Sustained-release injection

Abstract

To provide a novel pharmaceutical composition for use in the treatment of moderate to severe pulmonary arterial hypertension.SOLUTION: A pharmaceutical composition comprises, as an active ingredient, a pharmaceutically acceptable salt of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (compound B) for use in the treatment of moderate to severe pulmonary arterial hypertension.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound of formula: [ka] The present invention relates to a novel pharmaceutical composition for use in the treatment of moderate to severe pulmonary arterial hypertension, which contains as an active ingredient a pharmaceutically acceptable salt of the compound (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid, hereinafter referred to as "Compound B"), and a method for using the same. [Background technology]

[0002] Uptravi is sold as a therapeutic agent for pulmonary arterial hypertension, and selexipag, the active ingredient of Uptravi, is a prodrug of compound B (Non-Patent Document 1). However, selexipag cannot be used to treat moderate to severe pulmonary arterial hypertension, and it has also been difficult to stabilize selexipag in solution.

[0003] Currently, epoprostenol and treprostinil injections are commercially available as therapeutic agents for moderate to severe pulmonary arterial hypertension (Non-Patent Documents 2 and 3). However, epoprostenol needs to be prepared immediately before use (Non-Patent Document 2), and although subcutaneous depot formulations of treprostinil are available, pain during administration remains an issue (Non-Patent Document 4).

[0004] Compound B has a PGI2 receptor agonist effect and is known to exhibit platelet aggregation inhibitory effect, vasodilatory effect, bronchial smooth muscle dilating effect, lipid deposition inhibitory effect, and leukocyte activation inhibitory effect (see, for example, Patent Documents 1 to 6).

[0005] However, there have been no reports of the use of Compound B, the active ingredient of selexipag, to treat moderate to severe pulmonary arterial hypertension. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2002 / 088084 [Patent Document 2] International Publication No. 2009 / 157396 [Patent Document 3] International Publication No. 2009 / 107736 [Patent Document 4] International Publication No. 2009 / 154246 [Patent Document 5] International Publication No. 2009 / 157397 [Patent Document 6] International Publication No. 2009 / 157398 [Non-patent literature]

[0007] [Non-Patent Document 1] Uptravi package insert [Non-patent document 2] Package insert (active ingredient: epoprostenol) [Non-patent document 3] Package insert (active ingredient treprostinil) [Non-patent document 4] J.Clin.Med.,2019,8,481;doi:10.3390 / jcm8040481 Summary of the Invention [Problem to be solved by the invention]

[0008] The problem to be solved by the invention is to provide a novel pharmaceutical composition for use in the treatment of moderate to severe pulmonary arterial hypertension, or a novel method for treating moderate to severe pulmonary arterial hypertension. [Means for solving the problem]

[0009] The present inventors have solubilized and stabilized a pharmaceutically acceptable salt of compound B, and further found that the pharmaceutically acceptable salt of compound B exhibits a vasorelaxant effect compared to epoprostenol and treprostinil using an SuHx model, which is an animal model of severe pulmonary arterial hypertension, and have completed the present invention.

[0010] The present invention relates to the following: (1) A pharmaceutical composition for use in the treatment of moderate to severe pulmonary arterial hypertension, comprising a pharmaceutically acceptable salt of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B) as an active ingredient. (2) The pharmaceutical composition according to 1, wherein the pharmaceutically acceptable salt of compound B is a potassium salt or a tris salt of compound B. (3) The pharmaceutical composition according to 1 or 2, wherein the pharmaceutically acceptable salt of compound B is present in an amount of 1 to 50% by mass, preferably 2 to 20% by mass, more preferably 4 to 15% by mass, relative to the total mass of the composition. (4) The composition according to any one of 1 to 3, which contains a pH adjuster, preferably trishydroxymethylaminomethane. (5) The composition according to 4, wherein the pH adjuster, preferably trishydroxymethylaminomethane, is present in an amount of 1 to 50% by mass, preferably 2 to 20% by mass, more preferably 4 to 15% by mass, relative to the total mass of the composition. (6) The composition according to any one of 1 to 5, comprising at least one excipient selected from the group consisting of sucrose, mannitol, maltose, α-cyclodextrin, sucrose, maltose, β-cyclodextrin, dextran, L-arginine, and glycine, preferably selected from the group consisting of sucrose, mannitol, α-cyclodextrin, and L-arginine, and more preferably selected from the group consisting of sucrose and α-cyclodextrin. (7) The composition according to 6, wherein the excipient accounts for 40 to 150% by mass, preferably 60 to 120% by mass, more preferably 70 to 100% by mass, relative to the total mass of the composition. (8) The composition according to any one of 1 to 7, wherein the composition is a freeze-dried product. (9) The composition according to any one of 1 to 8, wherein the composition is stable for a pharmaceutically acceptable period. (10) The composition according to any one of 1 to 9, wherein compound B is stable in the composition. (11) A stable aqueous pharmaceutical composition comprising a pharmaceutically acceptable salt of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B) and trishydroxymethylaminomethane. (12) The composition according to 11, wherein the pH of the composition is 7.0 to 8.2, preferably 7.2 to 8.0, and more preferably 7.4 to 7.8. (13) The aqueous pharmaceutical composition according to 11 or 12, wherein the pharmaceutically acceptable salt of compound B is a potassium salt or a tris salt of compound B. (14) The aqueous pharmaceutical composition according to 13, wherein the mass ratio of the pharmaceutically acceptable salt of compound B to trishydroxymethylaminomethane in the composition is 1.0:0.1 to 1.0:2.0, preferably 1.0:0.5 to 1.0:1.5, and more preferably 1.0:0.9 to 1.0:1.3. (15) The aqueous pharmaceutical composition according to any one of (11) to (14), further comprising at least one excipient selected from the group consisting of sucrose, mannitol, maltose, α-cyclodextrin, sucrose, maltose, β-cyclodextrin, dextran, L-arginine, and glycine, preferably selected from the group consisting of sucrose, mannitol, α-cyclodextrin, and L-arginine, more preferably selected from the group consisting of sucrose and α-cyclodextrin. (16) The aqueous pharmaceutical composition according to 15, wherein the mass ratio of the pharmaceutically acceptable salt of compound B to the excipient in the composition is 1:1 to 1:100, preferably 1:2 to 1:20, and more preferably 1:5 to 1:15. (17) The composition according to any one of (11) to (16), wherein the composition is stable during continuous administration. (18) The composition according to any one of (11) to (17), wherein the composition is a long-acting injectable preparation and is used, for example, for continuous subcutaneous infusion (injected using a disposable injector, a syringe pump, or an infusion pump) or for continuous intravenous infusion (injected using a precision continuous infusion device (a syringe pump or an infusion pump)). (19) Use of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B) in the manufacture of a medicament for the treatment of moderate to severe pulmonary arterial hypertension. (20) A method for treating moderate to severe pulmonary arterial hypertension, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable salt of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B). (21) The composition according to any one of 1 to 18, the use according to 19, or the method according to 20, wherein the moderate to severe pulmonary arterial hypertension is NYHA / WHO functional class III or IV.

[0011] The above-mentioned configurations can be arbitrarily selected and combined. [Effects of the Invention]

[0012] The pharmaceutical composition of the present invention is useful for treating moderate to severe pulmonary arterial hypertension, has excellent stability and therapeutic effect as a pharmaceutical product, and can improve patient compliance with medication. DETAILED DESCRIPTION OF THE INVENTION

[0013] An embodiment of the present invention will be described.

[0014] Compound B can be synthesized by the method described in WO2002 / 088084.

[0015] Compound B can be used as a medicine in the form of a free base or acid, but can also be used in the form of a pharmaceutically acceptable salt by known methods. A pharmaceutically acceptable salt of Compound B can be prepared by the methods described in WO2021 / 033702 and used in the art. The crystalline form of the pharmaceutically acceptable salt of Compound B is not particularly limited as long as it can be used as a medicine. In one embodiment of the present invention, the crystalline form of the potassium salt of Compound B is, but is not particularly limited to, for example, Potassium salt Pattern 1 and / or Potassium salt Pattern 2 described in WO2021 / 033702, preferably Potassium salt Pattern 2 described in WO2021 / 033702.

[0016] Compound B exists as geometric isomers (Z- and E-isomers), and each geometric isomer and a mixture thereof are included in Compound B. Compound B also includes compounds having an asymmetric carbon, and each optical isomer and their racemates are also included in the heterocyclic derivative (1). Optical isomers can be produced by optically resolving the racemate obtained as described above using an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid) by a known method, taking advantage of its basicity, or by using a previously prepared optically active compound as a starting material.

[0017] One aspect of the present invention is a pharmaceutical composition for use in treating moderate to severe pulmonary arterial hypertension, comprising a pharmaceutically acceptable salt of Compound B as an active ingredient.

[0018] The dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition, such as body weight and age, the route of administration, the severity of symptoms, etc., but generally, for an adult, the amount of compound B is in the range of 0.001 mg to 100 mg per day, more preferably 0.01 mg to 10 mg. In some cases, a smaller dose may be sufficient, while in other cases a larger dose may be required. In addition, the composition can be administered once to several times a day, or at intervals of one day to several days.

[0019] In one embodiment of the present invention, although the severity of pulmonary arterial hypertension may vary depending on the doctor's diagnosis, the patient's condition, and other factors, moderate to severe pulmonary arterial hypertension is, for example, pulmonary arterial hypertension that is NYHA / WHO functional class III to IV.

[0020] In one embodiment of the present invention, the severity of pulmonary arterial hypertension may vary depending on the doctor's diagnosis, the patient's condition, and other factors. However, moderate to severe pulmonary arterial hypertension is classified, for example, using the severity classification of the "Study Group on Refractory Respiratory Diseases and Pulmonary Hypertension" which was created based on the NYHA Cardiac Functional Classification and the WHO Pulmonary Hypertension Functional Classification, and is, for example, moderate-risk to high-risk pulmonary arterial hypertension.

[0021] In one embodiment of the present invention, the pharmaceutical composition is a lyophilized product, and can be reconstituted with, for example, water for injection and used as a long-acting injectable preparation. For example, in the long-acting injectable preparation, the concentration of the pharmaceutically acceptable salt of Compound B is, for example, 0.0005 to 20 mg / mL, preferably 0.005 to 18 mg / mL, and the concentration of trishydroxymethylaminomethane is, for example, 0.0004 to 16 mg / mL, preferably 0.004 to 18 mg / mL.

[0022] In one embodiment of the present invention, the pharmaceutical composition is a long-acting injectable preparation used for continuous subcutaneous infusion, and the concentration of the pharmaceutically acceptable salt of compound B is, for example, 0.03 to 15 mg / mL.

[0023] In one embodiment of the present invention, the pharmaceutical composition is a long-acting injectable preparation used for continuous intravenous infusion, and the concentration of the pharmaceutically acceptable salt of compound B is, for example, 0.001 to 0.5 mg / mL. [Example]

[0024] The present invention will be explained in more detail below with reference to examples, test examples and formulation examples, but the present invention is not limited to these examples.

[0025] <Preparation of a pharmaceutically acceptable salt of compound B> The potassium salt of Compound B and the tris salt of Compound B were prepared according to the methods described in WO2021 / 033702 and used in the art.

[0026] <Test Example 1> 1. Test Sample Preparation Phosphate buffer (pH 7-8), carbonate-bicarbonate buffer (pH 9-10), Britton-Robinson buffer (pH 2-12), and Tris-HCl buffer (pH 7-9) were prepared. The potassium salt of Compound B (or Tris salt of Compound B) was added to each buffer solution in an amount that would result in a concentration of 0.1 mg / mL to 5.0 mg / mL in the buffer solution.

[0027] 2. Stability testing The appearance was visually inspected.

[0028] <Test Example 2> 1. Preparation of Lyophilized Materials Each component was weighed according to the formulation example, and trishydroxymethylaminomethane and the potassium salt of compound B (or the tris salt of compound B) were added to water for injection and stirred until a clear solution was obtained. An excipient (sucrose, etc.) was then added and dissolved by stirring, and the pH was adjusted to approximately 7.5 using hydrochloric acid. The solution was then diluted to a measuring volume using water for injection. After diluting to a measuring volume, the drug solution was filtered through a filter (0.22 μm, PVDF), and 3 mL was filled into a vial (TopLyo, 10R, manufactured by SCHOTT), partially stoppered with a rubber stopper (V10-F8W D21-7S, manufactured by Daikyo Seiko), and freeze-dried.

[0029] 2. Stability testing (1) Storage conditions for temperature stability test 25℃ / 60%RH, 40℃ / 75%RH, 60℃ / humidity (2) The appearance of the samples under each storage condition and after each time period was visually inspected, and the remaining percentage of the potassium salt of Compound B or the tris salt of Compound B was determined.

[0030] - Sample solution preparation method The lyophilized product was reconstituted by injecting 3 mL of water for injection. After reconstitution, exactly 1 mL of the drug solution was taken and made up to exactly 50 mL with 70% methanol solution. Exactly 2 mL of this solution was taken and made up to exactly 25 mL with 70% methanol solution to use as the sample solution.

[0031] ·HPLC analysis conditions Detector: ultraviolet absorption photometer (measurement wavelength: 302 nm) Column: Develosil ODS-HG, 5 μm, 4.6 / 150 mm (Manufacturer: Nomura Chemical) Column temperature: 40°C (set value) Mobile phase: 2.16 g of sodium 1-octanesulfonate was dissolved in 1000 mL of diluted phosphoric acid (1 → 1000). 700 mL of methanol was added to 300 mL of this solution. Flow rate: 1mL / min

[0032] <Prescription example>

[0033] [Table 1]

[0034] [Table 2]

[0035] [Table 3]

[0036] <Test Example 3 Sugen5416 / Vasorelaxing effect using isolated blood vessels in hypoxia-induced pulmonary hypertension model rats> 1. Creation of a rat model of Sugen5416 / hypoxia-induced pulmonary hypertension Sugen 5416 (synthesized by Nippon Shinyaku Co., Ltd.) was suspended at 5 mg / mL in a solvent (0.5% (w / v) carboxymethyl cellulose sodium salt, 0.9% (w / v) NaCl, 0.4% (v / v) polysorbate 80, 0.9% (v / v) benzyl alcohol) and administered subcutaneously at a dose of 20 mg / kg to SD rats (male, 6-7 weeks old) (Japan SLC Co., Ltd.). The rats were housed in a breeding facility maintained at 10% oxygen for 3 weeks, and then housed in a normoxic environment for an additional 4-7 weeks.

[0037] 2. Measurement of vasorelaxation in isolated blood vessels Sugen5416 / hypoxia-induced pulmonary hypertension model rats were sacrificed by exsanguination under isoflurane inhalation anesthesia, and the lungs were removed. The lung tissue was placed in a petri dish filled with Krebs solution (111.0 mmol / L NaCl, 5.9 mmol / L KCl, 2.5 mmol / L CaCl2·2H2O, 1.2 mmol / L MgCl2·6H2O, 1.2 mmol / L NaH2PO4·2H2O, 25.0 mmol / L NaHCO3, 11.5 mmol / L D-(+)-glucose) and examined under a stereomicroscope to prepare a ring preparation of the left pulmonary artery.

[0038] Changes in vascular tension were measured using a DMT wire myograph (610M, Danish Myo Technology) and a PowerLab (PowerLab 8 / 30, ADInstruments Pty Ltd.). The specimen was attached to a force transducer in a myograph chamber filled with Krebs solution using a tungsten wire (25 μm diameter) and maintained at approximately 37°C under aeration with a mixed gas (95% O2, 5% CO2). A resting tension of 0.145–0.155 g was applied to the specimen and it was left to stand until the tension stabilized. After that, the Krebs solution in the myograph chamber was filled with 30 mmol / LK. +The specimens were then replaced with Krebs solution (86.9 mmol / L NaCl, 30.0 mmol / L KCl, 2.5 mmol / L CaCl2·2H2O, 1.2 mmol / L MgCl2·6H2O, 1.2 mmol / L NaH2PO4·2H2O, 25.0 mmol / L NaHCO3, 11.5 mmol / L D-(+)-Glucose) to confirm the contractile response, and only specimens showing a response were used for evaluation. After washing the specimens with Krebs solution, the myograph bath was filled with Krebs solution and PGF was added. 2α (Final concentration: 10 -5 mol / L), Phenylephline (final concentration: 10 -7 ~10 -6 mol / L) or Endothelin-1 (final concentration: 10 -7 ~10 -8 A vasoconstrictor such as MRE-367 (10 mol / L) was added and the mixture was left to stand until the vasoconstriction reaction stabilized. -9 ~3×10 -5 mol / L), Treprostinil (10 -9 ~3×10 -5 mol / L), Epoprostenol (10 -8 ~10 -5 After the addition of the test substance was completed, papaverine (final concentration: 10 -4 mol / L) was added and the maximum relaxation response was measured.

[0039] Using the PowerLab Data Pad, the average tension for 30 seconds before each treatment point was calculated and used as the measurement value. Using Microsoft Excel 2016 (Microsoft), the relaxation rate (%) of papaverine relative to the contraction height caused by the vasoconstrictor was calculated from each measurement value. Next, from the measurement values of the relaxation response of the test substance, the relaxation rate (%) of the test substance was calculated, assuming the contraction height as the reference (relaxation rate 0%) and papaverine relaxation as the maximum relaxation (relaxation rate 100%). For the relaxation rate (%) at each concentration, nonlinear regression analysis using a two-parameter logistic equation was performed using the SAS system and EXSUS to determine the 50% inhibitory concentration (IC 50) and their 95% confidence intervals (95% CI) were estimated.

[0040] The results are shown in the table below.

[0041] [Table 4]

Claims

1. A pharmaceutical composition for use in treating moderate to severe pulmonary arterial hypertension, comprising a pharmaceutically acceptable salt of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B) as an active ingredient.

2. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of Compound B is a potassium salt or a tris salt of Compound B.

3. 3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of compound B is present in an amount of 1 to 50% by weight, preferably 2 to 20% by weight, more preferably 4 to 15% by weight, relative to the total weight of the composition.

4. A composition according to any one of claims 1 to 3, which contains a pH adjuster, preferably trishydroxymethylaminomethane.

5. 5. The composition according to claim 4, wherein the pH adjuster, preferably trishydroxymethylaminomethane, is present in an amount of 1 to 50% by weight, preferably 2 to 20% by weight, more preferably 4 to 15% by weight, relative to the total weight of the composition.

6. The composition according to any one of claims 1 to 5, comprising at least one excipient selected from the group consisting of sucrose, mannitol, maltose, α-cyclodextrin, sucrose, maltose, β-cyclodextrin, dextran, L-arginine and glycine, preferably from the group consisting of sucrose, mannitol, α-cyclodextrin and L-arginine, more preferably from the group consisting of sucrose and α-cyclodextrin.

7. The composition according to claim 6, wherein the excipients represent 40 to 150% by weight, preferably 60 to 120% by weight, more preferably 70 to 100% by weight, based on the total weight of the composition.

8. The composition according to any one of claims 1 to 7, wherein the composition is a lyophilisate.

9. The composition of any one of claims 1 to 8, wherein the composition is stable for a pharmaceutically acceptable period of time.

10. The composition according to any one of claims 1 to 9, wherein compound B is stable in the composition.

11. A stable aqueous pharmaceutical composition comprising a pharmaceutically acceptable salt of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B) and trishydroxymethylaminomethane.

12. The composition according to claim 11, wherein the pH of the composition is from 7.0 to 8.2, preferably from 7.2 to 8.0, more preferably from 7.4 to 7.

8.

13. 13. The aqueous pharmaceutical composition according to claim 11 or 12, wherein the pharmaceutically acceptable salt of compound B is a potassium salt or a tris salt of compound B.

14. 14. The aqueous pharmaceutical composition according to claim 13, wherein the mass ratio of the pharmaceutically acceptable salt of compound B to trishydroxymethylaminomethane in the composition is 1.0:0.1 to 1.0:2.0, preferably 1.0:0.5 to 1.0:1.5, and more preferably 1.0:0.9 to 1.0:1.

3.

15. The aqueous pharmaceutical composition according to any one of claims 11 to 14, further comprising at least one excipient selected from the group consisting of sucrose, mannitol, maltose, α-cyclodextrin, sucrose, maltose, β-cyclodextrin, dextran, L-arginine and glycine, preferably selected from the group consisting of sucrose, mannitol, α-cyclodextrin and L-arginine, more preferably selected from the group consisting of sucrose and α-cyclodextrin.

16. 16. The aqueous pharmaceutical composition according to claim 15, wherein the mass ratio of the pharmaceutically acceptable salt of compound B to the excipient in the composition is 1:1 to 1:100, preferably 1:2 to 1:20, and more preferably 1:5 to 1:

15.

17. The composition according to any one of claims 11 to 16, wherein the composition is stable for a period of continuous administration.

18. The composition according to any one of claims 11 to 17, wherein the composition is a long-acting injectable preparation, for example, used for continuous subcutaneous infusion (injected using a disposable injector, a syringe pump, or an infusion pump) or used for continuous intravenous infusion (injected using a precision continuous infusion device (a syringe pump or an infusion pump)).

19. Use of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B) in the manufacture of a medicament for the treatment of moderate to severe pulmonary arterial hypertension.

20. A method for treating moderate to severe pulmonary arterial hypertension, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable salt of (2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (Compound B).

21. 21. The composition according to any one of claims 1 to 18, the use according to claim 19, or the method according to claim 20, wherein the moderate to severe pulmonary arterial hypertension is NYHA / WHO functional class III or IV.

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