Pharmaceutical Compositions Containing Compound SMTP-7

Abstract

The present application provides a highly safe pharmaceutical composition containing SMTP-7 or a salt thereof, an ester thereof, or a solvate thereof as an active ingredient, and further containing one or both of a basic additive and an amphipathic additive. The present invention is useful for the prevention or treatment of ischemic disorders such as cerebral infarction including acute ischemic cerebral infarction, particularly for the treatment of patients who cannot be treated with thrombolytic drugs.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Japanese Patent Application No. 2021-070892, filed on April 20, 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 comprising SMTP-7 and a basic excipient and / or an amphiphilic excipient. [Background technology]

[0003] Ischemic damage is understood to be a pathological condition that includes all symptoms caused by the restriction of blood flow in any part of the body. In the ischemic area, cells die due to the depletion of energy, and as a result, this area becomes dysfunctional. As a treatment for ischemia caused by thrombus, thrombolytic drugs and thrombolytic therapy using these thrombolytic drugs have been developed for the purpose of dissolving thrombus and resupplying blood to the ischemic area.

[0004] For example, alteplase (recombinant tissue-type plasminogen activator (rt-PA)), a thrombolytic drug that focuses on the action of plasminogen activator (t-PA), has been developed. Alteplase activates plasminogen and converts it to plasmin, which degrades fibrin, the core that forms thrombi (Non-Patent Document 1).

[0005] SMTP (Stachybotrys Microspora triprenylphenol) compounds have a triprenylphenol skeleton, are a group of compounds produced by filamentous fungi, and are known to have thrombolytic and angiogenic inhibitory effects (Patent Documents 1-3). For the thrombolytic promotion effect, a mechanism of action has been proposed in which SMTP compounds cause a conformational change in plasminogen, thereby enhancing the sensitivity of plasminogen to t-PA and its binding with plasminogen (e.g., thrombus), and then promoting the dissolution of thrombus (Non-Patent Document 2). SMTP compounds have been reported to have excellent anti-inflammatory effects (Non-Patent Document 3), cell protective effects, and usefulness as a therapeutic agent for ischemic injury (Patent Document 4). Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a highly safe pharmaceutical composition which contains the SMTP compound SMTP-7 as an active ingredient. [Means for solving the problem]

[0007] The present inventors have found that the safety of SMTP-7 can be improved by using a basic additive and / or an amphiphilic additive in combination when formulating SMTP-7.

[0008] More specifically, the present invention relates to the following [1] to

[13] . [1] Compound represented by formula (I) [ka] or a salt thereof, an ester thereof, or a solvate thereof, and a pharmaceutical composition comprising either or both of a basic excipient and an amphiphilic excipient. [2] The pharmaceutical composition according to [1], wherein the compound is SMTP-7 represented by formula (II). [ka] [3] The pharmaceutical composition according to [1] or [2], wherein the basic additive comprises one or more selected from the group consisting of amino sugars, alkanolamines, and trometamol salts. [4] The pharmaceutical composition according to [1] or [2], wherein the basic additive comprises one or more selected from the group consisting of meglumine, triethanolamine, and trometamol hydrochloride. [5] The pharmaceutical composition according to any one of [1] to [4], wherein the amphipathic additive comprises 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 desoxycholate. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the amphiphilic additive comprises one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate. [7] The pharmaceutical composition according to any one of [1] to [6], comprising both the basic additive and the amphiphilic additive. [8] The pharmaceutical composition according to any one of [1] to [7], comprising meglumine as the basic excipient and polyoxyethylene hydrogenated castor oil as the amphiphilic excipient. [9] The pharmaceutical composition according to any one of [1] to [8], which is a formulation for intravenous administration.

[10] The pharmaceutical composition according to any one of [1] to [9], which is used for the prevention or treatment of an ischemic disorder or an inflammatory disease.

[11] The pharmaceutical composition according to

[10] , wherein the ischemic disorder is cerebral infarction or transient ischemic attack.

[12] The pharmaceutical composition described in

[11] , wherein the cerebral infarction is an ischemic cerebral infarction.

[13] The pharmaceutical composition described in

[12] , wherein the ischemic cerebral infarction is acute ischemic cerebral infarction.

[14] A method for producing the pharmaceutical composition according to any one of [1] and [3] to

[13] , comprising mixing the compound represented by formula (I) or a salt thereof, an ester thereof, or a solvate thereof with either or both of the basic additive and the amphipathic additive.

[15] A method for producing the pharmaceutical composition according to any one of [2] to

[13] , comprising mixing the compound represented by formula (II) or a salt thereof, an ester thereof, or a solvate thereof with either or both of the basic additive and the amphipathic additive. Effect of the Invention

[0009] The present invention provides a safe pharmaceutical composition containing SMTP-7 as an active ingredient, which can be used in a wide range of subjects and in a wide range of doses, thereby enabling the realization of highly effective drug therapy. [Brief description of the drawings]

[0010] [Figure 1] 1 shows the evaluation results of a safety test in Example 1 of the present invention. [Diagram 2] 1 shows the toxicity score of the pharmaceutical composition in Example 2 of the present invention. [Diagram 3] 1 shows the hemolysis levels of the pharmaceutical compositions tested in Example 3 of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] 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.

[0012] 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.

[0013] In this specification, the term "step" includes not only independent steps, but also steps that cannot be clearly distinguished from other steps as long as the intended task is accomplished by the step.

[0014] In this specification, "mass %" and "weight %" are used interchangeably, and "parts by mass" and "parts by weight" are used interchangeably.

[0015] In this specification, the terms "mass average molecular weight (Mw)" and "number average molecular weight (Mn)", unless otherwise specified, refer to molecular weights obtained by separation using a gel permeation chromatography (GPC) apparatus using a TSKgel GMHxL, TSKgel G4000HxL, or TSKgel G2000HxL (all trade names, manufactured by Tohso Corporation) column and THF (tetrahydrofuran) solvent, detection with a differential refractometer, and conversion using polystyrene as a standard substance.

[0016] 1. Pharmaceutical Composition of the Present Invention 1.1 Ingredients The pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I), specifically, SMTP-7 represented by formula (II), or a salt thereof, an ester thereof, or a solvate thereof, and either or both of a basic additive and an amphiphilic additive. Formula I: [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 Formula II: [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 51 H 68 N2O 10 Molecular weight: 868.49

[0017] As used herein, unless otherwise indicated, the term "SMTP-7" is defined to include not only SMTP-7, but also its salts, esters, or solvates thereof.

[0018] (1) SMTP-7 The present inventors have developed a compound represented by formula (II) which has a triprenylphenol skeleton and is used in the pharmaceutical composition of the present invention as a derivative of a compound (SMTP compound) produced by a filamentous fungus. SMTP-7 acts on plasminogen, which is present in blood and is a precursor of plasmin involved in thrombolysis, to induce a conformational change, and promotes activation by plasminogen activator, thereby exerting a thrombolysis promoting effect. SMTP-7 is further known to have anti-inflammatory, antioxidant, and cytoprotective effects.

[0019] SMTP-7 may be used as a free compound or in the form of a pharma- ceutically acceptable salt, ester, or solvate. For the formation of a pharma- ceutically acceptable salt of SMTP-7, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or citric acid, and organic acids such as formic acid, fumaric acid, malic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, or p-toluenesulfonic acid are suitable. Also, compounds containing an alkali metal, such as sodium, potassium, calcium, or magnesium, or an alkaline earth metal, such as a basic amine or a basic amino acid, are suitable for forming a pharma- ceutical acceptable salt of SMTP-7. Furthermore, for the formation of a pharma- ceutical acceptable ester of SMTP-7, alcohols or carboxylic acids having 1 to 10 carbon atoms, preferably, for example, methyl alcohol, ethyl alcohol, acetic acid, or propionic acid, are suitable. For example, water is suitable for forming a pharma- ceutical acceptable solvate of SMTP-7.

[0020] Among the pharma- ceutically acceptable salts, esters, or solvates (hydrates) of SMTP-7 in the pharmaceutical composition of the present invention described above, pharma- ceutically acceptable salts of SMTP-7 are preferred. More specifically, alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, or magnesium salt of SMTP-7 are preferred, and sodium salt of SMTP-7 is more preferred.

[0021] SMTP-7 may be obtained by chemical synthesis or by purification from cultures of filamentous fungi such as Stachybotrys microspore. Methods for producing SMTP-7 are described, for example, in JP 2004-224737 A, JP 2004-224738 A, and WO 2007 / 111203 A.

[0022] SMTP-7 may be an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers, which may be obtained by chemical synthesis or by purification from a culture of a filamentous fungus. When SMTP-7 is obtained by purification from a culture of a filamentous fungus, the corresponding isomer can be obtained by adding a D- or L-amino acid compound to the culture medium for the filamentous fungus.

[0023] In the pharmaceutical composition of the present invention, the content of SMTP-7 (free compound) varies depending on the dosage form of the pharmaceutical composition, but is preferably about 1% by mass to 80% by mass, more preferably about 5% by mass to 60% by mass, based on the total mass of the pharmaceutical composition. For example, in the case of an injection prepared (reconstituted) at the time of use, the content of SMTP-7 (excluding the mass of the injection for dilution) relative to the total mass of the pharmaceutical composition is preferably 10% to 80%, more preferably 20% to 60%.

[0024] In certain embodiments, the SMTP-7 containing pharmaceutical composition is a liquid formulation, hi other embodiments, the SMTP-7 containing pharmaceutical composition is a lyophilized formulation in which the liquid formulation has been lyophilized.

[0025] In certain embodiments, the SMTP-7 in the pharmaceutical composition is about 0.5 mg / mL to about 20 mg / mL. In other embodiments, the SMTP-7 in the pharmaceutical composition is about 1 mg / mL to about 15 mg / mL. In still other embodiments, the SMTP-7 in the pharmaceutical composition is about 1 mg / mL to about 10 mg / mL. In some embodiments, the SMTP-7 in the pharmaceutical composition is about 5 mg / mL to about 10 mg / mL. In some embodiments, the SMTP-7 in the pharmaceutical composition is about 10 mg / mL. In yet other embodiments, the SMTP-7 in the pharmaceutical composition is at a concentration of about 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 5.5 mg / mL, 6.0 mg / mL, 6.5 mg / mL, 7.0 mg / mL, 7.5 mg / mL, 8.0 mg / mL, 8.5 mg / mL, 9.0 mg / mL, 9.5 mg / mL, 10.0 mg / mL, or more.

[0026] (2) Basic additives Examples of basic excipients for use in the pharmaceutical compositions of the present invention include alkanolamines such as triethanolamine, monoethanolamine, diisopropanolamine, triisopropanolamine, diethanolamine, or 2-amino-2-methyl-1-propanol; trometamol (trishydroxymethylaminomethane (tromethamine)) or a salt thereof; amino acids such as glycine, arginine, histidine, or lysine; amino sugars such as meglumine or glucosamine; and amines such as triethylamine, ethylenediamine, epolamine, or guanidine.

[0027] Of these, it is preferable to include one or more selected from the group consisting of amino sugars, alkanolamines, and trometamol salts, it is more preferable to include one or more selected from the group consisting of meglumine, triethanolamine, and trometamol hydrochloride, it is more preferable to include one of meglumine and trometamol hydrochloride, and it is even more preferable to include meglumine.

[0028] When the pharmaceutical composition contains a basic additive, the content of the basic additive varies depending on the dosage form of the pharmaceutical composition, but is preferably 0.1% by mass to 50% by mass, more preferably 1% by mass to 30% by mass, based on the total mass of the pharmaceutical composition. For example, in the case of an injection prepared (reconstituted) at the time of use, the content of the basic additive (excluding the mass of the injection for dilution) relative to the total mass of the pharmaceutical composition is preferably 1 to 50%, more preferably 5 to 30%.

[0029] The content of the basic additive relative to the mass of SMPT-7 is preferably 5% by mass to 80% by mass, more preferably 10% by mass to 60% by mass, and further preferably 20% by mass to 50% by mass.

[0030] In certain embodiments, the basic additive in the SMTP-containing pharmaceutical composition is about 1 mM to about 200 mM. In some embodiments, the basic additive in the SMTP-containing pharmaceutical composition is about 2 mM to about 100 mM. In some embodiments, the basic additive in the SMTP-containing pharmaceutical composition is about 5 mM to about 50 mM. In some embodiments, the basic additive in the SMTP-containing pharmaceutical composition is about 10 mM to about 30 mM. In some embodiments, the basic additive in the SMTP-containing pharmaceutical composition is about 20 mM. In some embodiments, the basic additive in the SMTP-containing pharmaceutical composition is at a concentration of about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38 mM, 39 mM, 40 mM, or more.

[0031] In some embodiments, the basic excipient is meglumine.

[0032] (3) Amphiphilic additives The amphiphilic additive used in the pharmaceutical composition of the present invention is not particularly limited as long as it can be used in pharmaceutical preparations. Any one of anionic amphiphilic additives, cationic amphiphilic additives, amphoteric amphiphilic additives, and nonionic amphiphilic additives can be used. In particular, nonionic amphiphilic additives are preferred.

[0033] Nonionic amphiphilic additives include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 50 and 60), fatty acid polyoxyethylene sorbitan (e.g., polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monolaurate (polysorbate 20)), polyoxyethylene polyoxypropylene glycol, polysorbates, polyethylene glycol, ursodesoxycholic acid, sorbitan fatty acid esters, sodium desoxycholate, polyoxyl stearate, thiamine monophosphate, sorbitan glycerol ... One or more selected from the group consisting of loxapol, polyoxyethylene polyoxypropylene glycol, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, polyglyceryl-3-diolate, and phosphatidylcholine are preferred, one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate are more preferred, polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil are even more preferred, and polyoxyethylene hydrogenated castor oil is particularly preferred.

[0034] The total number of oxyethylene units contained in the polyoxyethylene hydrogenated castor oil is not particularly limited, but is preferably 2 to 150, more preferably 10 to 100, even more preferably 40 to 70, particularly preferably 50 or 60, and most preferably 60 (polyoxyethylene hydrogenated castor oil 60).

[0035] When the pharmaceutical composition contains an amphipathic additive, the content of the amphipathic additive varies depending on the dosage form of the pharmaceutical composition, but 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, based on the total mass of the pharmaceutical composition. For example, in the case of an injection prepared (reconstituted) at the time of use, the content of the amphipathic additive (excluding the mass of the injection for dilution) relative to the total mass of the pharmaceutical composition is preferably 10% to 80%, more preferably 20% to 60%.

[0036] The content of the amphiphilic additive relative to the amount of the SMPT compound is preferably 40% by mass to 300% by mass, more preferably 60% by mass to 200% by mass, and further preferably 70% by mass to 150% by mass.

[0037] In certain embodiments, the amphipathic additive in the SMTP-containing pharmaceutical composition is about 0.001% to about 10% (w / v). In some embodiments, the amphipathic additive in the SMTP-containing pharmaceutical composition is about 0.01% to about 10% (w / v). In some embodiments, the amphipathic additive in the SMTP-containing pharmaceutical composition is about 0.01 to about 1% (w / v). In some embodiments, the amphipathic additive in the SMTP-containing pharmaceutical composition is about 0.01% to about 1% (w / v). In some embodiments, the amphipathic additive in the SMTP-containing pharmaceutical composition is about 0.01%, about 0.1%, or about 1% (w / v). In some embodiments, the amphiphilic additive in the SMTP-containing pharmaceutical composition is at a concentration of about 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 3.0%, 4.0%, 5.0% (w / v) or more.

[0038] In some embodiments, the amphiphilic additive is polyoxyethylene hydrogenated castor oil.

[0039] Although not limited thereto, a preferred example of the pharmaceutical composition of the present invention contains SMTP-7 or a salt thereof (preferably the sodium salt), meglumine as a basic excipient, and polyoxyethylene hydrogenated castor oil as an amphiphilic excipient.

[0040] (4) Other additives The pharmaceutical composition of the present invention may contain other pharma- ceutically acceptable carriers (additives) appropriately selected depending on the application (target disease) of the pharmaceutical composition and the dosage form of the pharmaceutical composition.

[0041] When the pharmaceutical composition contains other additives, the content of the other additives varies depending on the dosage form of the pharmaceutical composition, but is preferably 0.1% by mass to 80% by mass, more preferably 1% by mass to 60% by mass, based on the total mass of the pharmaceutical composition.

[0042] 1.2 Dosage form The dosage form of the pharmaceutical composition of the present invention is not particularly limited, but is preferably a parenteral formulation, preferably an intravenous formulation (injection).When used as an intravenous formulation, the pharmaceutical composition may be a formulation prepared at the time of use or a formulation ready for use.

[0043] When used as an intravenous formulation, the pharmaceutical composition may contain, for example, as described above, a sterile aqueous or non-aqueous solution in addition to SMTP-7, a basic additive, and an amphipathic additive. Aqueous solvents include distilled water for injection or saline. Non-aqueous solvents include alcohols such as ethanol. In addition, 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, a pH adjuster, or a dissolution aid.

[0044] 1.3 Dosage and Administration It is known that SMTP-7 has not only a thrombolytic promoting effect, but also an anti-inflammatory effect, an antioxidant effect, and a cytoprotective effect. Therefore, the pharmaceutical composition of the present invention has not only a preventive or therapeutic effect against ischemic damage (based on a thrombolytic promoting effect), but also a preventive or therapeutic effect against ischemic damage and cell damage after ischemia / reperfusion (based on a cytoprotective effect), and also a preventive or therapeutic effect against inflammatory diseases (see, for example, WO2011-004620).

[0045] As used herein, "ischemic injury" refers to a pathological condition that includes all symptoms resulting from restriction of blood flow in any part of the body, including tissue damage following restoration of blood flow (resulting from ischemia / recanalization).

[0046] The pharmaceutical composition of the present invention is effective for ischemic disorders, particularly thrombosis. Thrombosis is generally understood as blood clots in blood vessels. More specifically, examples of thrombosis include transient ischemic attack, disseminated intravascular coagulation, thrombotic microangiopathy, thrombophlebitis, deep vein thrombosis, idiopathic thrombosis, cerebral infarction (cerebral thrombosis, cerebral embolism), myocardial infarction, and pulmonary thromboembolism. Among them, cerebral infarction is a disease to which the pharmaceutical composition of the present invention can be suitably applied.

[0047] In this specification, cerebral infarction and ischemic cerebral infarction are used without distinction. Ischemic cerebral infarction is generally acute ischemic cerebral infarction, which accounts for approximately 90% of all strokes.

[0048] In the present specification, "inflammatory disease" refers to all pathological conditions caused by inflammation due to external stimuli or internal causes. In particular, the pharmaceutical composition of the present invention is preferably used for nephritis such as interstitial nephritis, pyelonephritis, and glomerulonephritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, and autoimmune peripheral neuropathy such as Guillain-Barre syndrome and neuropathy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (see WO2007 / 040082 and WO2011 / 125930).

[0049] The dose of the pharmaceutical composition of the present invention varies depending on the application (target disease) and dosage form, but is usually preferably 0.01 mg / kg to 100 mg / kg, more preferably 0.1 mg / kg to 30 mg / kg, per adult, in terms of the equivalent amount of SMTP-7 (free form). The number of administrations is not particularly limited, but single administration, repeated administration, or continuous administration may be acceptable. The administration interval and administration period may be selected by those skilled in the art depending on clinical findings, image findings, hematological findings, comorbid diseases, and medical history.

[0050] The daily dose of the pharmaceutical composition of the present invention per adult varies depending on the type of SMTP-7, the severity of the ischemic injury, and the affected part of the body, but is preferably 0.01 mg / kg to 100 mg / kg, and more preferably 0.1 mg / kg to 50 mg / kg, in terms of the equivalent amount of SMTP-7 (free form).

[0051] In the case of repeated administration, the administration schedule is preferably immediately after the onset of symptoms, within 12 hours after the onset of symptoms, and then once a day for about 7 days. In the case of continuous administration, administration is preferably performed for 1 to 24 hours per day.

[0052] The method of administration of the pharmaceutical composition is not particularly limited, and may be selected from various administrations such as intravenous administration, subcutaneous administration, intramuscular administration, and oral administration. For example, in acute diseases, intravenous administration, more specifically, intravenous injection or drip infusion, is preferred in order to immediately and reliably administer the desired dose to the patient. For example, the administration method may be 10% of the dose administered as a bolus, and 90% of the dose administered by infusion over 30 minutes to 1 hour.

[0053] As long as the object of the present invention can be achieved, the pharmaceutical composition of the present invention can be used in combination with other drugs.Other drugs include, for example, thrombolytic drugs.Examples of thrombolytic drugs to be used in combination include alteplase, urokinase, desmoteplase, and monteplase.

[0054] After the onset of cerebral infarction, some patients are prone to bleeding due to vascular damage (e.g., during reperfusion). In contrast, the pharmaceutical composition of the present invention has a cytoprotective effect. Therefore, the composition can effectively prevent the transition to such a bleeding state and reduce the tendency to bleeding.

[0055] The pharmaceutical composition of the present invention is effectively applied to patients who have been discontinued from administering thrombolytic drugs because time has passed since the onset of the disease. For example, when the pharmaceutical composition of the present invention is applied to a cerebral infarction patient who has been in the cerebral infarction for more than 3 hours and cannot receive treatment such as administration of alteplase, ischemic damage may be suppressed. 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 showing symptoms) is regarded as the onset time.

[0056] When the pharmaceutical composition of the present invention is applied to thrombosis (including thromboembolism), it can also be applied to patients for whom thrombolytic drugs are contraindicated. Alternatively, the pharmaceutical composition of the present invention can be applied to patients for whom thrombolytic drug administration has been discontinued due to the appearance of contraindication symptoms or signs during administration of the thrombolytic drug. Examples of contraindication signs include bleeding diathesis, bleeding, hypertension, and glycemic disorder (control). In addition, the pharmaceutical composition of the present invention can be applied to cerebral infarction patients who cannot receive treatment with thrombolytic drugs due to a high risk of intracranial bleeding, for example.

[0057] When the pharmaceutical composition of the present invention is used for thrombosis (including thromboembolism), it can be effectively applied to normal patients who cannot be treated with thrombolytic drugs.Examples of such patients include patients with transient ischemic attack, disseminated intravascular coagulation, thrombotic microangiopathy, thrombophlebitis, deep vein thrombosis, and idiopathic thrombosis.

[0058] The use of the pharmaceutical composition of the present invention is not limited to humans, and the composition may be used in livestock such as cows, horses, and sheep, and pets such as dogs, cats, and monkeys.

[0059] 2. Method for producing pharmaceutical composition The method for producing the pharmaceutical composition of the present invention includes mixing SMTP-7 with a basic additive and / or an amphiphilic additive as described above. The method for mixing them is not particularly limited, and any method known in the art may be used. When the pharmaceutical composition contains other pharma-ceutically acceptable carriers (additives), the carriers may be mixed together with the basic additive and / or the amphiphilic additive in the mixing step.

[0060] The mixture of SMTP-7 and additives may be lyophilized, placed in an ampoule or vial, and hermetically sealed. When using a lyophilized formulation, it is reconstituted with a small amount of injection liquid, and then appropriately diluted with a diluent injection liquid such as saline, before use. Alternatively, the pharmaceutical composition of the present invention may be a ready-to-use formulation that has been previously manufactured to have an appropriate concentration.

[0061] 3. Method for treating or preventing ischemic injury The present invention provides a method for treating or preventing ischemic injury, comprising administering the pharmaceutical composition of the present invention to a patient in need thereof. The subject, dose, administration interval, administration period, and administration method of the pharmaceutical composition are as previously described in the description of the pharmaceutical composition of the present invention.

[0062] The pharmaceutical compositions of the present invention are less irritating and allow for more effective and safer SMTP-7 treatment. EXAMPLES

[0063] 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.

[0064] Example 1: Safety test of pharmaceutical compositions in mice Preparation of pharmaceutical compositions SMTP-7 (sodium salt) was obtained by culturing Stachybotrys microspora IFO30018 strain in a medium containing L-ornithine as an organic amino compound, and purifying the culture obtained by the method described in JP 2004-224738 A. The purified SMTP-7 was dried. 0.3 mol / L NaOH and physiological saline (0.9% by mass NaCl) were added to the dry solid SMTP-7 to prepare a 50 mg / ml solution. Next, the solution was adjusted to a concentration of 10 mg / ml and low pH (weakly alkaline) using 0.3 mol / L HCl and physiological saline. The solution was sterilized by filtration, divided into small portions, and frozen and stored at -30°C.

[0065] Different lots of SMTP-7 were obtained and designated SM0X02, N152403-01, GMP-like, and N01YH / G01HN, respectively.

[0066] Basic additives, amphiphilic additives, and reference compounds The basic additives, amphiphilic additives, and reference compounds used herein are as follows:

[0067] Meglumine (catalog number: M9179, manufactured by SIGMA-ALDRICH, St. Louis, MO, USA): simply referred to as Meg.

[0068] Polyoxyethylene hydrogenated castor oil 60 (NIKKOL HCO-60, manufactured by Nikko Chemicals Co., Ltd., Tokyo): in this example, it is simply referred to as HCO-60 or HCO.

[0069] Polyethylene glycol 4000 (Macrogol 4000, manufactured by NOF Corporation, Tokyo): simply referred to as PEG.

[0070] D-mannitol (D-mannitol injection as defined in the Japanese Pharmacopoeia, manufactured by Terumo Corporation, Tokyo): simply referred to as Man.

[0071] Mouse dosing Pharmaceutical compositions 1-8 and comparative pharmaceutical compositions 1-6 were prepared by dissolving SMTP-7 and either or both of the basic additive and the amphipathic additive in physiological saline, and dissolving the reference compound in physiological saline. The final concentration of SMTP-7 in the pharmaceutical compositions and comparative pharmaceutical compositions was controlled to 10 mg / mL. The lot numbers of SMTP-7 in the pharmaceutical compositions and comparative pharmaceutical compositions, as well as the types and concentrations of the basic additive, the amphipathic additive, and the reference compound are shown in Table 1.

[0072] The prepared pharmaceutical compositions and comparative pharmaceutical compositions were administered to ICR mice (6-12 weeks old) at a ratio (dose) of 10 mL / kg (100 mg / kg of SMTP-7 (free form)) through the tail vein. During administration, 1 / 10 of each pharmaceutical composition was administered as a bolus, and then the remaining 9 / 10 of the composition was administered continuously for 30 minutes. [Table 1]

[0073] In the above table, the notation "% (w / v)" refers to the mass (g) of the amphiphilic additive or reference compound contained in the pharmaceutical composition (100 mL). The notation "HCO+Meg" indicates the inclusion of both HCO-60 (0.01% (w / v) or 1% (w / v)) and meglumine (20 mM).

[0074] Evaluation method The condition of the mice was observed during and about 1 hour after administration. The observation items are as follows. The results are shown as a score ranging from 0 to the maximum value represented by an integer (shown in parentheses).

[0075] Observation items Condition of mice during administration: Increased permeability and redness of the tail vein (1), congestion of the tail (1), respiratory depression (4)

[0076] Approximately one hour after administration, the mouse showed the following symptoms: congestion in the tail (4), decreased physical activity (8), impaired breathing (8), and awakening from anesthesia (4).

[0077] The scores obtained when different lots of SMTP-7 sodium salt were administered alone (the scores obtained when comparative pharmaceutical compositions 1, 3, 4, or 5 were administered, more specifically, the total score obtained by adding up the scores of all observation items) were set to 1, and the scores obtained when the pharmaceutical compositions and comparative pharmaceutical compositions were administered were expressed as relative values.

[0078] The evaluation results are shown in Figure 1. In Figure 1, the vertical axis shows the ratio of the total score of the observation items when the pharmaceutical composition and the comparative pharmaceutical composition were administered to the total score of the observation items when SMTP-7 sodium salt was administered alone.

[0079] From FIG. 1, the following was found:

[0080] When D-mannitol was added to SMTP-7 (lot SM0X02), the score was 1.36 times that of the reference compound. On the other hand, when meglumine was added to SMTP-7 (lot 152403-01), the score was 0.90 times that of the reference compound, and when HCO-60 (1% (w / v)) and meglumine (20 mM, pH 8.5) were added in combination, the score was 0.61 times that of the reference compound. When meglumine was added to SMTP-7 (lot "GMP-like"), the score was 0.48 times. When HCO-60 (0.01% (w / v)) was added to SMTP-7 (lot "N01YH / G01HN"), the score was 1.05 times. When HCO-60 (0.01% (w / v)) and meglumine (20 mM, pH 8.5) were added in combination, the score was 0.34 times. When HCO-60 (0.1% (w / v)) and HCO-60 (1% (w / v)) were added, the scores were 0.79 and 0.44, respectively. When HCO-60 (1% (w / v)) and meglumine (20 mM, pH 8.5) were added in combination, the score was 0.34. On the other hand, when polyethylene glycol 4000 (1% (w / v)) was added to SMTP-7 (lot "N01YH / G01HN"), the score was 0.95 times that of the score without polyethylene glycol 4000.

[0081] From the above, it can be seen that the pharmaceutical composition according to the present disclosure enables SMTP-7 to be used more safely.

[0082] Example 2: Toxicity test of pharmaceutical composition in rats SMTP-7 (sodium salt) was prepared as described in Example 1. A different lot of SMTP-7 was obtained and designated N1533-62-1. The same Meg and HCO-60 as in Example 1 were used.

[0083] Pharmaceutical compositions 9 to 11 were each prepared by dissolving SMTP-7 and either or both of the basic additive and the amphipathic additive in physiological saline. The final concentration of SMTP-7 in the pharmaceutical composition was controlled to 10 mg / mL. The lot numbers of SMTP-7 in pharmaceutical compositions 9 to 11, as well as the types and concentrations of the basic additive, the amphipathic additive, and the reference compound, are shown in Table 2. [Table 2]

[0084] Pharmaceutical compositions 9 to 11 were administered to male and female SD rats (6 to 7 weeks old and 162 to 268 g) at a ratio (dose) of 10 mL / kg (100 mg / kg of SMTP-7 (free form)) via the tail vein. During administration, 1 / 10 of each pharmaceutical composition was administered immediately, and then the remaining 9 / 10 of the composition was administered continuously for 30 minutes.

[0085] The drug was administered intravenously into the tail vein via an indwelling needle. 10% of the administration volume was administered rapidly (rapid administration). During the rapid administration, the pharmaceutical composition was administered using a disposable syringe, an indwelling needle, and an extension tube. The rapid administration rate was 1 mL / kg / 5 seconds. After the rapid administration was completed, the syringe tube was immediately replaced. Then, the remaining 90% of the administration volume was administered continuously for 30 minutes (continuous administration). During the continuous administration, the pharmaceutical composition was administered using an infusion pump (BS-8000, Braintree Scientific Inc.). The continuous administration rate was 9 mL / kg / 30 minutes.

[0086] The condition of the rats was observed about 1 hour, about 4 hours, and the next day (about 24 hours after drug administration).

[0087] A urine test was performed. Urine was collected for 16 hours from administration until the next morning. New urine was collected within 4 hours of dissection on the day after administration. Dissection was performed on the day after drug administration.

[0088] For each of Pharmaceutical Compositions 9 to 11, toxicity was evaluated based on the average toxicity score of six experiments. The toxicity score is the sum of the evaluation items with different weighting coefficients (in parentheses) as follows: i. Injection site abnormality (1) ii. Abnormal urine color (1) iii. Red urine (2) iv. Edema at the injection site (1) v. Dark purple tail at injection site (1) vi. Red spots or crusts at the injection site (0.5) vii. Dark red foci in the lungs (4) viii. Renal dilatation (2) ix.Ureteral dilation (2) x. Dark green contents of the bladder (1)

[0089] The evaluation results are shown in Figure 2. In Figure 2, the vertical axis shows the average toxicity score (total of evaluation items) when each of Pharmaceutical Compositions 9 to 11 was administered.

[0090] On the other hand, the toxicity of Pharmaceutical Composition 9 is the same as that of Pharmaceutical Composition 10. The toxicity of Pharmaceutical Composition 11 is significantly lower than that of Pharmaceutical Compositions 9 and 10.

[0091] Example 3: Hemolysis test Citrated whole mouse blood (100 μl) was mixed with 1 ml of the pharmaceutical composition containing SMTP-7 in saline (200 μM), and the mixture was incubated at 37° C. for 1 minute. The pharmaceutical composition containing SMTP-7 is shown in Table 3 below. SMTP-7 (sodium salt) was prepared as described in Example 1. The same Meg and HCO-60 as in Example 1 were used.

[0092] The mixture was then centrifuged at 3,500 rpm for 2 min, and the resulting supernatant was diluted 10-fold with saline. The absorbance of the diluted supernatant (100 μl) at 530 nm was measured using a microplate reader. The hemolysis level (%) relative to the positive control (100% hemolysis) was calculated, as shown in Figure 3. [Table 3]

[0093] Industrial Applicability The present invention is useful for the prevention or treatment of ischemic disorders such as cerebral infarction, including acute ischemic cerebral infarction, particularly for the treatment of patients who cannot be treated with thrombolytic agents.

[0094] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety. References Patent Literature 1. Patent Document 1: JP 2004-224737 A 2. Patent Document 2: JP 2004-224738 A 3. Patent Document 3: WO2007 / 111203 4. Patent Document 4: WO2011 / 004620 Non-patent literature 1. Non-patent document 1: Kano et al., “Hemorrhagic transformation after fibrinolytic therapy with tissue plasminogen activator in a rat thromboembolic model of stroke” Brain Res2000, 854:245-248 2. Non-Patent Document 2: 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 3. Non-patent document 3: Matsumoto et al., “Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7” J Biol Chem2014, 289:35826-35838

Claims

1. Compounds represented by formula (I) 【Chemistry 1】 or a salt thereof, an ester thereof, or a solvate thereof, and a pharmaceutical composition comprising either or both of a basic excipient and an amphiphilic excipient.

2. The pharmaceutical composition according to claim 1, wherein the basic excipient comprises one or more selected from the group consisting of amino sugars, alkanolamines, and trometamol salts.

3. The pharmaceutical composition according to claim 1 , wherein the basic excipient comprises one or more selected from the group consisting of meglumine, triethanolamine, and trometamol hydrochloride.

4. The pharmaceutical composition according to claim 1, comprising, as the amphiphilic additive, 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 desoxycholate.

5. The pharmaceutical composition according to claim 1 , wherein the amphiphilic additive comprises one or more selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate.

6. 2. The pharmaceutical composition of claim 1, comprising both the basic excipient and the amphiphilic excipient.

7. The method of claim 1, wherein the basic additive is selected from an amino sugar, an alkanolamine, trometamol or a salt thereof, an amino acid, and an amine; The amphiphilic additive is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid, polyoxyethylene polyoxypropylene glycol, polysorbate, polyethylene glycol, ursodeoxycholic acid, sorbitan fatty acid ester, sodium deoxycholate, polyoxyl stearate, tyloxapol, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, polyglyceryl-3-diolate, and phosphatidylcholine; The pharmaceutical composition of claim 1.

8. The amino sugar selected from meglumine and glucosamine; the alkanolamine is selected from triethanolamine, monoethanolamine, diisopropanolamine, triisopropanolamine, diethanolamine, and 2-amino-2-methyl-1-propanol; The trometamol or a salt thereof is trishydroxymethylaminomethane; the amino acids are selected from glycine, arginine, histidine, and lysine; the amine is selected from triethylamine, ethylenediamine, epolamine, and guanidine; and The polyoxyethylene hydrogenated castor oil is selected from polyoxyethylene hydrogenated castor oil 50 and polyoxyethylene hydrogenated castor oil 60; The fatty acid polyoxyethylene sorbitan is selected from polyoxyethylene sorbitan monooleate (polysorbate 80) and polyoxyethylene sorbitan monolaurate (polysorbate 20); The pharmaceutical composition according to claim 7.

9. The pharmaceutical composition of claim 1, wherein the compound is SMTP-7 and is present in the pharmaceutical composition in an amount of 0.5 mg / mL to 20 mg / mL.

10. The pharmaceutical composition of claim 1, wherein the basic additive is present in the pharmaceutical composition at 1 mM to 200 mM.

11. The pharmaceutical composition of claim 1, wherein the amphiphilic additive is present in the pharmaceutical composition at 0.001% to 10% (w / v).

12. 2. The pharmaceutical composition of claim 1, comprising meglumine as the basic excipient and polyoxyethylene hydrogenated castor oil as the amphiphilic excipient.

13. The pharmaceutical composition of claim 9, comprising meglumine as the basic additive and polyoxyethylene hydrogenated castor oil as the amphiphilic additive.

14. (1) A compound which is SMTP-7 or a salt thereof; (2) meglumine; and (3) Polyoxyethylene hydrogenated castor oil The pharmaceutical composition of claim 1 , comprising:

15. The pharmaceutical composition according to claim 1 , which is an intravenous formulation.

16. The pharmaceutical composition according to claim 1, which is used for the prevention or treatment of an ischemic injury or an inflammatory disease.

17. The pharmaceutical composition of claim 14, for use in the prevention or treatment of an ischemic disorder or an inflammatory disease.

18. The pharmaceutical composition according to claim 16, wherein the ischemic disorder is cerebral infarction or transient ischemic attack.

19. The pharmaceutical composition of claim 17, wherein the ischemic disorder is cerebral infarction or transient ischemic attack.

20. The pharmaceutical composition according to claim 18, wherein the cerebral infarction is an ischemic cerebral infarction.

21. The pharmaceutical composition described in claim 19, wherein the cerebral infarction is an ischemic cerebral infarction.

22. The pharmaceutical composition according to claim 20, wherein the ischemic cerebral infarction is acute ischemic cerebral infarction.

23. The pharmaceutical composition described in claim 21, wherein the ischemic cerebral infarction is acute ischemic cerebral infarction.

24. A method for producing the pharmaceutical composition according to any one of claims 1 to 23, comprising mixing the compound represented by formula (I) or a salt thereof, an ester thereof, or a solvate thereof with either one or both of the basic additive and the amphiphilic additive.

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