Pharmaceutical composition for improving cardiac function

Abstract

To provide pharmaceutical compositions for improving cardiac function by administration during coronary artery bypass surgery for ischemic cardiomyopathy.SOLUTION: Provided is a pharmaceutical composition for improving cardiac function containing release formulations: (A) a release formulation containing at least a lactic acid / glycolic acid copolymer (PLGA) and a prostaglandin I2 receptor agonist, the PLGA having an average molecular weight of 10000 to 30000; and (B) a release formulation containing at least a copolymer of lactic acid and glycolic acid (PLGA) and a prostaglandin I2 receptor agonist, the PLGA having an average molecular weight of 40,000 to 60,000.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to a pharmaceutical composition for improving cardiac function. [Background technology]

[0002] ONO-1301, the active ingredient of the pharmaceutical composition disclosed herein, is a non-prostaglandin-based small molecule synthetic compound that is a selective prostaglandin I2 receptor (IP2 receptor) agonist that also inhibits thromboxane A2 (TXA2) synthase. Initially, it was investigated as an oral platelet aggregation inhibitor, but development was suspended due to a narrow safety margin determined in a phase I clinical trial based on the efficacy (platelet aggregation inhibitory effect) and side effects (upper abdominal pain, fever, cold sweat, diarrhea, etc.).

[0003] ONO-1301 acts on vascular smooth muscle cells, platelets, and vascular endothelial cells, exhibiting platelet aggregation inhibitory and vasodilatory effects. Subsequent studies have demonstrated that ONO-1301 acts on IP receptors in fibroblasts and smooth muscle cells at concentrations less than 1 / 20 of the platelet aggregation inhibitory effect, elevating cyclic adenosine monophosphate (cAMP) levels and inducing the production of various endogenous regenerative factors, including hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), and high mobility group box 1 (HMGB1). These actions have also led to the discovery that ONO-1301 exhibits angiogenic, anti-apoptotic, anti-fibrotic, and anti-inflammatory effects, as well as bone marrow mesenchymal stem cell (MSC) mobilization and accumulation (drug repositioning). Furthermore, its TXA2 synthase inhibitory effect suppresses tolerance to IP receptors even with long-term administration, and also promotes the production of endogenous prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2). Summary of the Invention [Problem to be solved by the invention]

[0004] An objective of the present disclosure is to provide a pharmaceutical composition that improves cardiac function by being administered during coronary artery bypass surgery for ischemic cardiomyopathy. More specifically, the present invention aims to provide a sustained-release formulation of microspheres (MS) of compound (A), a PGI2 passive agonist, etc., which maintains the blood concentration of the active ingredient ONO-1301 within a certain concentration range for a certain period of time, thereby exhibiting an effect of improving cardiac function, and which has been clinically confirmed to be safe and tolerable. [Means for solving the problem]

[0005] The inventors conducted various studies on the production of sustained-release formulations of MS containing PGI2 receptor agonists, and found that by mixing PGI2 receptor agonist-containing release formulations containing lactic acid / glycolic acid copolymers (PLGA) with different average molecular weights, the PGI2 receptor agonist is released over a certain period of time and at a certain concentration range.

[0006] The present inventors have found that the approved pharmaceuticals YS-1402-Gelfoam and YS-1402-Beriplast are optimal for applying the pharmaceutical composition of the present invention to the heart during coronary artery bypass surgery for ischemic cardiomyopathy.

[0007] The present invention was completed based on these findings and through further trial and error, and includes the following inventions. Section 1. (A): A release-type preparation containing at least a lactic acid-co-glycolic acid copolymer (PLGA) and a prostaglandin I2 receptor agonist, wherein the average molecular weight of the PLGA is 1,000 to 30,000; and (B): A release-type preparation containing at least a lactic acid-co-glycolic acid copolymer (PLGA) and a prostaglandin I2 receptor agonist, wherein the average molecular weight of the PLGA is 40,000 to 60,000; containing A pharmaceutical composition for improving cardiac function. Section 2. 2. The pharmaceutical composition for improving cardiac function according to claim 1, wherein the ratio (A:B) of the release type preparation (A) to the release type preparation (B) is 1:1 to 100:1 or 1:1 to 1:100. Section 3. 3. The pharmaceutical composition for improving cardiac function according to claim 1, wherein the release-type preparation (A) contains 0.5 to 50 mg of a PGI2 receptor agonist per vial, and / or the release-type preparation (B) contains 0.5 to 50 mg of a PGI2 receptor agonist per vial. Section 4. 4. The pharmaceutical composition according to claim 1, which comprises a patch liquid. Section 5. 5. The pharmaceutical composition according to claim 4, wherein the patch solution is a 5 w / v % aqueous solution of mannitol containing 0.2 w / v % polysorbate. Section 6. 6. The pharmaceutical composition according to claim 1, which comprises a gelatin patch. Section 7. 7. The pharmaceutical composition according to claim 6, wherein the gelatin patch is a porous sterile preparation containing 10 g of gelatin per 1000 cm. Section 8. 8. The pharmaceutical composition according to claim 1, comprising a plasma fraction preparation. Section 9. 9. The pharmaceutical composition according to claim 8, wherein the plasma fraction preparation comprises fibrinogen powder, aprotinin solution, thrombin powder, and calcium chloride solution. Section 10. The pharmaceutical composition according to any one of claims 1 to 9, comprising, as the prostaglandin I2 receptor agonist, at least a compound represented by the following general formula (I) or a salt thereof: [ka] [ka] (In the formula, R1 represents a hydrogen atom or a C1-4 alkyl group; R2 represents (i) a hydrogen atom, (ii) a C1-8 alkyl group, (iii) a phenyl group or a C4-7 cycloalkyl group, (iv) a 4- to 7-membered monocyclic ring containing one nitrogen atom, (v) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (vi) a C1-4 alkyl group substituted with a 4- to 7-membered monocyclic ring containing one nitrogen atom; R3 represents (i) a C1-8 alkyl group, (ii) a phenyl group or a C4-7 cycloalkyl group, (iii) a 4- to 7-membered monocyclic ring containing one nitrogen atom, (iv) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (v) a C1-4 alkyl group substituted with a 4- to 7-membered monocyclic ring containing one nitrogen atom; e represents an integer of 3 to 5; f represents an integer of 1 to 3; p represents an integer of 1 to 4; q represents 1 or 2; r represents an integer from 1 to 3 (however, [ka] When is a group represented by (iii) or (iv), -(CH2)p- and =CH-(CH2)s- are attached to the a or b position on the ring, and The ring structure in R2 and R3 may be substituted with 1 to 3 C1-4 alkyl groups, C1-4 alkoxy groups, halogen atoms, nitro groups or trihalomethyl groups). Section 11. The pharmaceutical composition according to any one of claims 1 to 10, comprising at least the following compound (A) or a salt thereof as the prostaglandin I2 receptor agonist: (A) Formula (II) below [ka] ({5-[2-({[(1E)-phenyl(pyridin-3-yl)methylene]amino}oxy)ethyl]-7,8-dihydronaphthalen-1-yl}oxy)acetic acid (ONO-1301). Section 12. 12. The pharmaceutical composition according to claim 1, which is in the form of a sheet-type patch. Section 13. 13. The pharmaceutical composition according to claim 1, which is administered to a patient with ischemic cardiomyopathy who is to undergo coronary artery bypass surgery. Section 14. 14. The pharmaceutical composition according to claim 1, wherein the prostaglandin I2 receptor agonist is released over a period of 4 weeks after administration. Section 15. 15. The pharmaceutical composition according to claim 1, which is a sustained-release preparation of microspheres (MS). Section 16. 16. The pharmaceutical composition according to claim 15, wherein the sustained-release preparation has an average particle size of 3 to 300 μm. [Effects of the Invention]

[0008] The pharmaceutical composition of the present disclosure is useful for improving cardiac function because the blood concentration of the active ingredient, ONO-1301, is maintained within a certain concentration range for a certain period of time. [Brief explanation of the drawings]

[0009] [Figure 1] Schematic diagram of the preparation of a YS-1402 administration sheet of the present invention for a 30 mg administration. [Figure 2] Schematic diagram of the cardiac administration method of the YS-1402 administration sheet. [Figure 3] A diagram showing the breakdown of subjects in this clinical trial. [Figure 4] Graph showing the time course of ONO-1301 blood concentration after a single application of YS-1402-10mg, 30mg, or 100mg at the time of thoracotomy for coronary artery bypass surgery. [Horizontal axis (time: equal intervals at each blood sampling point), Vertical axis (blood drug concentration: real number)] [Figure 5]Graph showing the time course of ONO-1301 blood concentration after a single application of YS-1402-10mg, 30mg, or 100mg at the time of thoracotomy for coronary artery bypass surgery. [Horizontal axis (time: proportional to actual time), Vertical axis (blood drug concentration: real number)] [Figure 6] Graph showing the time course of ONO-1301 blood concentration after a single application of YS-1402-10mg, 30mg, or 100mg at the time of thoracotomy for coronary artery bypass surgery. [Horizontal axis (time: proportional to actual time), Vertical axis (blood drug concentration: logarithmic)] [Figure 7] This graph shows the time course of LVEF measured by echocardiography after a single application of YS-1402-10mg, 30mg, or 100mg at the time of open chest surgery for coronary artery bypass surgery. [Figure 8] This graph shows the time course of change in LVEF measured by echocardiography after a single application of YS-1402-10mg, 30mg, or 100mg at the time of open chest surgery for coronary artery bypass surgery. [Figure 9] Graph showing the change in LVEF from baseline to 26 weeks after administration. [Figure 10] Graph showing the correlation between the percentage change in total myocardial blood flow from baseline and the change in LVEF 26 weeks after administration of the study drug. [Figure 11] Graph showing the time course of the measured CI values ​​of cardiac-gated CT. [Figure 12] Graph showing the time course of the rate of change in CI in cardiac-gated CT. [Figure 13] A graph showing the rate of change in CI from baseline to 26 weeks after administration in cardiac-gated CT. [Figure 14] Graph showing the correlation between the percentage change in total myocardial blood flow and the percentage change in CI from baseline 26 weeks after administration of the study drug. [Figure 15] Graph showing the time course of measured LVESVI values ​​using cardiac-gated CT. [Figure 16] Graph showing the time course of change in LVESVI on cardiac-gated CT. [Figure 17] Graph showing the time course of measured LVEDVI values ​​using cardiac-gated CT. [Figure 18] Graph showing the time course of the rate of change of LVEDVI in cardiac-gated CT. [Figure 19]A graph showing the time course of LVDs measured by cardiac ultrasound examination. [Figure 20] Graph showing the change rate of LVDs over time in echocardiography. [Figure 21] A graph showing the time course of the actual LVDd measured by cardiac ultrasound examination. [Figure 22] Graph showing the change rate of LVDd over time as determined by echocardiography. [Figure 23] A graph showing the time course of measured CTR values ​​in chest X-ray examinations. [Figure 24] A graph showing the change in CTR of chest X-ray examination over time. [Figure 25] A graph showing the change in NYHA classification over time. Percentages were calculated based on a population of 6 subjects. The standard number of subjects for evaluation is 6, but 26 weeks after administration, one subject in each of the placebo and YS-1402 100 mg groups discontinued treatment, resulting in 5 subjects in each group, and one subject in the 30 mg group who was unable to be measured due to right-sided hemiplegia, resulting in 5 subjects at all measurement points. [Figure 26] A graph showing the time course of the actual measured 6-minute walking distance. [Figure 27] A graph showing the rate of change in 6-minute walking distance over time. [Figure 28] A graph showing the rate of change in 6-minute walking distance from baseline to 26 weeks after administration. [Figure 29] A graph showing the rate of change from baseline to 26 weeks after administration in the 6-minute walking distance in the YS-1402 30 mg group, excluding cases of congestive heart failure due to poor medication compliance. [Figure 30A] Graph showing the time course of measured values ​​of myocardial blood flow at rest in the RCA using ammonia PET. [Figure 30B] Graph showing the time course of actual measurements of LAD resting myocardial blood flow using ammonia PET. [Figure 30C] Graph showing the time course of actual measurements of myocardial blood flow at rest in the LCX using ammonia PET. [Figure 30D] Graph showing the time course of measured total myocardial blood flow using ammonia PET. [Figure 31A] Time course of change from baseline in RCA resting myocardial blood flow measured by ammonia PET. [Figure 31B] Graph showing the time course of the rate of change from baseline in LAD resting myocardial blood flow measured by ammonia PET. [Figure 31C] Time course of change from baseline in LCX resting myocardial blood flow measured by ammonia PET. [Figure 31D] Graph showing the time course of the rate of change from baseline in total myocardial blood flow measured by ammonia PET. [Figure 32] Graph showing the percent change in total myocardial blood flow from baseline to 26 weeks after administration. [Figure 33] Graph showing the rate of change in LAD resting myocardial blood flow from baseline to 26 weeks after administration. [Figure 34] A graph showing the correlation between blood concentration (AUC0-t) and the percent change in total myocardial blood flow from baseline 26 weeks after administration of the investigational drug. [Figure 35] A graph showing the correlation between blood concentration (Cmax) and the rate of change in total myocardial blood flow from baseline 26 weeks after administration of the investigational drug. [Figure 36] A graph showing the correlation between AUC0-t and the rate of change in LAD resting myocardial blood flow from baseline 26 weeks after administration of the study drug. [Figure 37] A graph showing the time course of measured blood BNP concentrations. [Figure 38] A graph showing the rate of change in blood BNP concentration over time. [Figure 39A] This graph shows the time course of the actual measured scores for the SF-36 subscale [Physical Function], which was established to assess QOL. [Figure 39B] This graph shows the time course of the actual measured scores for the SF-36 subscale [Daily Role Functioning (Physical)], which was established for the purpose of assessing QOL. [Figure 39C] This graph shows the time course of the actual measured scores for the SF-36 subscale [bodily pain], which was established for QOL assessment. [Figure 39D] This graph shows the time course of the actual measured scores for the SF-36 subscale [general health perception], which was established to assess QOL. [Figure 39E] This graph shows the time course of the actual scores for the SF-36 subscale [Vitality], which was established to assess QOL. [Figure 39F]This graph shows the time course of the actual measured scores for the SF-36 subscale [social functioning], which was established to assess QOL. [Figure 39G] This graph shows the time course of the actual measured scores for the SF-36 subscale [Daily Role Functioning (Mental)], which was established for QOL assessment. [Figure 39H] A graph showing the time course of the actual scores for the SF-36 subscale [Mental Health], which was established to assess QOL. [Figure 40A] A graph showing the change over time in the score for the SF-36 subscale [physical function], which was established to assess QOL. [Figure 40B] This graph shows the change over time in the score for the SF-36 subscale [Daily Role Functioning (Physical)], which was established to assess QOL. [Figure 40C] A graph showing the change over time in the score for the SF-36 subscale [bodily pain], which was established to assess QOL. [Figure 40D] This graph shows the change over time in the score for the SF-36 subscale [general health perception], which was established to assess QOL. [Figure 40E] A graph showing the change over time in the score for the SF-36 subscale [Vitality], which was established to assess QOL. [Figure 40F] This graph shows the change over time in the score for the SF-36 subscale [social functioning], which was established to assess QOL. [Figure 40G] This graph shows the change over time in the score for the SF-36 subscale [Daily Role Functioning (Mental)], which was established to assess QOL. [Figure 40H] A graph showing the change over time in the score for the SF-36 subscale [Mental Health], which was established to assess QOL. [Figure 41] A diagram showing the relationship assessment (FAS) between cardiac ultrasound (LVEF) and cardiac-gated CT (LVESVI). DETAILED DESCRIPTION OF THE INVENTION

[0010] 1. Pharmaceutical composition for improving cardiac function The pharmaceutical composition for improving cardiac function of the present invention comprises: A release formulation (A) containing a lactic acid-co-glycolic acid copolymer (PLGA) having an average molecular weight of 10,000 to 30,000 and a prostaglandin I2 (PGI2) receptor agonist. (B) a release formulation containing a lactic acid-co-glycolic acid copolymer (PLGA) having an average molecular weight of 40,000 to 60,000 and a prostaglandin I2 (PGI2) receptor agonist; Patches, Gelatin patches, and plasma derivatives, Contains:

[0011] 1.1. Release formulation containing poly(lactic acid-co-glycolic acid) (PLGA) and prostaglandin I2 (PGI2) receptor agonist The pharmaceutical composition for improving cardiac function of the present invention contains two types of PLGA having different average molecular weights, and release-type preparations (A) and (B) containing a PGI2 receptor agonist.

[0012] The pharmaceutical composition for improving cardiac function of the present invention is prepared (suspended) at the time of use using two types of release formulations (A) and (B). Release formulation (A) is a sterile formulation produced using PLGA with an average molecular weight of 10,000 to 30,000, and is a 2-week release formulation containing 0.5 to 50 mg of a PGI2 receptor agonist per vial. Release formulation (B) is a sterile formulation produced using PLGA with an average molecular weight of 40,000 to 60,000, and is a 4-week release formulation containing 0.5 to 50 mg of a PGI2 receptor agonist per vial.

[0013] The "average molecular weight" may be any molecular weight, including weight average molecular weight and number average molecular weight.

[0014] In the pharmaceutical composition for improving cardiac function of the present invention, the content ratio (A:B) of the two types of release formulations (A) and (B) is not particularly limited, but is preferably 1:1 to 100:1 or 1:1 to 1:100, and more preferably 1:1.

[0015] The content of PLGA and PGI2 receptor agonist is not particularly limited, but it is preferable that the PGI2 receptor agonist is contained in an amount of 1 to 100% relative to PLGA1, and more preferably 5 to 90%, of the total amount of the sustained-release formulation of the present invention.

[0016] The PGI2 receptor agonist used in the pharmaceutical composition for improving cardiac function of the present invention is not particularly limited, and known PGI2 receptor agonists can be suitably used. Known PGI2 receptor agonists include, for example, PGI2 receptor agonists represented by the general formula (I): [ka] [ka] (In the formula, R1 represents a hydrogen atom or a C1-4 alkyl group; R2 represents (i) a hydrogen atom, (ii) a C1-8 alkyl group, (iii) a phenyl group or a C4-7 cycloalkyl group, (iv) a 4- to 7-membered monocyclic ring containing one nitrogen atom, (v) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (vi) a C1-4 alkyl group substituted with a 4- to 7-membered monocyclic ring containing one nitrogen atom; R3 represents (i) a C1-8 alkyl group, (ii) a phenyl group or a C4-7 cycloalkyl group, (iii) a 4- to 7-membered monocyclic ring containing one nitrogen atom, (iv) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (v) a C1-4 alkyl group substituted with a 4- to 7-membered monocyclic ring containing one nitrogen atom; e represents an integer of 3 to 5; f represents an integer of 1 to 3; p represents an integer of 1 to 4; q represents 1 or 2; r represents an integer from 1 to 3 (however, [ka] When is a group represented by (iii) or (iv), -(CH2)p- and =CH-(CH2)s- are attached to the a or b position on the ring, and The ring structure in R2 and R3 may be substituted with 1 to 3 C1-4 alkyl groups, C1-4 alkoxy groups, halogen atoms, nitro groups or trihalomethyl groups. or a salt thereof, a PGI2 derivative and a PGE derivative. Preferably, the PGI2 receptor agonist is (A) Formula (II) below [ka] ({5-[2-({[(1E)-phenyl(pyridin-3-yl)methylene]amino}oxy)ethyl]-7,8-dihydronaphthalen-1-yl}oxy)acetic acid (CAS 176391-41-6; compound (A) (ONO-1301)); (B) Carbacyclin-based PGI2 derivatives (compound (B)) including (±)-(1R,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butanoic acid sodium salt (CAS: 88475-69-8; beraprost) and the like; (C) [4-(5,6-diphenylpyrazinyl)(1-methyletyl)amino]butoxy]-acetic acid (CAS: 475085-57-5; MRE-269; compound (C)); (D) (2E)-7{-(1R,2R,3R)-3-hydroxy-2[-(1E,3S,5S)-3-hydroxy-5-methylnon-1-en-1-yl]-5-oxocyclopentyl}-hept-2-enoic acid (CAS: 74397-12-9; limaprostil), ornoprostil; PGE derivatives (compound (D)) including 17S,20-dimethyl-6-oxo-PGE1 methyl ester, enprotil, misoprostol, etc.; or A preferred PGI2 receptor agonist is (E)2-{4-[(5,6-diphenylpyrazin-2-)yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide (CAS: 475086-01-2; selexipag; NS-304 (compound (E))).

[0017] 1.2.Liquid Patch The pharmaceutical composition for improving cardiac function of the present invention contains a patch solution used for preparing (suspending) two types of release formulations (A) and (B) just before use.

[0018] The patch solution is preferably a 5 w / v % aqueous solution of mannitol containing 0.2 w / v % polysorbate.

[0019] 1.3. Gelatin patches The pharmaceutical composition for improving cardiac function of the present invention contains a gelatin patch used to prepare an administration sheet for the pharmaceutical composition for improving cardiac function of the present invention.

[0020] As a gelatin patch, it is preferable to use the commercially available product YS-1402-Gelfoam (Gelfoam®, Pfizer Inc.). YS-1402-Gelfoam is a sponge-like sheet made by blowing air into Japanese Pharmacopoeia gelatin, and is a white, porous, sterile preparation containing 10 g of Japanese Pharmacopoeia gelatin per 1000 cm3. YS-1402-Gelfoam is an approved drug, but its use in the present invention is outside its indicated scope.

[0021] 1.4. Plasma derivatives The pharmaceutical composition for improving cardiac function of the present invention contains a plasma fraction preparation as the physiological tissue adhesive of the present invention so that the administration sheet of the pharmaceutical composition for improving cardiac function of the present invention that has been applied to the heart does not peel off from the heart.

[0022] The preferred plasma fraction preparation is YS-1402-Beriplast (Beriplast (registered trademark) P Combicet for tissue adhesion: plasma fraction preparation, CSL Behring Co., Ltd.). YS-1402-Beriplast contains fibrinogen powder, aprotinin solution, thrombin powder, and calcium chloride solution. YS-1402-Beriplast is administered by dripping it around the application site of the administration sheet of the sustained-release preparation of the present invention. YS-1402-Beriplast is an approved drug, but its use in the present invention is outside its indicated scope.

[0023] YS-1402-Beriplast, a 3 ml formulation, consists of vials 1 to 4 in one set. Vial 1 contains 240 mg of fibrinogen and 180 international units of human blood coagulation factor XIII, vial 2 contains 3000 KIE of aprotinin solution, vial 3 contains 900 units of thrombin (JP), and vial 4 contains 17.64 mg of calcium chloride hydrate (JP). Vials 1 and 2 are mixed to form solution A, and vials 3 and 4 are mixed to form solution B. Mixing solutions A and B forms a fibrin glue.

[0024] 1.5.Other Ingredients The pharmaceutical composition for improving cardiac function of the present invention may contain ingredients other than those mentioned above, as long as they do not impair the effects of the present invention.

[0025] 2. Form, preparation method, and clinical administration method of pharmaceutical composition for improving cardiac function The pharmaceutical composition for improving cardiac function of the present invention is a sustained-release preparation of microspheres (MS).

[0026] The sustained-release preparation of the present invention is not particularly limited, but preferably has an average particle size of about 3 to 300 μm, more preferably about 5 to 200 μm, and even more preferably about 10 to 100 μm. In this specification, "particle size" refers to the diameter of a particle measured by any method including laser diffraction. The method for adjusting the particle size is not particularly limited.

[0027] The pharmaceutical composition for improving cardiac function of the present invention is not particularly limited in its form, but is preferably a sheet-type sustained-release preparation of MS.

[0028] The method for preparing an administration sheet for the pharmaceutical composition for improving cardiac function of the present invention comprises the following steps: (a) suspending two types of release formulations (A) and (B) using a patch solution; and (b) A step of adding the suspension obtained in step (a) dropwise to YS-1402-Gelfoam to form a dosing sheet. Includes:

[0029] In step (a), hydrolysis begins upon addition of the patch solution, and the release of the active ingredient, a PGI2 receptor agonist, begins. Therefore, cardiac patch administration should be performed within approximately 6 hours after the start of preparation of the administration sheet. To prevent hydrolysis, the administration sheet is stored refrigerated in a sterile dish.

[0030] The method for clinically administering the administration sheet of the pharmaceutical composition for improving cardiac function of the present invention to the heart comprises the following steps: (c) applying the administration sheet obtained in step (b) to a site in the ischemic area of ​​the heart that does not affect the running of the graft; and (d) A step of dropping YS-1402-Beriplast around the application area and enclosing the administration sheet obtained in step (b). Includes:

[0031] The pharmaceutical composition of the present invention for improving cardiac function is preferably administered at the end of coronary artery bypass surgery, and the PGI2 receptor agonist is released over a period of 4 weeks after administration.

[0032] In the present disclosure, "release over 4 weeks" means that the blood concentration of the active ingredient, a PGI2 receptor agonist, is maintained within a certain concentration range for 4 weeks after administration of the pharmaceutical composition for improving cardiac function of the present invention.

[0033] The dosage of the pharmaceutical composition for improving cardiac function of the present invention depends on the severity of the symptoms to be treated, but it is desirable that the dosage of the PGI2 receptor agonist, which is the active ingredient contained therein, be 1000 mg or less. [Example]

[0034] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0035] Preparation of YS-1402 administration sheet and placebo formulation Administration sheets for the cardiac function improving composition of the present invention (hereinafter referred to as YS-1402) containing 10 mg, 30 mg, and 100 mg of ONO-1301, respectively, and a placebo formulation not containing ONO-1301 were prepared (Groups 1 to 3). Group 1: YS-1402 (ONO-1301 content 10 mg) and placebo group Group 2: YS-1402 (ONO-1301 content 30 mg) and placebo group Group 3: YS-1402 (ONO-1301 content 100 mg) and placebo group

[0036] The YS-1402 administration sheet and placebo preparation containing 10 mg, 30 mg, and 100 mg of ONO-1301, respectively, can be manufactured, for example, by the following method. The preparations shown in Table 1 were used for preparation. [Table 1]

[0037] Preparation of YS-1402 administration sheet containing 10 mg of ONO-1301 Use a syringe equipped with a 20G or larger needle to collect the attached liquid. Remove the needle from the syringe that collected the attached liquid and attach a needle of the same diameter. Use this to add the attached liquid to the YS-1402-2 vial. Stir thoroughly and collect the liquid from the vial, then remove the syringe from the needle and add the same liquid to the YS-1402-1 vial. Stir thoroughly, then collect the liquid from the vial and remove the syringe from the needle. Connect the syringe to the three-way stopcock. Take a new syringe and collect the attached liquid through the needle inserted into the vial containing the attached liquid. After that, rinse each vial in turn and attach it to the three-way stopcock to which the syringe is connected. Mix the liquid collected in the syringe through the three-way stopcock, being careful not to create bubbles. Collect the mixed liquid in one syringe and add it evenly to two YS-1402-Gelfoam sheets. After adding the suspension, fix the MS powder and drip in YS-1402-Beriplast so that it is hidden. After dripping, apply it to the heart as quickly as possible.

[0038] Preparation of YS-1402 administration sheet containing 30 mg of ONO-1301 Figure 1 shows an outline of the preparation of the YS-1402 administration sheet containing 30 mg of ONO-1301. The attached liquid is collected using a syringe equipped with a 20G or larger needle. The needle is removed from the syringe that collected the attached liquid, and a needle of the same diameter is attached. This is used to add the attached liquid to the YS-1402-2 vial. After thoroughly stirring and collecting the liquid from the vial, the syringe is removed from the needle. A new needle is then attached, and the same liquid is added to the YS-1402-2 vial. After thoroughly stirring, the liquid from the vial is collected and the syringe is removed from the needle. This procedure is performed for three YS-1402-2 vials and three YS-1402-1 vials, and the syringe is connected to the three-way stopcock. A new syringe is taken out and the attached solution is collected through the needle inserted into the vial of attached solution. After that, each vial is rinsed in turn and attached to the three-way stopcock connected to the syringe. The collected solution in the syringe is mixed through the three-way stopcock without creating bubbles. The mixed solution is collected in one syringe and added evenly to two YS-1402-Gelfoam sheets. After adding the suspension, physiological tissue adhesive (YS-1402-Beriplast) is dripped in to fix and hide the MS powder. After dripping, the sheet is applied to the heart as quickly as possible.

[0039] Preparation of YS-1402 administration sheet containing 100 mg of ONO-1301 The attached liquid is collected using a syringe equipped with a 20G or larger needle. The needle is removed from the syringe that collected the attached liquid and a needle of the same diameter is attached. This is used to add the attached liquid to the YS-1402-2 vial. Stir thoroughly, collect the liquid from the vial, and then remove the syringe from the needle. A new needle is attached and the same liquid is added to the YS-1402-2 vial. Stir thoroughly, collect the liquid from the vial, and then remove the syringe from the needle. This procedure is performed for 10 YS-1402-2 vials and 10 YS-1402-1 vials, and the syringe is connected to the three-way stopcock. A new syringe is removed and the attached liquid is collected through the needle inserted into the attached liquid vial. After that, each vial is rinsed in turn and the syringe is attached to the three-way stopcock. The liquid collected in the syringe is mixed through the three-way stopcock, taking care not to create bubbles. The mixture was collected in one syringe and added evenly to two YS-1402-Gelfoam sheets. After adding the suspension, a drop of physiological tissue adhesive (YS-1402-Beriplast) was added to fix and hide the MS powder. After the drop, the sheet was attached to the heart as quickly as possible.

[0040] Preparation of placebo formulation After applying the attached solution evenly to two similar YS-1402-Gelfoam sheets, apply a drop of physiological tissue adhesive (YS-1402-Beriplast) so that the applied area is hidden. After application, apply the solution to the heart as quickly as possible.

[0041] How to select the administration site and administration method At the end of coronary artery bypass surgery via open-chest surgery, a YS-1402 administration sheet was attached to the left ventricle (Figure 2). The application locations were determined by identifying areas of reduced myocardial blood flow using preoperative ammonia positron emission tomography (ammonia PET). During coronary artery bypass surgery, complex lesions and multivessel lesions, where complete restoration of blood flow to the ischemic area of ​​the heart is difficult, including areas of advanced fibrosis and poor contraction, were identified visually and tactilely. Two YS-1402 administration sheets were then applied to areas surrounding the lesions, where the graft path would not be affected.

[0042] Number of doses This investigational drug was administered once, as it was administered at the time of thoracotomy for coronary artery bypass surgery.

[0043] Post-administration treatment To prevent the two YS-1402 administration sheets attached to the heart from peeling off, YS-1402-Beriplast was dripped around the area where the YS-1402 administration sheets were attached, and the YS-1402 administration sheets were sealed and the chest was closed.

[0044] Identification of therapeutic drugs YS-1402 is a sustained-release formulation of MS with a particle size of approximately 30 μm (average), containing approximately 15% ONO-1301 in two types of lactic acid / glycolic acid copolymer (1:1) with molecular weights of 20,000 and 50,000. The formulation is designed to maintain blood concentrations of ONO-1301 within a certain range for approximately four weeks after administration.

[0045] Safety and tolerability evaluation Safety and tolerability were evaluated comprehensively based on the following items 1) to 5). 1) Adverse events This study was designed to evaluate the safety and tolerability of YS-1402 when applied to the heart. The type, severity, seriousness, frequency, and duration of adverse events were confirmed. 2) General clinical tests The study was designed to evaluate the overall safety of YS-1402 when applied to the heart (Table 2). (1) Hematological tests (2) Blood biochemistry tests (3) Blood coagulation system tests 3)Clinical symptoms This study was designed to evaluate the overall safety of YS-1402 when applied to the heart. (1) Vital signs: blood pressure (diastolic, systolic), heart rate, respiratory rate, body temperature (armpit) (2) Subjective symptoms: In particular, the presence or absence of diarrhea and a heavy feeling in the head was confirmed. (3) Physical examination: The presence or absence of moist rales, edema, and extra heart sounds was confirmed. 4) Standard 12-lead electrocardiogram and Holter electrocardiogram at rest The test was set to check for the presence or absence of arrhythmia and myocardial ischemia. The presence or absence of arrhythmia, abnormal Q waves (only in 12-lead electrocardiograms), and abnormal findings was checked. 5) Presence and degree of bleeding after application (post-surgery) The presence and severity of postoperative bleeding after cardiac attachment was evaluated using the BARC bleeding criteria, which are commonly used to evaluate bleeding after coronary artery bypass surgery. The BARC bleeding criteria are shown in Table 3. [Table 2] [Table 3]

[0046] Pharmacokinetic evaluation 1) Secondary endpoints (1) Plasma drug concentration This was set up to investigate the blood pharmacokinetics of the active compound ONO-1301. Evaluation was based on the pharmacokinetic parameter (Cmax) after application. Blood concentration was measured at 1, 3, 6, 24 hours, 7 days, 10 days, 14 days, 28 days (4 weeks), 6 weeks, and 8 weeks after administration to confirm the disappearance of blood concentration. 5 ml of blood was collected from each sample using a blood collection tube containing heparin sodium, kept on ice until centrifugation, and then immediately centrifuged (3000 rpm x 10 minutes). The plasma fraction was collected and stored frozen (-20°C). 2) Exploratory endpoints (1) Change in left ventricular ejection fraction (LVEF) at 26 weeks after application The study was designed to assess global left ventricular contractility. Improvement in global left ventricular contractility was assessed by changes in LVEF obtained by echocardiography (weeks 0 and 26). (2) Changes in left ventricular pump function (cardiac index [CT]) before and after application To evaluate left ventricular pump function, CT measurements were performed. CT (ml / min / m2) was calculated using the following formula: CT(ml / min / m2)=((LVEDV(ml))-(LVESV(ml)))×(heart rate(times / min)) / (body surface area(m2)) Body surface area (m2) = weight (kg) 0.425 × height (cm) 0.725 × 0.007184 (Dubois formula) The height and weight were measured at the following times. Height: Measured at screening. Body weight: Value measured on the day of cardiac-synchronized CT scan. (3) Changes in left ventricular remodeling before and after application The following items were established to evaluate the suppression of left ventricular remodeling from multiple angles. [1]LVESVI LVESVI is an index of ventricular remodeling and indicates the progression of heart failure pathology. LVESVI has also been reported in many publications as a prognostic predictor. Changes in LVESVI correlate with changes in prognosis, and survival is said to change in proportion to the direction and magnitude of the change. Therefore, it was established as an index of cardiac function. Regarding the degree of improvement in LVESVI, a reduction of 10% or more has been reported as the criterion for determining a responder to cardiac resynchronization therapy, and considering measurement error, a change of less than 10% was considered "unchanged." [2]LVEDVI [3]LVDs [4]LVDd [5] Changes in CTR (4) Changes in heart failure symptoms before and after application The following items were set to evaluate the severity of heart failure and improvement of symptoms. [1] NYHA classification To examine the improvement in the severity of heart failure, the NYHA classification was used as an endpoint. [2] 6-minute walking distance The 6-minute walking distance is frequently used as a simple method to measure exercise tolerance, and was therefore set as an index of QOL. (5) Changes in myocardial blood flow; ammonia PET scan This is a useful evaluation method for confirming the recovery of blood flow in the ischemic local area (where the test drug is applied). By administering 13NH3:ammonia intravenously, ammonia accumulates in the heart according to the blood flow, and by examining the degree of accumulation with PET / CT, it is possible to understand the flow and movement of blood in the local area of ​​the heart. (6) Changes in brain natriuretic peptide (BNP) BNP was selected as a clinical indicator of heart failure because it is a very useful and widely used indicator. Changes in blood BNP levels were evaluated from before application to 26 weeks after application. (7) Evaluation of QOL This was set up to evaluate the subjects' QOL after cardiac placement. The patient's QOL status was assessed using the Japanese version of the SF-36 (Version 2) interview questionnaire.

[0047] A summary of secondary and exploratory endpoints is shown in Table 4. [Table 4]

[0048] The observation and examination schedule for this clinical trial is shown in Table 5. [Table 5]

[0049] The breakdown of subjects in this clinical trial is shown in Figure 3. Twenty-four subjects were assigned to this trial, with eight subjects each in Groups 1, 2, and 3 (six in the YS-1402 group and two in the placebo group). All subjects in Groups 1 and 2 completed the trial, but one subject in the YS-1402-100 mg group and one subject in the placebo group in Group 3 were discontinued. The reasons for discontinuation were: "During the trial period, surgical treatment or other procedures were performed that were deemed to have a significant impact on the results of this trial" for one subject in the YS-1402-100 mg group; and "The subject stopped coming to the hospital, making examinations and observations impossible" for one subject in the placebo group.

[0050] The breakdown of the analysis population is shown in Table 6. The FAS was the group of registered cases excluding those who did not receive the patch and those with no observations regarding safety after application of the investigational drug. Analysis was performed on the FAS. [Table 6]

[0051] At the end of coronary artery bypass surgery via open-chest surgery, a YS-1402 administration sheet was applied to the left ventricle. Because the drug was administered during the thoracotomy, it was applied only once. The principal investigator or clinical trial physician confirmed that the investigational drug had been applied properly at the end of the coronary artery bypass surgery.

[0052] Pharmacokinetic analysis The subjects in the FAS whose blood drug concentrations were measured were evaluated by dose group, excluding the placebo group. The blood concentration measurement was for ONO-1301, the active ingredient in the investigational drug YS-1402. Figure 4 shows the time course of blood ONO-1301 concentrations [horizontal axis (time: equally spaced at each blood sampling point), vertical axis (blood drug concentration: real number)] following a single application of YS-1402-10 mg, 30 mg, or 100 mg at the time of thoracotomy for coronary artery bypass surgery. For reference, time course graphs for the horizontal axis (time: proportional to actual time) and vertical axis (blood drug concentration: real number, logarithm) are shown in Figures 5 and 6. Summary statistics for blood ONO-1301 concentrations are shown in Table 7, and a summary of the pharmacokinetic parameters of ONO-1301 in blood is shown in Table 8. The time course graphs for blood ONO-1301 concentrations (vertical axis: real number and logarithm), a list of blood ONO-1301 concentration trends, and a list of pharmacokinetic parameters for each subject are attached in [Appendix 16.2.5]. Summary statistics of the pharmacokinetic parameters of ONO-1301 in blood were as follows: Cmax (mean ± standard deviation, hereinafter the same) was 2.0788 ± 1.1579, 4.2967 ± 1.5310, and 8.8383 ± 2.1971 ng / ml for the 10 mg, 30 mg, and 100 mg YS-1402 groups, respectively; Tmax was 230.486 ± 87.933, 184.097 ± 143.597, and 419.250 ± 121.598 hours; MRT0-t was 341.856 ± 30.693, 400.176 ± 35.353, and 397.548 ± 34.640 hours; and AUC0-t was 1059.9076 ± The t1 / 2 (0-4w) for the YS-1402-100mg group and the t1 / 2 (4w-8w) for all YS-1402-administered groups were 522.3988, 2640.5036 ± 730.4192, and 5572.9516 ± 1190.7685 ng·h / ml, respectively. Blood ONO-1301 concentrations increased over time in all YS-1402 groups. The 10 mg and 30 mg YS-1402 groups reached a plateau 7 days after administration and maintained high concentrations until 28 days after administration. The 100 mg group reached a peak 14 days after administration and maintained high concentrations until 28 days after administration (a sustained range of approximately 4 ng / ml to 9 ng / ml from 24 hours after administration until 28 days after administration). The Cmax and AUC0-t of blood ONO-1301 increased with increasing YS-1402 dose. When the Cmax and AUC0-t of the 10 mg YS-1402 group were set to 1, the Cmax and AUC0-t of the 30 mg YS-1402 group were 2.07-fold and 2.49-fold, respectively, and the Cmax and AUC0-t of the 100 mg YS-1402 group were 4.25-fold and 5.26-fold, respectively, both of which were less than the common ratio. Meanwhile, the MRT0-t remained nearly constant. Furthermore, blood ONO-1301 concentrations gradually decreased from 14 days after administration, then rapidly decreased from 28 days after administration, and were almost completely eliminated by 8 weeks after administration in all groups. The maximum Cmax of ONO-1301 in the YS-1402-100 mg group, which was the maximum dose, was 11,900 ng / ml, and none of the doses exceeded the no-observed-effect level of 15.61 ng / ml and the no-toxic-effect level of 23.69 ng / ml, both of which were obtained in the oral Phase I study. [Table 7] TIFF0007779470000016.tif124169 [Table 8]

[0053] Analysis of exploratory endpoints (1) Change in left ventricular ejection fraction (LVEF) at 26 weeks after application Figure 7 shows the time course of measured LVEF values ​​in echocardiography after a single application of YS-1402-10 mg, 30 mg, or 100 mg at the time of thoracotomy for coronary artery bypass surgery. Figure 8 shows the time course of change, Table 9 shows summary statistics of measured values, Table 10 shows summary statistics of change, and Table 11 shows the results of analysis of variance for repeated measurements. For reference, Figure 9 shows the change in LVEF from baseline to 26 weeks after administration, and Figure 10 shows the correlation between the percentage change in total myocardial blood flow from baseline to 26 weeks after administration of the study drug and the change in LVEF. A time course of measured LVEF values ​​and changes, as well as a list of measured values ​​and changes, for each subject are attached in [Appendix 16.2.6]. The changes in LVEF (mean ± standard deviation) in the YS-1402-10 mg, 30 mg, 100 mg, and placebo groups were 3.5 ± 4.7, 1.4 ± 5.4, 1.4 ± 4.0, and 0.0 ± 4.5% at 2 weeks, 3.3 ± 4.6, 5.4 ± 8.3, 2.7 ± 4.4, and 3.3 ± 4.7% at 6 weeks, and 10.8 ± 9.5, 3.6 ± 11.0, 6.8 ± 7.7, and 5.0 ± 4.4% at 26 weeks. Analysis of variance of repeated measurements with dose group, measurement time, and dose group x measurement time as factors revealed that the variations between dose group and dose group x measurement time were not significant, but only the variation between measurement time was significant. For the two groups, the active drug group and the placebo group, which combined the three doses of YS-1402, the variations in dose group and dose group x measurement time were not significant, but only the variation in measurement time was significant. The placebo group showed a slight increase over time. All YS-1402 groups showed improvement at 26 weeks after administration, but no dose-related improvement was observed. At 26 weeks, the 10 mg group showed a 5.8% improvement compared to the placebo group. It is expected that cardiac function will improve with an increase in myocardial blood flow. Therefore, when the percent change in total myocardial blood flow and change in LVEF from baseline at 26 weeks after administration of the study drug were examined, a positive correlation was observed, but it was not significant (p value 0.340). One patient (CV-B003) in the YS-1402 30 mg group experienced a serious adverse event (congestive heart failure) due to poor medication compliance one week prior to the 26-week examination, resulting in a significant decrease in LVEF. Excluding this patient, the change in LVEF at 26 weeks after administration was 3.6 ± 110% to 6.3 ± 10.7%. [Table 9] [Table 10] [Table 11]

[0054] (2) Changes in left ventricular pump function (cardiac index [CI]) before and after application The time course of the measured values ​​of CI on cardiac-gated CT is shown in Figure 11, the time course of the rate of change is shown in Figure 12, summary statistics of the measured values ​​are shown in Table 12, summary statistics of the rate of change are shown in Table 13, and the results of the analysis of variance of repeated measurements are shown in Table 14. For reference, the rate of change in CI from baseline to 26 weeks after administration is shown in Figure 13, and the correlation between the rate of change in total myocardial blood flow from baseline to 26 weeks after administration of the study drug and the rate of change in CI is shown in Figure 14. In addition, the time course of the measured values ​​and rate of change of CI for each subject, as well as a list of the measured values ​​and changes, are attached in [Appendix 16.2.6]. The percent change in CI (mean ± SD) for the YS-1402-10 mg, 30 mg, 100 mg, and placebo groups was 16.03 ± 16.34, 8.22 ± 25.27, 6.99 ± 22.64, and -4.56 ± 14.84%, respectively, at 2 weeks after administration of the study drug, and 12.82 ± 25.10, 18.14 ± 25.39, 20.78 ± 28.83, and 10.62 ± 23.01%, respectively, at 26 weeks. Analysis of variance for repeated measures with dose group, measurement time, and dose group × measurement time as factors was not significant. Similar results were obtained for the two groups (active drug and placebo) combining the three doses of YS-1402. The placebo group showed a decrease at 2 weeks after administration, but an increase was observed at 26 weeks. The YS-1402 group generally increased over time, and all showed improvement at 26 weeks compared to the placebo group, with a dose-related increase. At 26 weeks after administration, the 100 mg group showed a 10.16% improvement compared to the placebo group. From the above, at 26 weeks after administration, CI increased dose-related in the order of placebo, YS-1402-10 mg, 30 mg, and 100 mg. Furthermore, a positive correlation was observed between the rate of change in total myocardial blood flow and the rate of change in CI from baseline at 26 weeks after administration of the study drug, but this was not significant (p-value 0.102). [Table 12] [Table 13] [Table 14]

[0055] (3) Changes in left ventricular remodeling before and after application 1) Changes and improvement in left ventricular end-systolic volume index (LVESVI) before and after application to the heart [increase / no change / decrease] The time course of the measured values ​​of LVESVI on cardiac gated CT is shown in Figure 15, the time course of the rate of change is shown in Figure 16, summary statistics of the measured values ​​are shown in Table 15, summary statistics of the rate of change are shown in Table 16, and the results of the analysis of variance of repeated measurements are shown in Table 17. In addition, the time course of the measured values ​​and change in LVESVI for each subject, as well as a list of the measured values ​​and change are attached in [Appendix 16.2.6]. The percent change in LVESVI (mean ± SD) for the YS-1402-10 mg, 30 mg, 100 mg, and placebo groups was -18.68 ± 20.22, -10.09 ± 12.32, -21.18 ± 18.11, and -5.70 ± 7.60% at 2 weeks post-dose, respectively, and -38.49 ± 14.79, -10.48 ± 35.42, -35.51 ± 30.81, and -18.03 ± 27.42% at 26 weeks. Analysis of variance for repeated measures with dose group, measurement time, and dose group × measurement time as factors was not significant. Similar results were obtained for the combined active and placebo groups for the three doses of YS-1402. The placebo group showed a decrease over time. The YS-1402 group also showed a decrease over time, and the degree of decrease in the YS-1402 group at 2 weeks was particularly greater than that of the placebo group, but this did not depend on the dose. The degree of improvement was examined in 11.4.7.2 Conclusion of Exploratory Endpoints. [Table 15] [Table 16] [Table 17]

[0056] 2) Changes in left ventricular end-diastolic volume index (LVEDVI) before and after application to the heart The time course of the measured values ​​of LVEDVI on cardiac gated CT is shown in Figure 17, the time course of the rate of change is shown in Figure 18, summary statistics of the measured values ​​are shown in Table 18, summary statistics of the rate of change are shown in Table 19, and the results of the analysis of variance of repeated measurements are shown in Table 20. In addition, the time course of the measured values ​​and change in LVEDVI for each subject, as well as a list of the measured values ​​and change are attached in [Appendix 16.2.6]. The percent change in LVEDVI (mean ± SD) for the YS-1402-10 mg, 30 mg, 100 mg, and placebo groups was -14.00 ± 10.99, -8.98 ± 9.16, -19.30 ± 18.78, and -9.30 ± 8.52% at 2 weeks after administration, respectively, and -22.56 ± 10.73, -5.98 ± 27.50, -19.30 ± 25.82, and -12.41 ± 15.73% at 26 weeks. Analysis of variance for repeated measures with dose group, measurement time, and dose group × measurement time as factors was not significant. Similar results were obtained for the combined active and placebo groups for the three doses of YS-1402. The placebo group showed a decrease over time, while the YS-1402 group showed a similar decrease over time, but this did not depend on the dose. [Table 18] [Table 19] [Table 20]

[0057] 3) Changes in left ventricular end-systolic diameters (LVDs) before and after application to the heart The time course of the measured values ​​of LVDs in echocardiography is shown in Figure 19, the time course of the rate of change is shown in Figure 20, summary statistics of the measured values ​​are shown in Table 21, summary statistics of the rate of change are shown in Table 22, and the results of the analysis of variance of repeated measurements are shown in Table 23. In addition, the time course of the measured values ​​and rate of change of LVDs for each subject, as well as a list of the measured values ​​and rate of change, are attached in [Appendix 16.2.6]. The percent changes in LVDs (mean ± SD) in the YS-1402-10 mg, 30 mg, 100 mg, and placebo groups were -8.33 ± 9.16, -16.56 ± 7.86, -15.51 ± 6.29, and -3.70 ± 6.89% at 2 weeks after administration of the study drug, -10.67 ± 11.43, -16.41 ± 8.95, -14.13 ± 11.60, and -10.74 ± 7.06% at 6 weeks, and -8.33 ± 14.92, -7.12 ± 13.65, -15.34 ± 19.89, and -12.15 ± 3.76% at 26 weeks. Analysis of variance on repeated measurements with dose group, measurement time, and dose group × measurement time as factors was not significant. For the two groups, the active drug group and the placebo group, which combined the three doses of YS-1402, the variations in dose group and dose group x measurement time were not significant, but only the variation in measurement time was significant. The placebo group showed a decrease over time. The YS-1402 group showed a decrease compared to the placebo group at 2 weeks after administration, but this decrease was not dose-dependent. At 6 and 26 weeks after administration, the decrease was not consistent with time, and was not dose-dependent. [Table 21] [Table 22] [Table 23]

[0058] 4) Change in left ventricular end-diastolic diameter (LVDd) before and after application to the heart The time course of measured values ​​of LVDd in echocardiography is shown in Figure 21, the time course of the rate of change is shown in Figure 22, summary statistics of the measured values ​​are shown in Table 24, summary statistics of the rate of change are shown in Table 25, and the results of the analysis of variance of repeated measurements are shown in Table 26. In addition, the time course of measured values ​​and rate of change of LVDd for each subject, as well as a list of measured values ​​and rate of change, are attached in [Appendix 16.2.6]. The rate of change in LVDd (mean ± standard deviation) in the YS-1402-10 mg group, 30 mg group, 100 mg group, and placebo group was -7.46 ± 9.12, -15.14 ± 4.40, -13.84 ± 3.80, and -4.06 ± 8.29% at 2 weeks after administration of the study drug, -8.03 ± 10.36, -14.41 ± 3.71, -13.26 ± 9.94, and -8.96 ± 7.15% at 6 weeks, and -4.14 ± 12.91, -2.40 ± 8.22, -9.82 ± 9.69, and -9.21 ± 2.20% at 26 weeks, respectively. Analysis of variance of repeated measurements with dose group, measurement time, and dose group x measurement time as factors showed that the variations between dose group and dose group x measurement time were not significant, but only the variation between measurement time was significant.For the two groups, the active drug group and the placebo group, which combined the three doses of YS-1402, the variations between dose group and dose group x measurement time were not significant, but only the variation between measurement time was significant. The placebo group showed a decrease over time. The YS-1402 group, like LDVs, showed a decrease compared to the placebo group at 2 weeks after administration, but this did not correspond to the dose. At 6 and 26 weeks after administration, there was no decrease over time, and the decrease was not dose-dependent. [Table 24] [Table 25] [Table 26]

[0059] 5) Change in cardiothoracic ratio (CTR) before and after application to the heart The time course of the measured CTR values ​​for chest X-ray examinations is shown in Figure 23, the time course of the change is shown in Figure 24, summary statistics of the measured values ​​are shown in Table 27, summary statistics of the change are shown in Table 28, and the results of the analysis of variance of repeated measurements are shown in Table 29. In addition, the time course of the measured CTR values ​​and change rate for each subject, as well as a list of the measured values ​​and change are attached in [Appendix 16.2.6]. The changes in CTR (mean ± standard deviation) in the YS-1402-10 mg group, 30 mg group, 100 mg group, and placebo group were 12.08 ± 4.10, 4.63 ± 3.92, 11.58 ± 4.09, and 8.63 ± 3.93 at day 1 after administration of the study drug, 6.17 ± 4.93, 4.58 ± 4.31, 9.22 ± 3.54, and 2.87 ± 3.92 at week 2, 0.27 ± 4.56, -1.00 ± 5.20, 2.92 ± 2.79, and 0.58 ± 4.17% at week 6, and -0.75 ± 3.62, -1.48 ± 4.41, -2.80 ± 4.08, and -0.82 ± 4.86% at week 26. Analysis of variance of repeated measurements with dose group, measurement time, and dose group x measurement time as factors showed that the variations between dose group and dose group x measurement time were not significant, but only the variation between measurement time was significant.For the two groups, the active drug group and the placebo group, which combined the three doses of YS-1402, the variations between dose group and dose group x measurement time were not significant, but only the variation between measurement time was significant. In the placebo group, the level reached a maximum on day 1 after administration and then decreased over time. Similarly, in the YS-1402 group, the level reached a maximum on day 1 after administration and then decreased over time. The maximum and intermediate levels did not depend on the dose. [Table 27] [Table 28] [Table 29]

[0060] (4) Changes in heart failure symptoms before and after application 1) Change in NYHA classification before and after cardiac placement The time course of NYHA classification is shown in Figure 25, a cross-tabulation of NYHA classification between baseline and each examination period is shown in Table 30, the dose-response relationship of the improvement rate of NYHA classification from baseline at each examination period is shown in Table 31, and the results of analysis of variance of repeated measurements are shown in Table 32. In addition, a list of changes in heart failure symptoms, including the actual measured values ​​and changes in NYHA classification for each subject, is attached in [Appendix 16.2.6]. The degree of improvement was defined as the amount of change from baseline, as grade II or greater improvement, grade I improvement, unchanged, or worsening. The distribution of the percentage of improvement in each YS-1402 dose group was compared with the placebo group using the Wilcoxon rank-sum test, but no significant differences were observed between any of the YS-1402 dose groups and the placebo group. Furthermore, the dose-response relationship was evaluated using the Cochran-Armitage test for the two patterns of grade II or greater improvement and grade I or greater improvement, but neither was significant. Analysis of variance for repeated measurements with dose group, measurement time, and dose group x measurement time as factors revealed that the variations in dose group and dose group x measurement time were not significant, but only the variation in measurement time was significant. For the two groups, the active drug group and the placebo group, which combined the three doses of YS-1402, the variations in dose group and dose group x measurement time were not significant, but only the variation in measurement time was significant. The placebo group improved over time. The YS-1402 group also improved over time, and in particular, all patients in the 100 mg group improved to Grade 1 by 26 weeks after administration. [Table 30] [Table 31] [Table 32]

[0061] 2) Change in 6-minute walking distance after application of the heart The time course of the measured 6-minute walking distance is shown in Figure 26, the time course of the rate of change is shown in Figure 27, summary statistics of the measured values ​​are shown in Table 33, summary statistics of the rate of change are shown in Table 34, a summary table of the rate of change in 6-minute walking distance at 26 weeks after administration is shown in Table 35, and the results of the analysis of variance of repeated measures are shown in Table 36. For reference, the rate of change in 6-minute walking distance from baseline to 26 weeks after administration is shown in Figure 28. In addition, a time course of the measured 6-minute walking distance and rate of change for each subject, as well as a list of changes in heart failure symptoms, including the measured 6-minute walking distance and rate of change, are attached in [Appendix 16.2.6]. The percent change in 6-minute walking distance (mean ± SD) for the YS-1402-10 mg, 30 mg, 100 mg, and placebo groups was 12.07 ± 10.91, 10.67 ± 13.06, 6.07 ± 11.88, and 3.57 ± 9.13%, respectively, at 6 weeks after administration of the study drug, and 14.33 ± 20.14, -4.83 ± 26.07, 20.77 ± 20.69, and 14.28 ± 7.24%, respectively, at 26 weeks. Analysis of variance for repeated measures with dose group, measurement time, and dose group × measurement time as factors was not significant. Similar results were obtained for the two groups (active drug and placebo) that combined the three doses of YS-1402. In both the placebo and YS-1402 groups, walking distance generally increased over time, and at 6 weeks after administration, the YS-1402 group showed a greater increase than the placebo group, but the increase did not depend on the dose. At 26 weeks after administration, the 6-minute walking distance in the 10 mg group was similar to the placebo group, and in the 100 mg group it was greater than the placebo group, but in the 30 mg group it actually decreased, and there was no dose-related increase. At 26 weeks after administration, the 100 mg group showed a 6.49% increase compared to the placebo group. One patient (CV-B003) in the YS-1402 30 mg group experienced a serious adverse event (congestive heart failure) due to poor compliance one week prior to the 26-week examination, resulting in a significant decrease in 6-minute walking distance. For reference, the results excluding this patient are shown in Figure 29. The rate of change in 6-minute walking distance at 26 weeks after administration increased from -4.83 ± 26.07% to 6.23 ± 9.54%, but this was not a dose-related increase. [Table 33] [Table 34] [Table 35] [Table 36]

[0062] (5) Changes in myocardial blood flow Figure 30 shows the time course of actual measured values ​​of RCA resting myocardial blood flow, LAD resting myocardial blood flow, LCX resting myocardial blood flow, and total myocardial blood flow by ammonia PET. Figure 31 shows the time course of the percentage changes from baseline. Table 37 shows summary statistics of the actual measured values. Table 38 shows summary statistics of the percentage changes from baseline. Table 39 shows the results of analysis of variance for repeated measurements. Table 40 also shows a summary table of the percentage changes in myocardial blood flow from baseline to 26 weeks after administration. For reference, Figure 32 shows the percentage changes in total myocardial blood flow, Figure 33 shows the percentage changes in LAD resting myocardial blood flow, Figures 34 and 35 show the correlation between blood concentrations (AUC0-t and Cmax) and the percentage changes in total myocardial blood flow from baseline at 26 weeks after administration of the study drug, and Figure 36 shows the correlation between AUC0-t and the percentage changes in LAD resting myocardial blood flow from baseline at 26 weeks after administration of the study drug. In addition, a time-course graph of the actual measured values ​​and rate of change for each ammonia PET parameter for each subject, as well as a list of the actual measured values ​​and rate of change [including the names of the left ventricular myocardium areas (classified into 17 segments) where the investigational drug was applied] are attached in [Appendix 16.2.6]. For reference, the blood flow volume for each of the 17 segments of the left ventricular myocardium for each subject is attached in [Appendix 16.2.9]. The change rates (mean ± standard deviation) in RCA resting myocardial blood flow were -3.01 ± 23.11, 26.78 ± 30.22, 0.82 ± 18.49, and 0.21 ± 23.17% in the YS-1402-10 mg, 30 mg, 100 mg, and placebo groups, respectively, at 6 weeks after administration of the study drug, and -1.73 ± 17.50, 11.76 ± 14.33, 16.13 ± 24.20, and -0.91 ± 23.85% at 26 weeks. Similarly, the LAD resting myocardial blood flow was 13.31 ± 29.16, 19.77 ± 34.62, 13.86 ± 23.11, and 5.32 ± 24.69% at 6 weeks after administration of the study drug, and 13.38 ± 19.48, 14.59 ± 16.85, 27.59 ± 32.47, and 6.41 ± 32.39% at 26 weeks. The LCX resting myocardial blood flow was 9.12 ± 30.95, 16.05 ± 32.75, 8.77 ± 20.53, and 6.27 ± 3.11% at 6 weeks after administration of the study drug, and 8.32 ± 20.96, 6.58 ± 15.81, 4.98 ± 18.23, and 0.71 ± The mean values ​​for total myocardial blood flow were 6.64 ± 26.28, 20.07 ± 31.94, 7.53 ± 13.54, and 3.67 ± 15.38% at 6 weeks after administration of the study drug, and 6.78 ± 15.98, 11.15 ± 13.34, 16.66 ± 21.04, and 1.89 ± 20.80% at 26 weeks. Analysis of variance for repeated measurements with dose group, measurement time, and dose group x measurement time as factors was not significant. Similar results were obtained for the active drug and placebo groups, which combined the three doses of YS-1402. There was no change in RCA resting myocardial blood flow over time in the placebo group. In the YS-1402 group, the increase in blood flow was generally greater than that in the placebo group at 6 weeks after administration, but there was no dose correlation. On the other hand, at 26 weeks after administration, blood flow increased in a dose-related manner, although it varied depending on the administration group, remaining the same, decreasing, or increasing compared to 6 weeks. LAD resting myocardial blood flow increased slightly over time in the placebo group. At 6 weeks after administration, the YS-1402 group showed a greater increase in blood flow compared to the placebo group, but there was no dose-related correlation. At 26 weeks after administration, blood flow increased dose-related, although it remained constant, decreased, or increased depending on the treatment group. The 100 mg group showed a 21.18% increase in blood flow compared to the placebo group. Thus, at 26 weeks after administration, LAD myocardial blood flow increased dose-related in the placebo, 10 mg, 30 mg, and 100 mg groups. A positive correlation was observed between blood concentration (AUC0-t) and the percent change in LAD resting myocardial blood flow from baseline at 26 weeks after administration, but this was not significant (p=0.149). Regarding LCX resting myocardial blood flow, the placebo group showed an increase in blood flow at 6 weeks after administration. Furthermore, by 26 weeks after administration, the blood flow in the placebo group had returned to near baseline. In the YS-1402 group, blood flow increased at 6 weeks after administration, but there was no dose-related increase. Furthermore, by 26 weeks after administration, the increase in blood flow continued from 6 weeks after administration, but the degree of increase had decreased. Although blood flow exceeded that of the placebo group, there was no dose-related increase. Thus, at 26 weeks after administration, the placebo group showed the lowest LCX myocardial blood flow compared to the YS-1402 group. On the other hand, there was no dose-related increase in the YS-1402 group. Total myocardial blood flow increased in the placebo group at 6 weeks after administration. Furthermore, by 26 weeks after administration, blood flow in the placebo group had returned to near baseline. The YS-1402 group exceeded the placebo group at 6 weeks after administration, but no dose-related increase was observed. On the other hand, at 26 weeks after administration, blood flow increased in a dose-related manner, although it varied depending on the administration group, remaining the same, decreasing, or increasing compared to week 6. The 100 mg group showed a 14.77% increase in blood flow compared to the placebo group. Thus, at 26 weeks after administration, total myocardial blood flow increased in a dose-related manner in the order of placebo, YS-1402-10 mg, 30 mg, and 100 mg. A positive correlation was observed between blood concentrations (AUC0-t and Cmax) and the rate of change in total myocardial blood flow from baseline 26 weeks after administration of the study drug, but this was not significant (p-value, AUC0-t: 0.160, Cmax: 0.258). [Table 37] TIFF0007779470000047.tif230169TIFF0007779470000048.tif230170TIFF0007779470000049.tif231168TIFF0007779470000050.tif53169 [Table 38] TIFF0007779470000052.tif217168TIFF0007779470000053.tif219170TIFF0007779470000054.tif219170 [Table 39] TIFF0007779470000056.tif93170 [Table 40]

[0063] (6) Changes in brain natriuretic peptide (BNP) The time course of the actual measured values ​​of BNP concentration in blood is shown in Figure 37, the time course of the rate of change is shown in Figure 38, summary statistics of the actual measured values ​​are shown in Table 41, summary statistics of the rate of change are shown in Table 42, and the results of the analysis of variance of repeated measurements are shown in Table 43. In addition, a list of the time course of the actual measured values ​​and rate of change of BNP concentration for each subject, as well as the actual measured values ​​and the amount of change, is attached in [Appendix 16.2.6]. The rate of change in blood BNP concentration (mean ± standard deviation) in the YS-1402-10 mg group, 30 mg group, 100 mg group, and placebo group was 148.41 ± 156.07, 184.81 ± 207.24, 255.29 ± 247.65, and 77.53 ± 66.69 on day 1 after administration of the study drug, 104.10 ± 132.51, 268.73 ± 283.06, 356.63 ± 381.21, and 131.60 ± 101.04 on week 1, 150.38 ± 250.68, 150.47 ± 232.24, 237.35 ± 212.48, and 73.67 ± 78.76 on week 2, and 13.57 ± 101.04 on week 6. At week 1, the mean values ​​were 78.60, 66.24 ± 128.44, 162.51 ± 228.08, and -12.21 ± 25.15%, and at week 26, the mean values ​​were -8.84 ± 57.09, 49.44 ± 161.03, 28.00 ± 90.06, and -26.84 ± 26.45%. Analysis of variance on repeated measurements with dose group, measurement time, and dose group x measurement time as factors showed that the variations in dose group and dose group x measurement time were not significant, but only the variation in measurement time was significant. For the two groups, the active drug group and placebo group, which combined the three doses of YS-1402, none of the differences were significant. Regarding the rate of change in blood BNP concentration, in both the placebo and YS-1402 groups, the concentration increased after administration and then decreased, but no consistent trend was observed even 26 weeks after administration. [Table 41] [Table 42] [Table 43]

[0064] (7) Evaluation of QOL Figure 39 shows the time course of the measured scores for the eight SF-36 subscales established for QOL assessment [physical functioning, role-functioning (physical), bodily pain, general health, vitality, social functioning, role-functioning (mental), and mental health], Figure 40 shows the time course of the changes, Table 44 shows summary statistics for the measured values, Table 45 shows summary statistics for the changes, and Table 46 shows the results of the analysis of variance for repeated measures. In addition, the time course of the measured values ​​and changes for the SF-36 subscale scores for each subject, as well as a list of QOL assessments of the measured values ​​and changes, are attached in [Appendix 16.2.6]. Analysis of variance showed that for the seven items excluding bodily pain, none of the repeated measurements with dose group, measurement time, and dose group x measurement time as factors were significant. Similar results were obtained for the two groups, the active drug group and the placebo group, which combined the three doses of YS-1402. For bodily pain, analysis of variance for repeated measurements with dose group, measurement time, and dose group x measurement time as factors showed that the variations between dose group and dose group x measurement time were not significant, but only the variation between measurement time was significant. For the two groups, the active drug group and the placebo group, which combined the three doses of YS-1402, the variations between dose group and dose group x measurement time were not significant, but only the variation between measurement time was significant. The placebo group showed improvements in physical function, bodily pain, general well-being, vitality, social function, and mental health 26 weeks after administration. However, no improvement was observed in role-based functioning (physical) or role-based functioning (mental). Physical function improved in the YS-1402 group compared to the placebo group after 6 weeks of administration, but there was no difference between the group and the placebo group at 26 weeks after administration. Other items showed no change compared to the placebo group. [Table 44] TIFF0007779470000062.tif239170TIFF0007779470000063.tif238169TIFF0007779470000064.tif239170TIFF0007779470000065.tif240169 TIFF0007779470000066.tif241170TIFF0007779470000067.tif240169TIFF0007779470000068.tif239170TIFF0007779470000069.tif173169 [Table 45] TIFF0007779470000071.tif226170TIFF0007779470000072.tif240168TIFF0007779470000073.tif239170TIFF0007779470000074.tif23716 9TIFF0007779470000075.tif239169TIFF0007779470000076.tif241170TIFF0007779470000077.tif236169TIFF0007779470000078.tif69167 [Table 46] TIFF0007779470000080.tif223168TIFF0007779470000081.tif223170TIFF0007779470000082.tif224169

[0065] Relationship between LVEF and LVESVI To examine the correlation between improvement in left ventricular remodeling and improvement in cardiac function, i.e., the correlation between the decrease in LVESVI on cardiac-gated CT and the increase in LVEF on echocardiography, the LVEF value was plotted on the x-axis and the LVESVI value on the y-axis, and the changes between baseline and 26 weeks after administration for each individual subject were plotted by dose group and shown in Figure 41. Furthermore, the proportion of subjects for whom the line sloped downward (the coefficient of the slope of the line was negative and the LVESVI value at 26 weeks after administration was lower than the baseline value) was calculated by dose group and shown in Table 47. The number of cases in which the line sloped downward to the right was 5 / 6 cases (83.3%) in the YS-1402-10 mg group, 2 / 5 cases (40.0%) in the 30 mg group, 100 mg group, and placebo group, respectively, and there was no increase with dose. [Table 47]

[0066] Conclusion of the analysis of the pharmacokinetics of ONO-1301 when YS-1402 is applied to the left ventricle during coronary artery bypass surgery for ischemic cardiomyopathy During coronary artery bypass surgery for ischemic cardiomyopathy, the pharmacokinetics of the active compound ONO-1301 was investigated when YS-1402 was applied to the left ventricle. Summary statistics of the pharmacokinetic parameters of ONO-1301 in blood were as follows: Cmax (mean ± standard deviation, hereinafter the same) was 2.0788 ± 1.1579, 4.2967 ± 1.5310, and 8.8383 ± 2.1971 ng / ml for the 10 mg, 30 mg, and 100 mg YS-1402 groups, respectively; AUC0-t was 1059.9076 ± 522.3988, 2640.5036 ± 730.4192, and 5572.9516 ± 1190.7685 ng·h / ml; Cmax and AUC0-t increased dose-dependently. On the other hand, when the Cmax and AUC0-t of the 10 mg YS-1402 group were set to 1, the Cmax and AUC0-t of the 30 mg group were 2.07 times and 2.49 times, respectively, and similarly, the Cmax and AUC0-t of the 100 mg group were 4.25 times and 5.26 times, respectively, which were less than the common ratio. The MRT0-t was almost constant. ONO-1301 blood concentrations increased after administration and plateaued between 7 and 14 days in the YS-1402-10 mg and 30 mg groups. Blood concentrations in the 100 mg group remained constant at approximately 4 to 9 ng / ml from 24 hours to 28 days after administration, then rapidly decreased. In all groups, drug concentrations had nearly disappeared from the blood by 8 weeks after administration. The maximum ONO-1301 Cmax in the YS-1402-100 mg group, the highest dose, was 11,900 ng / ml, which did not exceed the no-observed-effect level (NOAEL) of 15.61 ng / ml or the maximum NOAEL of 23.69 ng / ml, satisfying the secondary hypothesis of a Cmax of 23.7 ng / ml or less.

[0067] Conclusion of the analysis of changes in indicators related to cardiac function improvement when YS-1402 is applied to the left ventricle during coronary artery bypass surgery for ischemic cardiomyopathy We investigated changes in indicators related to cardiac function improvement when YS-1402 was applied to the left ventricle during coronary artery bypass surgery for ischemic cardiomyopathy. The application site was determined by identifying areas of reduced myocardial blood flow using preoperative ammonia PET. During coronary artery bypass surgery, lesions such as areas of advanced fibrosis or poor contractility in complex or multivessel lesions where complete restoration of blood flow to the ischemic area of ​​the heart is difficult were identified visually and palpably, and the drug was applied to areas of the left ventricle, including the surrounding areas, that would not affect graft path. For each evaluation item, analysis of variance of repeated measurements with factors of dose group, measurement time, and dose group x measurement time showed that the variations in dose group and dose group x measurement time were not significant, and similar results were obtained for the two groups, the active drug group and placebo group, which combined the three doses of YS-1402.On the other hand, the variations in measurement time were significant for various evaluation items, suggesting that coronary artery bypass surgery had a significant impact. The change in LVEF measured by echocardiography showed a slight increase over time in the placebo group. Compared to the placebo group, the YS-1402 group showed improvement at 26 weeks after administration, but no dose-related improvement was observed. Furthermore, the 10 mg group showed a 5.8% improvement compared to the placebo group at 26 weeks after administration. A positive correlation was observed between the percentage change in total myocardial blood flow from baseline at 26 weeks after administration of the study drug and the change in LVEF, but this was not significant (p=0.340). One patient in the YS-1402 30 mg group experienced a serious adverse event (congestive heart failure) due to poor medication compliance one week before the 26-week examination, resulting in a significant decrease in LVEF, which also affected the mean LVEF. Regarding the rate of change in cardiac-gated CT, the placebo group showed a decrease two weeks after administration, but increased from pre-administration by 26 weeks. The YS-1402 group generally increased over time, exceeding the placebo group by 26 weeks, demonstrating a dose-related increase. The 100 mg group showed a 10.16% improvement in change rate compared to the placebo group. A positive correlation was observed between the rate of change in total myocardial blood flow from baseline and the rate of change in CT by 26 weeks after administration of the study drug, but this was not significant (p value 0.102). Regarding changes in left ventricular remodeling, the rate of change in LVESVI on cardiac-gated CT decreased over time in the placebo group. The YS-1402 group also showed a similar decrease over time, with the degree of decrease being greater in the YS-1402 group than in the placebo group, particularly at 2 weeks after administration, but this decrease was not dose-dependent. Given that a 10% or greater decrease in LVESVI change rate has been reported as a responder to cardiac resynchronization therapy (CRT), and considering measurement error, fluctuations within 10% were considered "unchanged," and data were compiled for each subject. The results showed that the rates of decrease, no change, and increase at 2 and 26 weeks after administration were 1 / 5 / 0 and 4 / 0 / 1, respectively, in the placebo group. Similarly, the rates were 3 / 2 / 0 and 6 / 0 / 0 in the YS-1402-10 mg group, 3 / 2 / 0 and 3 / 1 / 2 in the 30 mg group, and 4 / 2 / 0 and 4 / 1 / 0 in the 100 mg group. The placebo group generally improved over time. The YS-1402 group showed a greater improvement at 2 weeks post-administration than the placebo group, and this improvement was dose-dependent. At 26 weeks, increases were observed in the YS-1402 30 mg and placebo groups, while improvements were greater in the 10 mg and 100 mg groups, but not dose-dependent. The placebo group showed a decrease in the rate of change in LVEDVI measured by cardiac-gated CT scan over time. The YS-1402 group also showed a similar decrease over time, but this was not dose-dependent. The placebo group showed a decrease in the rate of change in LVDs and LVDd measured by echocardiography over time. The YS-1402 group showed a decrease compared to the placebo group at 2 weeks post-administration, but this was not dose-dependent. At 6 and 26 weeks post-administration, there was no significant decrease over time, and this was not dose-dependent. Regarding the change in CTR in chest X-ray examination, the placebo group reached a maximum value one day after administration and then decreased over time. Similarly, the YS-1402 group also reached a maximum value roughly one day after administration and then decreased over time. The maximum value and interim values ​​did not depend on the dose. Regarding changes in heart failure symptoms, both the placebo and YS-1402 groups showed similar improvements over time in NYHA classification. In particular, all patients in the 100 mg group improved to Class I by 26 weeks after administration. Regarding the rate of change in 6-minute walking distance, walking distance generally increased over time in both the placebo and YS-1402 groups, with the YS-1402 group showing a greater increase than the placebo group at 6 weeks after administration. Meanwhile, the 6-minute walking distance at 26 weeks after administration was similar to that of placebo in the 10 mg group, but exceeded that of the placebo group in the 100 mg group, showing a 6.49% increase compared to the placebo group. The 30 mg group showed a decrease compared to the placebo group. This was thought to be due to the occurrence of a serious adverse event (congestive heart failure) due to poor medication compliance in one patient in the 30 mg group one week before the 26-week examination after administration, resulting in a significant reduction in distance traveled compared to before administration.For reference, the 26-week data for this patient was excluded from the data, but no dose-related increase was found. Regarding changes in myocardial blood flow measured by ammonia PET, slight increases in LAD resting myocardial blood flow, LCX resting myocardial blood flow, and total myocardial blood flow were observed compared to baseline in the placebo group at 26 weeks after administration. At 26 weeks after administration, dose-related increases in LAD resting myocardial blood flow, RCA resting myocardial blood flow, and total myocardial blood flow were observed in the YS-1402-10 mg, 30 mg, and 100 mg groups. Furthermore, at 26 weeks after administration, increases in LAD resting myocardial blood flow, RCA resting myocardial blood flow, and total myocardial blood flow were observed in the 100 mg group compared to the placebo group: LAD resting myocardial blood flow (change rate: 21.18%), RCA resting myocardial blood flow (change rate: 17.04%), and total myocardial blood flow (change rate: 14.77%). However, no dose-related increases in LCX resting myocardial blood flow were observed. A positive correlation was observed between AUC0-t and the rate of change in total myocardial blood flow from baseline 26 weeks after administration of the study drug, but it was not significant (p value 0.160). No consistent trend was observed in blood BNP levels 26 weeks after administration. Regarding the SF-36, which was established to assess QOL, the progress of each subscale varied, and no consistent trend was observed. No dose-response was observed in the relationship between LVEF and LVESVI. The relationship between myocardial blood flow, cardiac function (CT, LVEF), and 6-minute walking distance over time was examined in the placebo and YS-1402 groups. Myocardial blood flow increased at 6 weeks after administration, and even in cases where it remained the same or decreased at 26 weeks, cardiac function (CT, LVEF) increased and 6-minute walking distance increased at 26 weeks compared to 6 weeks (CT at 2 weeks). This suggests that cardiac function and heart failure symptoms improve with an increase in myocardial blood flow, but that these improvements continue even after the increase in myocardial blood flow ceases. For example, in the YS-1402-100 mg group, myocardial blood flow generally increased at 26 weeks compared to 6 weeks after administration, and further improvement in cardiac function (CT, LVEF) and an increase in 6-minute walking distance were also observed, suggesting the need for follow-up beyond 26 weeks.

[0068] Safety evaluation 1) Adverse events The incidence of adverse events and side effects is shown in Table 48. Adverse events were observed in all 6 patients in both treatment groups. Of these, those judged to be side effects occurred in 2 patients (33.3%) in the YS-1402-10 mg group, 1 patient (16.7%) in the 30 mg group, and 1 patient (16.7%) in the placebo group. However, no side effects were observed in the 100 mg group. Serious adverse events were observed in 2 cases (33.3%) in the YS-1402-10 mg group and 30 mg group, 3 cases (50.0%) in the 100 mg group, and 2 cases (33.3%) in the placebo group. Of these, pneumonia in 1 case (16.7%) in the YS-1402-10 mg group and lung abscess in 1 case (16.7%) in the placebo group were judged to be serious side effects. There were no adverse events leading to discontinuation or deaths. [Table 48]

[0069] The incidence of adverse events and adverse reactions by SOC and PT is shown in Tables 49 and 50, by severity in Tables 51 and 52, and by duration of onset in Tables 53 and 54. The incidence of adverse events by causality is shown in Table 55, and the incidence by outcome in Table 56. Because abnormal laboratory values ​​are frequently observed in patients undergoing coronary artery bypass surgery, adverse events were classified into those related to laboratory tests and those related to non-laboratory tests. Non-laboratory adverse events were considered if they occurred in two or more patients (33.3%) in any of the treatment groups, and similarly, laboratory adverse events were considered if they occurred in five or more patients (83.3%) in any of the treatment groups. Adverse events other than laboratory tests included atrial fibrillation, tachycardia, diarrhea, edema, fever, dehydration, restlessness, sleep disturbance, and pleural effusion. Laboratory tests included increased alanine aminotransferase, increased aspartate aminotransferase, decreased blood albumin, increased blood creatine phosphokinase, increased blood lactate dehydrogenase, increased C-reactive protein, decreased hematocrit, decreased hemoglobin, decreased lymphocyte count, increased neutrophil count, decreased platelet count, decreased red blood cell count, increased platelet count, and increased brain natriuretic peptide. Of these, pleural effusion was suspected to be related to the YS-1402 dose. No other adverse events were suspected to be related to laboratory tests, including those occurring in four or fewer patients in any treatment group. Pleural effusion was observed in four patients (66.7%) in the YS-1402-10 mg group, six patients (100.0%) in each of the 30 mg and 100 mg groups, and two patients (33.3%) in the placebo group. The severity of the effusion was mild in four patients (66.7%) in the YS-1402-10 mg group, mild in five patients (83.3%) and moderate in one patient (16.7%) in the 30 mg group, mild in one patient (16.7%) and moderate in five patients (83.3%) in the 100 mg group, and mild in two patients (33.3%) in the placebo group. All events occurred within one week after administration, and all patients recovered. The causes of the pleural effusion were attributed to coronary artery bypass surgery and heart failure, and were not considered adverse events. Pleural effusion could be managed by diuretic administration or paracentesis, and was not considered a serious adverse event. Adverse events that were judged to be side effects occurred in 2 cases (33.3%) in the YS-1402-10 mg group, 1 case (16.7%) in the 30 mg group, and 1 case (16.7%) in the placebo group. By PT, there was one case of pneumonia (16.7%), one case of increased blood triglycerides and one case of increased blood uric acid (16.7%) in the YS-1402-10 mg group, one case of increased alanine aminotransferase and one case of increased aspartate aminotransferase (16.7%) in the 30 mg group, and one case of lung abscess (16.7%) in the placebo group. Of these, the pneumonia observed in the YS-1402-10 mg group and the lung abscess observed in the placebo group were judged to be serious, with the pneumonia being severe and the lung abscess being moderate. All four laboratory findings were non-serious and mild. [Table 49] TIFF0007779470000086.tif223169TIFF0007779470000087.tif206168TIFF0007779470000088.tif244170TIFF0007779470000089.tif223170 [Table 50] [Table 51] TIFF0007779470000092.tif223169TIFF0007779470000093.tif225169TIFF0007779470000094.tif223170TIFF0007779470000095.tif221165TIFF0007779470000096.tif222170TIFF0007779470000097.tif227170TIFF0007779470000098.tif225169TIFF0007779470000099.tif235170TIFF0007779470000100.tif229170TIFF0007779470000101.tif228169TIFF0007779470000102.tif228170TIFF0007779470000103.tif130169TIFF0007779470000104.tif186170TIFF0007779470000105.tif126170TIFF0007779470000106.tif187169TIFF0007779470000107.tif129170TIFF0007779470000108.tif185170TIFF0007779470000109.tif122169TIFF0007779470000110.tif187169TIFF0007779470000111.tif127169TIFF0007779470000112.tif190167TIFF0007779470000113.tif127170TIFF0007779470000114.tif187169TIFF0007779470000115.tif122169TIFF0007779470000116.tif183170TIFF0007779470000117.tif125168TIFF0007779470000118.tif189169TIFF0007779470000119.tif135169TIFF0007779470000120.tif195169TIFF0007779470000121.tif133169TIFF0007779470000122.tif195169TIFF0007779470000123.tif132170TIFF0007779470000124.tif195170TIFF0007779470000125.tif132170TIFF0007779470000126.tif193170TIFF0007779470000127.tif241170TIFF0007779470000128.tif208170TIFF0007779470000129.tif87169TIFF0007779470000130.tif247167TIFF0007779470000131.tif208170TIFF0007779470000132.tif89167TIFF0007779470000133.tif242168TIFF0007779470000134.tif210169TIFF0007779470000135.tif86168TIFF0007779470000136.tif239168TIFF0007779470000137.tif208168TIFF0007779470000138.tif87167TIFF0007779470000139.tif214168TIFF0007779470000140.tif92168TIFF0007779470000141.tif216169TIFF0007779470000142.tif91166TIFF0007779470000143.tif212169TIFF0007779470000144.tif90169TIFF0007779470000145.tif214167TIFF0007779470000146.tif230167TIFF0007779470000147.tif221168TIFF0007779470000148.tif193169TIFF0007779470000149.tif225169TIFF0007779470000150.tif229169TIFF0007779470000151.tif234170TIFF0007779470000152.tif233169TIFF0007779470000153.tif234169TIFF0007779470000154.tif231165TIFF0007779470000155.tif240169TIFF0007779470000156.tif236168TIFF0007779470000157.tif236167TIFF0007779470000158.tif232170TIFF0007779470000159.tif209168TIFF0007779470000160.tif206168TIFF0007779470000161.tif212169TIFF0007779470000162.tif226169.

Table 52

Table 53

Table 54

Table 55

Table 56

Claims

1. (A): A release-type preparation containing at least a lactic acid-glycolic acid copolymer (PLGA) and a prostaglandin I2 receptor agonist, wherein the average molecular weight of the PLGA is 10,000 to 30,000; (B): A release-type preparation containing at least a lactic acid-glycolic acid copolymer (PLGA) and a prostaglandin I2 receptor agonist, wherein the average molecular weight of the PLGA is 40,000 to 60,000; A porous gelatin patch containing 10 g of gelatin per 1000 cm 3 , and A plasma fraction containing fibrinogen powder, aprotinin solution, thrombin powder, and calcium chloride solution Contains The prostaglandin I2 receptor agonist comprises at least the following compound (A) or a salt thereof: (A) a compound represented by the following formula (II): 【Chemistry 1】 ({5-[2-({[(1E)-phenyl(pyridin-3-yl)methylene]amino}oxy)ethyl]-7,8-dihydronaphthalen-1-yl}oxy)acetic acid (ONO-1301), A pharmaceutical composition for improving cardiac function to be administered to patients with ischemic cardiomyopathy undergoing coronary artery bypass surgery.

2. 2. The pharmaceutical composition for improving cardiac function according to claim 1, wherein the ratio (A:B) of the release-type formulation (A) to the release-type formulation (B) is 1:1 to 100:1 or 1:1 to 1:

100.

3. 3. The pharmaceutical composition for improving cardiac function according to claim 1, wherein the release-type preparation (A) contains 0.5 to 50 mg of the PGI2 receptor agonist per vial, and / or the release-type preparation (B) contains 0.5 to 50 mg of the PGI2 receptor agonist per vial.

4. The pharmaceutical composition according to any one of claims 1 to 3, comprising a patch liquid.

5. The pharmaceutical composition according to claim 4, wherein the patch solution is a 5 w / v % aqueous solution of mannitol containing 0.2 w / v % polysorbate.

6. The pharmaceutical composition according to any one of claims 1 to 5, which is in the form of a sheet-type patch.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the prostaglandin I2 receptor agonist is released over a period of 4 weeks after administration.

8. The pharmaceutical composition according to any one of claims 1 to 7, which is a sustained-release formulation of microspheres (MS).

9. The pharmaceutical composition according to claim 8, wherein the sustained-release preparation has an average particle size of 3 to 300 μm.

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