meglumine is even more preferably contained.

[0122] The content of the basic additive is preferably 0.1% by mass to 60% by mass, more preferably 1% by mass to 40% by mass, and further preferably 2% by mass to 30% by mass, based on the total mass of the pharmaceutical composition.

[0123] As the amphiphilic additive that can be used, any one of anionic amphiphilic additives, cationic amphiphilic additives, amphoteric amphiphilic additives, and nonionic amphiphilic additives can be used. Among these, nonionic amphiphilic additives are preferred.

[0124] The nonionic amphiphilic additive is preferably at least one selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol, polysorbate, polyethylene glycol, ursodesoxycholic acid, sorbitan fatty acid ester, and sodium desoxycholate, more preferably at least one selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate, polyoxyethylene castor oil, or polyoxyethylene hydrogenated castor oil, and particularly preferably polyoxyethylene hydrogenated castor oil.

[0125] The total number of oxyethylene units contained in the polyoxyethylene hydrogenated castor oil is not particularly limited, but is preferably 2-150, and more preferably 10-100.

[0126] When the above-mentioned amphipathic additive is contained, the content of the amphipathic additive relative to the total mass of the pharmaceutical composition is preferably 1% by mass to 80% by mass, more preferably 5% by mass to 70% by mass, and even more preferably 5% by mass to 60% by mass.

[0127] A preferred pharmaceutical composition of the present invention contains the sodium salt of Compound I, meglumine, and polyoxyethylene hydrogenated castor oil.

[0128] The pharmaceutical composition of the present invention may contain a sterile aqueous solution or a non-aqueous solvent. Examples of aqueous solvents include distilled water for injection and saline. Examples of non-aqueous solvents include alcohols such as ethanol. In addition to these, the pharmaceutical composition of the present invention may further contain a pharmacologically acceptable carrier such as an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, a pH adjuster (e.g., hydrochloric acid, sodium hydroxide), or a dissolution aid.

[0129] When the pharmaceutical composition contains other additives, the content of the other additives relative to the total mass of the pharmaceutical composition is preferably 0.1% by mass to 80% by mass, more preferably 1% by mass to 60% by mass, although this varies depending on the dosage form of the pharmaceutical composition. For example, in the case of a freeze-dried injection preparation prepared at the time of use, the content of the other additives (excluding the mass of the diluent injection agent) relative to the total mass of the pharmaceutical composition is preferably 0.1% by mass to 80% by mass, more preferably 1% by mass to 60% by mass.

[0130] The pharmaceutical composition of the present invention may be a preparation prepared at the time of use, or may be a preparation ready to use.For example, the pharmaceutical composition may be the preparation obtained by putting Compound I or its salt together with pharmacologically acceptable carrier into an ampoule or a syringe and sealing it airtight.

[0131] The pharmaceutical composition of the present invention may contain a sterile aqueous solution or a non-aqueous solvent in addition to the basic additive and amphipathic additive described above. Examples of aqueous solvents include distilled water for injection and saline. Examples of non-aqueous solvents include alcohols such as ethanol. In addition to these, the pharmaceutical composition of the present invention may further contain a pharmacologically acceptable carrier such as an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a dissolving agent.

[0132] 2. Target (Efficacy / Effectiveness) The pharmaceutical composition of the present invention is used for the prevention or treatment of cerebral infarction, and is particularly used for the treatment of cerebral infarction.

[0133] The cerebral infarction (including cerebral thrombosis and cerebral embolism) targeted by the pharmaceutical composition of the present invention includes cerebral infarction occurring within 12 hours after the onset.

[0134] The pharmaceutical composition of the present invention may be applied to subjects to whom conventional reperfusion therapy is not easily applicable or is not applicable. Examples of conventional reperfusion therapy include administration of thrombolytic agents and physical thrombectomy (percutaneous transluminal cerebral thrombectomy).

[0135] Examples of thrombolytic agents include urokinase, pro-urokinase, tissue plasminogen activator (t-PA), nasaruplase, and streptokinase. t-PA may be naturally occurring t-PA or recombinant t-PA. Currently available t-PA in clinical practice is all recombinant t-PA (rt-PA), including, for example, alteplase, tisokinase, pamiteplase, and rt-PAs currently under development, such as tenecteplase and desmoteplase.

[0136] When a thrombolytic agent is applied to cerebral infarction, the administration period of the thrombolytic agent is limited. For example, urokinase must be applied within 6 hours from the onset, and t-PA must be applied within 4.5 hours (e.g., in Japan) or within 3 hours (e.g., in the United States) from the onset. The pharmaceutical composition of the present invention has a long administration period and is therefore suitable for patients to whom conventional thrombolytic agents cannot be applied, for example, patients 3 to 12 hours or 4.5 to 12 hours after the onset of cerebral infarction. Please note that when the onset time is not clearly known, the most recent asymptomatic time (the most recent time when it is confirmed that the patient is not symptomatic) is regarded as the onset time.

[0137] The pharmaceutical composition of the present invention can be applied to patients who have stopped administering thrombolytic agents because of the appearance of contraindication symptoms or signs during administration of thrombolytic agents. Examples of contraindication signs include bleeding diathesis, bleeding, hypertension, and glycemic disorders. In addition, the pharmaceutical composition of the present invention can be applied to cerebral infarction patients who cannot be administered thrombolytic agents due to the high risk of intracranial bleeding.

[0138] The pharmaceutical composition of the present invention may be applied before or after thrombectomy using a percutaneous transluminal cerebral thrombectomy device.

[0139] Cerebral infarction is roughly classified into lacunar cerebral infarction, cardiogenic cerebral infarction, and atherothrombotic cerebral infarction (atherothrombotic cerebral infarction and atherothrombotic cerebral infarction) according to the cause. The pharmaceutical composition of the present invention can be applied to any one of cerebral infarction. Cerebral infarction is used interchangeably with ischemic stroke. Acute cerebral infarction is used interchangeably with acute ischemic stroke. Ischemic stroke is usually acute ischemic stroke, which accounts for nearly 90% of all strokes.

[0140] 3. Dosage and Administration The dose of the pharmaceutical composition of the present invention is not particularly limited, but is preferably within the range of 1 to 6 mg / kg in terms of the equivalent amount of compound I (free form) for an adult. The dose is not limited as long as it is within the range of 1 to 6 mg / kg. The dose may be any one of 1 to 3 mg / kg, 3 to 6 mg / kg, 1 mg / kg, 3 mg / kg, and 6 mg / kg.

[0141] The frequency of administration is not particularly limited, and may be once or multiple times a day. The interval and period of multiple administrations can be selected by those skilled in the art according to clinical findings, imaging findings, hematological findings, coexisting diseases, and medical history.

[0142] The route of administration of the pharmaceutical composition of the present invention is not particularly limited, but is preferably intravenous administration.

[0143] The pharmaceutical composition of the present invention, more specifically, a single dose of compound I or a salt thereof, can be contained in a sealed container together with a pharmacologically acceptable carrier. A single dose can be obtained by multiplying the dose per kg of body weight by the patient's body weight. Usually, a single dose can be obtained by multiplying the dose per kg of body weight (e.g., 1-6 mg / kg) by the average adult body weight (e.g., 50 kg, 60 kg, 70 kg). For example, when the dose per kg of body weight is 1-6 mg / kg and the average adult body weight is 60 kg, the single dose is 60-360 mg (equivalent to compound I (free form)).

[0144] In the pharmaceutical composition of the present invention, the compound I or a salt thereof may be contained in a sealed container together with a pharmacologically acceptable carrier in an amount 10%, 20%, or 30% more than a single dose (standard dose) to allow flexible control. Alternatively, a half dose of the compound I or a salt thereof may be contained in a sealed container together with a pharmacologically acceptable carrier. In other words, in the pharmaceutical composition of the present invention, 20 mg to 1000 mg of the compound I or a salt thereof may be contained in a sealed container together with a pharmacologically acceptable carrier, preferably 30 to 900 mg of the compound I or a salt thereof, more preferably 40 to 800 mg of the compound I or a salt thereof may be contained in a sealed container together with a pharmacologically acceptable carrier.

[0145] The method of administration of the pharmaceutical composition of the present invention is not limited, but a single dose of compound I is first administered as a bolus, followed by continuous administration. For example, a method can be used in which 10% of the single dose is administered as a bolus, followed by 90% of the dose administered by infusion over 30 minutes to 1 hour. Usually, intravenous administration is performed over 1 minute, followed by infusion over 30 minutes.

[0146] For repeated administration, it is preferred to administer immediately after onset of symptoms, within 12 hours of onset of symptoms, and once daily for 7 days. It is preferred to administer intravenously over 1 minute per hour, followed by a 30 minute infusion.

[0147] The pharmaceutical composition of the present invention may be used in combination with other drugs, provided that the use is not contrary to the object of the present invention. As described above, the pharmaceutical composition of the present invention may be administered to patients to whom a thrombolytic agent cannot be applied. However, this specification does not intend to prohibit the use in combination with a thrombolytic agent. Therefore, the pharmaceutical composition of the present invention may be used in combination with a thrombolytic agent, a platelet aggregation inhibitor, and a blood coagulation inhibitor (anticoagulant).

[0148] After the onset of cerebral infarction, some patients are likely to bleed due to vascular damage (e.g., during reperfusion). However, the pharmaceutical composition of the present invention effectively prevents the transition to a hemorrhagic state and reduces the tendency to bleed.

[0149] The pharmaceutical composition of the present invention reduces the risk of bleeding compared to conventional cerebral infarction drugs or therapies (e.g., tPA). In particular, the risk of intracranial bleeding, such as symptomatic intracranial hemorrhage, is lower than that of conventional therapies. In a clinical phase II study (described below), symptomatic intracranial hemorrhage with a worsening of NIHSS score of 4 or more points was shown.

[0150] The fundamental treatment for cerebral infarction is the recanalization of the occluded site, but the re-supply of blood flow to the pre-formed cerebral infarction site may induce hemorrhagic cerebral infarction, which may worsen the life and functional prognosis. This is a dilemma case. tPA, which is the first-choice drug used to treat the recanalization of occluded blood vessels in the acute stage of cerebral infarction, has a strong thrombolytic effect, but is highly likely to cause hemorrhagic side effects. The pharmaceutical composition of the present invention has a lower risk of causing hemorrhagic side effects (e.g., symptomatic intracranial hemorrhage) compared with conventional cerebral infarction drugs (e.g., tPA). Since the pharmaceutical composition of the present invention has thrombolytic ability, the occluded blood vessels are recanalized, and the symptoms of cerebral infarction patients are improved. Therefore, the pharmaceutical composition of the present invention can be administered to subjects at risk of hemorrhage, such as intracranial or extracranial hemorrhage, and subjects suffering from cerebral infarction accompanied by vascular occlusion, including partial occlusion.

[0151] 3. Methods for treating or preventing cerebral infarction The present invention provides a method for treating or preventing cerebral infarction, comprising administering the pharmaceutical composition of the present invention or compound I or a salt thereof to a patient in need thereof. The dose, administration interval, administration period, and administration method of the pharmaceutical composition (compound I or a salt thereof) are the same as those described for the pharmaceutical composition of the present invention. The method is characterized by reducing the risk of causing bleeding in the subject and reopening occluded blood vessels, including partial occlusion.

[0152] The present invention also provides a method for reopening a blood vessel occluded by cerebral infarction, comprising administering the pharmaceutical composition of the present invention or compound I or a salt thereof to a patient in need thereof.

[0153] The present invention also provides a method for improving independent life after cerebral infarction, comprising administering the pharmaceutical composition of the present invention or compound I or a salt thereof to a patient in need thereof. The improvement in independent life can be evaluated, for example, based on a result of mRS (modified Rankin Scale) of 0 to 1 on the 90th day after administration, or a result of mRS (modified Rankin Scale) of 0 to 2 on the 90th day after administration.

[0154] By administering the pharmaceutical composition of the present invention, cerebral infarction can be improved, and at least one selected from the group consisting of neurological symptoms associated with cerebral infarction, impaired ability to perform daily living associated with cerebral infarction, and functional impairment associated with cerebral infarction can be improved. EXAMPLES

[0155] The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. In addition, unless otherwise specified, "%" represents % by mass.

[0156] Reference Example 1: Toxicity test by repeated administration to rats for 2 weeks Under non-anesthetized and non-restrained conditions, rats (12 males and 12 females) were repeatedly and intravenously administered TMS-007 (prepared as its sodium salt) at doses of 2.4, 12, and 60 mg / kg (continuously over 30 minutes) once a day for 2 weeks. The rats were dissected the day after completing the repeated administration. As a result, the NOAEL of the repeated administration toxicity test in rats was determined to be 60 mg / kg or higher.

[0157] Reference Example 2: Toxicity test using repeated administration to cynomolgus monkeys for 2 weeks Under non-anesthetized and non-restrained conditions, cynomolgus monkeys (3 males per group and 3 females per group) were repeatedly and intravenously administered TMS-007 (prepared as its sodium salt) at doses of 3, 10, and 30 mg / kg (continuously over 30 minutes) once daily for 2 weeks. The cynomolgus monkeys were dissected the day after completing the repeated administration. As a result, the NOAEL of the toxicity study by repeated administration to cynomolgus monkeys was determined to be 10 mg / kg or more in both male and female groups.

[0158] Example 1: Placebo-controlled randomized double-blind study in healthy subjects (Phase I study) 1. Test Method A Phase I study (placebo-controlled, randomized, double-blind study) was conducted in healthy adult males. Five cohorts, each consisting of eight subjects (six receiving active drug and two receiving placebo), were included in the study. TMS-007 (SMTP-7 sodium salt formulation) or placebo was administered intravenously over 31 minutes (1 minute bolus + 30 minutes continuous administration) at doses of 0.05, 0.25, 1, 3, and 6 mg / kg (equivalent). Subjects who were deemed eligible for the screening study were admitted to the hospital the day before administration. Three days after completion of administration, subjects were discharged. A post-hoc (follow-up) study was conducted on the seventh day after completion of administration to confirm safety, tolerability, and PK. A flow chart of the study is shown in Figure 1.

[0159] 2.Results All observed adverse events were non-serious / mild / resolvable.

[0160] The Cmax values ​​for the individual cohorts (administration of 0.05, 0.25, 1, 3, and 6 mg / kg) were 0.346 ± 0.026, 1.86 ± 0.15, 6.70 ± 1.44, 20.3 ± 2.8, and 49.9 ± 5.2 μg / mL, respectively. The AUC0-24 values ​​for the individual cohorts were 15.1 ± 1.7, 83.1 ± 11.7, 301 ± 73, 959 ± 154, and 2330 ± 330 μg min / mL, respectively. The blood concentrations of TMS-007 increased rapidly after administration, reaching a peak 31 minutes after completion of administration, after which TMS-007 was rapidly cleared from the blood. The half-lives of TMS-007 in the blood were all approximately 10 to 15 minutes, regardless of dose. No urinary forms of TMS-007 were observed in any one of the cohorts. Pharmacokinetic (PK) data are shown in Figures 2 and 3, while pharmacodynamic (PD) data are shown in Figure 4.

[0161] As mentioned above, when TMS-007 was administered intravenously once in a dose-escalation study, no signs of bleeding risk were observed in healthy subjects. Satisfactory results were obtained in terms of safety and tolerability. No notable problems were observed in the PK and PD profiles.

[0162] 3. Consider For example, in pharmacological studies using mice, rats, and monkeys, TMS-007 has already been shown to have pharmacological effects such as reducing infarct area and improving neurological symptoms at doses of 1 to 10 mg / kg. The CMAX and AUC0-24 values ​​when TMS-007 was administered to rats and monkeys were as follows. In rats, the Cmax and AUC0-24 values ​​were 20.2 μg / mL and 1540 μg·min / mL, respectively (mean values ​​for the 12 mg / kg dose group on the first day of the repeated dose study in male rats). In monkeys, the Cmax and AUC0-24 values ​​were 45.8-58.6 μg / mL and 1930-2410 μg·min / mL, respectively (mean values ​​for the 10 mg / kg dose group in the extended single dose study and repeated dose study (day 1) in male monkeys).

[0163] Based on the above, it is expected that the efficacy of TMS-007 in humans will be achieved at doses of 1 to 6 mg / kg. In Phase II trials, the doses were set at 1, 3, and 6 mg / kg based on the above safety results and the expected therapeutic dose.

[0164] Example 2: Single-dose study on cerebral infarction patients (Phase II study) 1. Test Method (1) Clinical trial design Randomized, double-blind, placebo-controlled, single-dose, intravenous, parallel-group, and dose-escalation regimen

[0165] (2) Target The subjects were cerebral infarction patients within 12 hours of onset. The study subjects (90 patients: 1st cohort: 9, 2nd cohort: 27, 3rd cohort: 54) were determined according to the following inclusion and exclusion criteria. Selection criteria: 1) Individuals who have received sufficient information about participating in this clinical trial and have subsequently provided written informed consent (including informed consent provided by a proxy) 2) Japanese men aged 20 to 88 years and Japanese women aged 60 to 88 years with symptoms of cerebral infarction 3) Subjects weighing 30kg or more 4) Subjects who can receive the investigational drug within 12 hours from the time when the onset of cerebral infarction was confirmed or the most recent time when they were asymptomatic 5) Subjects whose NIHSS score at the time of registration is determined to be between 6 and 23 6) Subjects whose MRI (DWI)-ASPECTS value (11-point method) is judged to be 5 or more at the time of registration review Exclusion criteria: Clinical manifestations / clinical trials: 1) Subjects who are judged by a physician to be suitable for administration of rt-PA or endovascular therapy 2) Bleeding: a. Those who are bleeding (intracranial bleeding, gastrointestinal bleeding, urinary tract bleeding, retroperitoneal bleeding, hemoptysis) b. Those suspected of having subarachnoid hemorrhage C. Pre-treatment platelet count is 100,000 / mm 3 The following people d. Subjects with a prothrombin time international normalized ratio (PT-INR) of 2.6 or higher before administration 3) Blood Pressure: a. Those who have a systolic blood pressure of 185mmHg or more or a diastolic blood pressure of 110mmHg or more even if antihypertensive therapy is appropriately applied before administration 4) Blood sugar: a. Subjects with pre-treatment blood glucose levels of less than 50 mg / dL or more than 400 mg / dL 5) Pathology: a. Subjects with extensive early ischemic changes (slightly decreased absorption values ​​of the brain parenchyma or loss of sulci) observed on MRI before administration b. Subjects with midline deviation or other deviations observed on MRI before administration c. Those who have seizures suspected to be epileptic at the time of onset d. Patients with mild symptoms of cerebral infarction or those with rapidly progressing severe symptoms of cerebral infarction e. Subjects with mRS score of 2 or more before onset f. In the third cohort, patients suspected of having acute total occlusion of the internal carotid artery based on clinical and imaging data obtained by a physician at the time of enrollment review. Medical conditions, medical history, pregnancy status: 6) Subjects with a history of intracranial hemorrhage within one month prior to administration of the study drug, or subjects with intracranial tumor, cerebral arteriovenous malformation, cerebral aneurysm, or aortic dissection at the time of administration of the study drug 7) Subjects who have had intracranial or spinal surgery or injury within one month prior to administration of the study drug, or who have had a history of cerebral infarction 8) Subjects with a history of gastrointestinal or urinary bleeding within 14 days prior to administration of the study drug 9) Subjects who underwent major surgery within 7 days prior to administration of the study drug 10) Subjects with severe liver disorder 11) Subjects with acute pancreatitis 12) Subjects who have suffered a serious trauma within 7 days prior to administration of the study drug 13) Subjects who also have acute myocardial infarction or post-myocardial infarction pericarditis 14) Subjects with severe malignant tumors 15) Pregnant persons (if pregnancy is suspected, a pregnancy test based on hCG in the blood or urine should be performed) Allergic and Adverse Drug Reactions: 16) Subjects with a history of clinically significant drug hypersensitivity or hypersensitivity to any component of the drug being tested Substances / Drug History: 17)Subjects who have participated in other clinical trials and received an investigational drug (including placebo) within the past 3 months others: 18) Persons who do not provide informed consent (including informed consent for pregnancy prevention precautions) 19) Those who do not have health insurance 20) Subjects who cannot undergo follow-up examination 21) Subjects who cannot undergo MRI scanning due to reasons such as the use of pacemakers, aneurysm clips, or implant devices, or claustrophobia 22) For example, those who are judged inappropriate by the investigator of the clinical trial (3) Drugs studied Test drug (TMS-007 (SMTP-7 sodium salt preparation)) Control medication (placebo)

[0166] (4) Administration schedule Patients with acute cerebral infarction within 12 hours of onset were given a single intravenous dose of TMS-007 (SMTP-7 sodium salt formulation) or placebo (bolus over 1 minute + continuous infusion over 30 minutes). The ratio of the number of patients who should receive the active drug (TMS-007 sodium salt formulation) to the number of patients who should receive the placebo was 2:1 in the first and second cohorts, and 1:1 in the third cohort, as shown in Table 1 below. [Table 1]

[0167] (5) Dose escalation and discontinuation criteria The items to determine dose escalation are safety items, NIHSS, brain MRI, vital signs, and, if necessary, PK data of all subjects in each cohort up to 7 days after administration of the investigational drug. If a problem is found in the safety items, consideration will be given to whether to reduce the dose in the next cohort or to cancel the transition to the next cohort. The extent of dose reduction is basically 20% of the estimated dose of the next cohort, and can be up to 50%.

[0168] If any one of the following conditions is met, the scheduled progression to the next cohort will be canceled. If necessary, a dose modification may be considered: 1) Four or more deaths in cohort 1, eight or more deaths in cohort 2, and 16 or more deaths in cohort 3, regardless of whether the deaths were related to the study drug. 2) The frequency of symptomatic intracranial hemorrhage causing a worsening of the NIHSS score by 4 or more points within 24 hours is 4 or more times in Cohort 1, 11 or more times in Cohort 2, and 22 or more times in Cohort 3, regardless of whether the event is causally related to the study drug. 3) If an independent data monitoring committee recommends discontinuing the study

[0169] In addition, safety will be further evaluated in elderly people aged 86 years or older.

[0170] (6)Endpoint Primary endpoint Incidence of symptomatic intracranial hemorrhage resulting in a worsening of NIHSS score of 4 or more points within 24 hours after administration of TMS-007 Secondary endpoints Overall mortality during the study period Safety up to 7 days after administration (e.g., extracranial bleeding, major bleeding) Symptomatic and non-symptomatic intracranial hemorrhage within 24 hours after administration mRS value 90 days after administration Recanalization rate observed on MRA images 24 hours after administration PK when TMS-007 was administered (concentration of unchanged form of TMS-007, Cmax, AUC) others (7) Analysis population Safety analysis population: subjects who received the investigational drug Efficacy analysis population: The FAS will be the primary analysis population, and sensitivity will be analyzed based on the analysis of the PPS population. -FAS (Full Analysis Set) population: subjects who have received the investigational drug and have efficacy evaluation data defined by the clinical trial protocol -PPS (Protocol-Performant Population) population: FAS subjects who do not deviate from the clinical trial protocol PK analysis population: Subjects who have been appropriately administered the investigational drug and for whom plasma TMS-007 concentrations can be appropriately measured PD analysis population: subjects who are appropriately administered the investigational drug and whose blood markers are appropriately measured

[0171] Details of the subjects are shown in FIG. 5 and details of the analysis population are shown in FIG.

[0172] Background information on the safety analysis population was analyzed, including gender, presence or absence of complications, subtype of cerebral infarction (type of disease), cerebral vascular recanalization / occlusion status, age, weight, PT-INR value, NIHSS score, DWI-ASPECTS score, time since onset, systolic blood pressure, and diastolic blood pressure, but no statistically significant differences were observed between the TMS-007 (1, 3, 6 mg / kg) group, the TMS-007 combination group, and the placebo group.

[0173] The mean ages of subjects in the TMS-007 (1, 3, 6 mg / kg) group, the TMS-007 combination group, and the placebo group were 66.3, 71.1, 74.1, 72.3, and 72.3 years, respectively. Their mean time from onset was 9.16, 9.21, 9.76, 9.50, and 9.33 hours, respectively. All subjects (n=90) were administered TMS-007 within 3-12 hours of onset, and then 88 of the 90 subjects were administered TMS-007 within 4.5-12 hours.

[0174] 2.1 Safety Regarding the safety analysis population, no symptomatic intracranial hemorrhage with worsening of NIHSS score by 4 or more points was observed in the TMS-007 group, and it was observed in 1 / 38 cases (2.6%) in the placebo group. The incidence of symptomatic intracranial hemorrhage with worsening of NIHSS score by 4 or more points in the individual TMS-007 groups, the combination group, and the placebo group was compared using Fisher's exact test. As a result, none of the results were statistically significant. This suggested that TMS-007 did not promote symptomatic intracranial hemorrhage with worsening of NIHSS score by 4 or more points up to 24 hours after administration compared with the placebo group. Similar results were obtained in the PPS population.

[0175] In the safety analysis population, no incidence of major bleeding events was observed in either the TMS-007 or placebo groups up to 7 days after treatment. The same results were obtained in the PPS population.

[0176] In the safety analysis population, no symptomatic intracranial hemorrhage was observed within 24 hours after administration in the TMS-007 group, and 2 / 38 cases (5.3%) were observed in the placebo group. The incidence of symptomatic intracranial hemorrhage within 24 hours in the individual TMS-007 groups, the combination group, and the placebo group was compared using Fisher's exact test. None of the results were statistically significant. This suggested that TMS-007 did not promote symptomatic intracranial hemorrhage within 24 hours after administration compared with the placebo group. Similar results were obtained in the PPS population.

[0177] Regarding the safety analysis population, the overall mortality rates during the study period (up to day 90) in the TMS-007 (1, 3, 6 mg / kg) group and the placebo group were 0 / 6 (0.0%), 1 / 18 (5.6%), 0 / 28 (0.0%), and 2 / 38 (5.3%), respectively. The overall mortality rate in the TMS-007 combination group was 1 / 52 (1.9%). The overall mortality rates of the individual TMS-007 groups, the combination group, and the placebo group were compared by Fisher's exact test. As a result, none of the results were statistically significant. This suggested that TMS-007 did not promote overall mortality during the study period (up to day 90) compared with the placebo group. Similar results were obtained in the PPS population.

[0178] The incidence of adverse events, serious adverse events, side effects, serious side effects, and adverse events leading to discontinuation during the study period (up to day 90) in the individual TMS-007 groups, the combination group, and the placebo group was compared using Fisher's exact test. As a result, none of the differences were statistically significant. Similar results were obtained in the PPS population (Figure 8).

[0179] 2.2 Validity (1)mRS In the FAS group, the mRS 0-1 ratios in the TMS-007 (1, 3, 6 mg / kg) group, the combination group, and the placebo group were 3 / 6 cases (50.0%), 7 / 18 cases (38.9%), 11 / 28 cases (39.3%), 21 / 52 cases (40.4%), and 7 / 38 cases (18.4%), respectively. Similar results were obtained in the PPS population. In the FAS group, the mRS 0-2 ratios in the TMS-007 (1, 3, 6 mg / kg) group, the combination group, and the placebo group were 4 / 6 cases (66.7%), 9 / 18 cases (50.0%), 15 / 28 cases (53.6%), 28 / 52 cases (53.8%), and 14 / 38 cases (36.8%), respectively.

[0180] In the FAS group, a logistic model was applied to the mRS assessment of each dose group on Day 90 after administration (mRS 0-1 is assigned a score of 1, and mRS 2-6 is assigned a score of 0), using response, dose group (TMS-007 combination group and placebo group), baseline mRS, NIHSS score, age, and blood pressure (systolic blood pressure) as explanatory variables, and the odds ratio and 95% confidence interval of the TMS-007 combination group relative to the placebo group were estimated. Similar estimations were performed by using the TMS-007 dose group as the dose group relative to the placebo group. More specifically, the odds ratio and 95% confidence interval of each TMS-007 dose group relative to the placebo group were estimated.

[0181] The results are shown in Figures 7 to 10 and Tables 2 to 4. The intercept estimates for mRS were -6.193 and -6.434, respectively. The odds ratio of mRS in the dose group to that in the placebo group was 0.299, with a 95% confidence interval of 0.099 to 0.902. This suggested that the mRS in the dose group was statistically significantly lower than that in the placebo group (there was a treatment effect). The odds ratios and 95% confidence intervals (shown in parentheses) of the mRS of the TMS-007 group relative to the mRS of the placebo group were 0.088 (0.010-0.787) for the TMS-007 (1 mg / kg) dose group, 0.484 (0.120-1.945) for the TMS-007 (3 mg / kg) dose group, and 0.299 (0.083-1.072) for the TMS-007 (6 mg / kg) dose group. These values ​​were smaller than the odds ratio of 1 for these dose groups relative to the placebo group, suggesting that there was a treatment effect. In particular, the values ​​for the dose groups (1 mg / kg) show a statistically significant difference. This suggested that there was a treatment effect. [Table 2] [Table 3]

[0182] Furthermore, the proportion of patients who achieved mRS0-2 results 90 days after administration (shown below) was a value that did not show a statistically significant difference, and thus suggested the efficacy of TMS-007. [Table 4]

[0183] (2) Recanalization rate The recanalization rate was evaluated by MRA. Patients who were observed to have occlusion at enrollment and were observed to have "patency" or "partial patency" on the second day (39 cases) were evaluated as recanalized cases. The proportion of recanalized cases was 14 / 21 cases (58.3%) in the TMS-007 group and 4 / 15 cases (26.7%) in the placebo group. Thus, improvement was observed in the TMS-007 group (odds ratio: 4.23, 95% confidence interval CI: 0.99, 18.07).

[0184] As described above, TMS-007 was confirmed to be safe and effective in patients with acute cerebral infarction within 12 hours of onset at doses of 1 to 6 mg / kg.

[0185] 2.3 Pharmacokinetics (PK) In the PK analysis population, counting / analysis was performed for dose groups other than the placebo group. The plasma TMS-007 concentrations (original scale values, mean ± standard deviation) of the TMS-007 (1, 3, 6 mg / kg) groups (hereinafter described in the same order) 31 minutes after administration of the study drug were 7.294 ± 1.472, 29.28 ± 8.425, and 52.19 ± 12.76 μg / mL, respectively, and the plasma TMS-007 concentrations 2 hours after administration were 0.1379 ± 0.09777, 0.8970 ± 0.5752, and 3.033 ± 2.924 μg / mL, respectively. For the plasma concentration values ​​(logarithmic converted values) 31 minutes after the start of administration of the study drug, the differences between doses were evaluated by one-way analysis of variance using dose as a factor. As a result, the p value was less than 0.0001, and the differences were statistically significant.

[0186] When the dose-proportionality of the plasma TMS-007 concentration of the investigational new drug was evaluated 31 minutes after the start of administration, the point estimate (two-sided 95% confidence interval) of the slope b of the regression equation of the power model was 1.042 (0.895-1.189), confirming the linearity of TMS-007 in the dose range of 1-6 mg / kg (see Figure 11).

[0187] 3. Consider The drug t-PA, which is widely used as a treatment for cerebral infarction, is thought to show clinical usefulness mainly due to its thrombolytic effect. Other compounds such as desmoteplase and tenecteplase have been developed as thrombolytic agents, which are proteins similar to t-PA. In fact, no small molecule compounds that are effective in removing thrombus in patients with cerebral infarction are known to date (Mican et al., Computational and Structural Biotechnology Journal, Vol. 17, 2019, Pages 917-938; Nikitin et al., J Stroke. 2021; 23 (1): 12-36).

[0188] The drug t-PA is known to increase symptomatic intracranial hemorrhage in stroke patients. Other stroke treatment candidates with thrombolytic effects are known to promote intracranial hemorrhage (Wardlaw et al., Lancet. 2012 Jun 23; 379 (9834): 2364-72). Similarly, it is thought that the thrombolytic effect increases the risk of intracranial hemorrhage (Shi et al., Sci Rep 6, 33989 (2016); Kvistad et al., Stroke. Stroke. 2019 May; 50 (5): 1279-1281). However, the above results actually obtained in clinical trials of stroke patients demonstrate that TMS-007 does not increase the incidence of symptomatic intracranial hemorrhage compared to the placebo group.

[0189] Industrial Applicability INDUSTRIAL APPLICABILITY The present invention is useful for treating cerebral infarction, particularly for treating patients with cerebral infarction to whom conventional thrombolytic therapy and thrombectomy therapy cannot be applied.

[0190] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety. Prior art documents Patent Literature Patent Document 1: JP 2004-224737 A Patent Document 2: JP 2004-224738 A Patent Document 3: WO2007 / 111203 Patent Document 4: WO2011 / 004620 Non-patent literature Non-Patent Document 1: Takayasu et al., “Enhancement of fibrin binding and activation of plasminogen by staplabin through induction of a conformational change in plasminogen” FEBS Letter 1997; 418: 58-62 Non-patent document 2: Matsumoto et al., “Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7” J Biol Chem 2014;289:35826-35838

Claims

1. A pharmaceutical composition for treating cerebral infarction, comprising compound I having a structure of formula (I) or a salt thereof, wherein compound I is administered to a subject at a dose of 1 to 6 mg / kg. 【Chemistry 1】

2. The pharmaceutical composition according to claim 1, wherein compound I is administered to a subject at a dose of 1 mg / kg.

3. The pharmaceutical composition according to claim 1, wherein compound I is administered to a subject at a dose of 3 mg / kg.

4. The pharmaceutical composition according to claim 1, wherein compound I is administered to a subject at a dose of 6 mg / kg.

5. The pharmaceutical composition according to any one of claims 1 to 4, which is administered to a subject within 12 hours after the onset of cerebral infarction.

6. The pharmaceutical composition according to any one of claims 1 to 4, which is administered to a subject 3 to 12 hours after the onset of cerebral infarction.

7. The pharmaceutical composition according to any one of claims 1 to 4, which is administered to a subject 4.5 to 12 hours after the onset of cerebral infarction.

8. The pharmaceutical composition according to any one of claims 1 to 4, which is administered to a subject at risk of causing bleeding.

9. The pharmaceutical composition of claim 8, wherein the bleeding is intracranial or extracranial bleeding.

10. The pharmaceutical composition according to any one of claims 1 to 4, which is administered to a subject suffering from cerebral infarction accompanied by vascular occlusion, including partial occlusion.

11. The pharmaceutical composition according to any one of claims 1 to 4, which is administered intravenously.

12. The pharmaceutical composition according to any one of claims 1 to 4, which is administered once a day, preferably in a single dose.

13. The pharmaceutical composition according to any one of claims 1 to 4, which is administered as a bolus followed by continuous administration.

14. 14. The pharmaceutical composition of claim 13, which is administered intravenously over 1 minute, followed by infusion over 30 minutes.

15. The pharmaceutical composition according to any one of claims 1 to 4, which can be administered to a subject for whom administration of a thrombolytic agent or physical thrombectomy is difficult or impossible.

16. 16. The pharmaceutical composition of claim 15, wherein the thrombolytic agent is tissue plasminogen activator.

17. The pharmaceutical composition according to any one of claims 1 to 4, wherein the cerebral infarction is atherothrombotic / embolic cerebral infarction, cardiogenic cerebral infarction, or lacunar cerebral infarction.

18. The pharmaceutical composition according to any one of claims 1 to 4, wherein a single dose of Compound I or a salt thereof is contained in a sealed container together with a pharmacologically acceptable carrier.

19. The pharmaceutical composition according to any one of claims 1 to 4, wherein 20 mg to 1000 mg of Compound I or a salt thereof is contained in a sealed container together with a pharmacologically acceptable carrier.

20. A pharmaceutical composition for treating cerebral infarction, comprising compound I having the structure of formula (I) or a salt thereof, which is administered to a subject within 12 hours after the onset of cerebral infarction. 【Chemistry 2】

21. The pharmaceutical composition according to claim 20, which is administered to a subject 3 to 12 hours after the onset of cerebral infarction.

22. The pharmaceutical composition according to claim 20, which is administered to a subject 4.5 to 12 hours after the onset of cerebral infarction.

23. The pharmaceutical composition according to claim 20, wherein compound I is administered to a subject at a dose of 1 to 6 mg / kg.

24. The pharmaceutical composition of claim 20, wherein compound I is administered to a subject at a dose of 1 mg / kg.

25. The pharmaceutical composition according to claim 20, wherein compound I is administered to a subject at a dose of 3 mg / kg.

26. The pharmaceutical composition of claim 20, wherein compound I is administered to a subject at a dose of 6 mg / kg.

27. The pharmaceutical composition according to any one of claims 20 to 26, which is administered to a subject at risk of causing bleeding.

28. 28. The pharmaceutical composition of claim 27, wherein the bleeding is intracranial or extracranial bleeding.

29. The pharmaceutical composition according to any one of claims 20 to 26, which is administered to a subject suffering from cerebral infarction accompanied by vascular occlusion, including partial occlusion.

30. The pharmaceutical composition according to any one of claims 20 to 26, which is administered intravenously.

31. The pharmaceutical composition according to any one of claims 20 to 26, which is administered once a day, preferably in a single dose.

32. The pharmaceutical composition according to any one of claims 20 to 26, which is administered as a bolus and then continuously.

33. 33. The pharmaceutical composition of claim 32, wherein the composition is administered intravenously over 1 minute, followed by infusion over 30 minutes.

34. The pharmaceutical composition according to any one of claims 20 to 26, which may be administered to a subject for whom administration of a thrombolytic agent or physical thrombectomy is difficult or impossible.

35. 35. The pharmaceutical composition of claim 34, wherein the thrombolytic agent is tissue plasminogen activator.

36. The pharmaceutical composition according to any one of claims 20 to 26, wherein the cerebral infarction is atherothrombotic / embolic cerebral infarction, cardiogenic cerebral infarction, or lacunar cerebral infarction.

37. A pharmaceutical composition for treating cerebral infarction, comprising compound I having the structure of formula (I) or a salt thereof, said pharmaceutical composition recanalizing an occluded blood vessel in cerebral infarction. 【Chemistry 3】

38. A pharmaceutical composition for treating cerebral infarction, comprising compound I having the structure of formula (I) or a salt thereof, the pharmaceutical composition being administered to a subject at risk of causing bleeding. 【Chemistry 4】

39. A pharmaceutical composition for reducing the risk of causing hemorrhage in cerebral infarction, comprising compound I having the structure of formula (I) or a salt thereof. 【Chemistry 5】

40. A pharmaceutical composition for treating cerebral infarction, comprising compound I having the structure of formula (I) or a salt thereof, said pharmaceutical composition improving independent life after cerebral infarction. 【Chemistry 6】

41. The pharmaceutical composition of claim 40, wherein the indicator of improvement in independent living is a result of 0 to 1 on the mRS (modified Rankin Scale) 90 days after administration.

42. The pharmaceutical composition of claim 40, wherein the indicator of improvement in independent living is a result of 0 to 2 on the mRS (modified Rankin Scale) 90 days after administration.

43. A pharmaceutical composition for treating cerebral infarction, comprising compound I having the structure of formula (I) or a salt thereof, said pharmaceutical composition having an effect of dissolving thrombus in a patient suffering from cerebral infarction. 【Chemistry 7】

44. A pharmaceutical composition for treating cerebral infarction, comprising compound I having the structure of formula (I) or a salt thereof, said pharmaceutical composition having a low risk of hemorrhagic side effects. 【Chemistry 8】

45. 45. The pharmaceutical composition of claim 44, wherein the bleeding side effect is symptomatic intracranial hemorrhage.

46. 27. The pharmaceutical composition according to any one of claims 1 to 4 and 20 to 26, comprising either or both of a basic excipient and an amphiphilic excipient.

47. 47. The pharmaceutical composition of claim 46, wherein the basic additive is one or more selected from the group consisting of amino sugars, alkanolamines, and trometamol salts, preferably one or more selected from the group consisting of meglumine, triethanolamine, and trometamol hydrochloride, and the amphiphilic additive is one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol, polysorbate, polyethylene glycol, ursodeoxycholic acid, sorbitan fatty acid ester, and sodium deoxycholate, preferably one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate.

48. The pharmaceutical composition according to any one of claims 1 to 4 and 20 to 26, wherein compound I is SMTP-7.

49. The pharmaceutical composition according to any one of claims 1 to 4 and 20 to 26, wherein the cerebral infarction is ischemic stroke.

50. 50. The pharmaceutical composition of claim 49, wherein the cerebral infarction is an acute cerebral infarction or the ischemic stroke is an acute ischemic stroke.

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