Pharmaceutical compositions containing isoquinolinone compounds and methods for preparing the same

Abstract

The present disclosure relates to a pharmaceutical composition containing an isoquinolinone compound and a method for preparing the same. Specifically, the present disclosure provides a pharmaceutical composition containing 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof and polysorbate 80. The pharmaceutical composition of the present disclosure exhibits good physicochemical stability after storage for several months.

Description

[Technical Field]

[0001] The present disclosure is in the field of drug formulations and relates to pharmaceutical compositions containing isoquinolinone compounds and methods for preparing the same. [Background technology]

[0002] The development of new molecules with both PDE3 and PDE4 inhibitory activity has the potential to combine the bronchodilatory effects of β-adrenergic receptor agonists with the anti-inflammatory effects of inhaled glucocorticoids, resulting in a more complementary dual-targeting effect than single-targeting. For example, RPL554 (9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one) is a PDE3 / PDE4 dual-targeting inhibitor disclosed in WO 00 / 58308. Recent Phase II clinical data have shown that it significantly improves bronchodilation and symptoms in patients with chronic obstructive pulmonary disease, and is well tolerated with no significant adverse events, such as mild cardiac events, nausea, and diarrhea. The drug's safety and its "limited systemic exposure" are encouraging.

[0003] 9,10-Dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one is a kind of new PDE3 / 4 inhibitor with better PDE3 and PDE4 inhibitory activity. [ka]

[0004] There is a need to develop pharmaceutical (formulation) compositions that are more suitable for administration so that new PDE3 / 4 inhibitors can be administered, maintain stability during storage and subsequent use, and exert better effects. Summary of the Invention

[0005] The disclose provides a pharmaceutical composition comprising the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof, and polysorbate 80.

[0006] The concentration of the active ingredient in the pharmaceutical composition described in the present disclosure is 0.01 to 40 mg / mL, including 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.3 mg / mL, 0.5 mg / mL, 0.7 mg / mL, 0.9 mg / mL, 1.1 mg / mL, 1.3 mg / mL, 1.5 mg / mL, 1.7 mg / mL, 1.9 mg / mL, 2.1 mg / mL, 2.3 mg / mL, 2.5 mg / mL, 2.7 mg / mL, 2.9 mg / mL, 3.1 mg / mL, 3.3 mg / mL, 3.5 mg / mL, 3.7 mg / mL, 3.9 mg / mL, 4.1 mg / mL, 4.3 mg / mL, 4.5 mg / mL, 4.7 mg / mL, 4.9 mg / mL, 5.1 mg / mL, 5.3 mg / mL, 5.5 mg / mL, 5.7 mg / mL, 5.9 mg / mL, 6.1 mg / mL, 6.3 mg / mL, 6.5 mg / mL, 6.7 mg / mL, 6.9 mg / mL, 7.1 mg / mL, 7.3 mg / mL, 7.5 mg / mL, 7.7 mg / mL, 7.9 mg / mL, 8.1 mg / mL, 8.3 mg / mL, 8.5 mg / mL, 8.7 mg / mL, 8.9 mg / mL, 9.1 mg / mL, 9.3 mg / mL, 9.5 mg / mL, 9.7 mg / mL, 9.9 mg / mL, 10.1 mg / mL, 10.3 mg / mL, 10.5 mg / mL, 10.7 mg / mL, 10.9 mg / mL, 11.1 mg / mL, 11.3 mg / mL, 11.5 mg / mL, 11.7 mg / mL, 11.9 mg / mL, 12.1 mg / mL, 12.3 mg / mL, 12.5 mg / mL, 12.7 mg / mL, 12.9 mg / mL, 13.1 mg / mL, 13.3 mg / mL, 13.5 mg / mL, 13.7 mg / mL, 13.9 mg / mL, 14.1 mg / mL, 14.3 mg / mL, 14.5 mg / mL, 14.7 mg / mL, 14.9 mg / mL, 15.1 mg / mL, 15.3 mg / mL, 15.5 mg / mL, 15.7 mg / mL, 15.9 mg / mL, 16.1 mg / mL, 16.3 mg / mL, 16.5 mg / mL, 16.7 mg / mL, 16.9 mg / mL, 17.1 mg / mL, 17.3 mg / mL, 17.5 mg / mL, 17.7 mg / mL, 17.9 mg / mL, 18.1 mg / mL, 18.3 mg / mL, 18.5 mg / mL, 18.7 mg / mL, 18.9 mg / mL, 19.Including, but not limited to, 1 mg / mL, 19.3 mg / mL, 19.5 mg / mL, 19.7 mg / mL, 19.9 mg / mL, 20.0 mg / mL, or any value between two of these values.

[0007] In some embodiments, the concentration of the active ingredient in the pharmaceutical composition is 0.05 to 20 mg / mL.

[0008] Furthermore, the pharmaceutical composition described herein further comprises a buffer, wherein the buffer is selected from a citrate buffer, a phosphate buffer, or an acetate buffer. In some embodiments, the buffer is selected from a phosphate buffer. In other embodiments, the buffer is selected from a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer. In other embodiments, the buffer is selected from a sodium acetate-acetic acid buffer.

[0009] In alternative embodiments, the concentration of the buffer is between 1 mM and 50 mM, and is selected from the group consisting of 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, The range includes, but is not limited to, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38 mM, 39 mM, 40 mM, 41 mM, 42 mM, 43 mM, 44 mM, 45 mM, 46 mM, 47 mM, 48 mM, 49 mM, 50 mM, or a value between any two of these values.

[0010] In some embodiments, the concentration of the buffer solution is 5 to 30 mM.

[0011] In another aspect, the concentration of polysorbate 80 in the pharmaceutical compositions provided in some embodiments is 0.05 to 5.0 mg / mL, and is selected from the group consisting of 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, and 2.1 mg / mL. g / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0 mg / mL, 4.1 mg / mL, 4.2 mg / mL, 4.3 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.6 mg / mL, 4.7 mg / mL, 4.8 mg / mL, 4.9 mg / mL, 5 mg / mL, or a value between any two data points.

[0012] In some embodiments, the concentration of polysorbate 80 in the pharmaceutical composition is 0.08 to 0.5 mg / mL.

[0013] Furthermore, the pH of the pharmaceutical compositions described herein is 3.0 to 8.0, including, but not limited to, 3.0, 4.0, 5.0, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, or any value between any two of these values.

[0014] In some embodiments, the pharmaceutical composition has a pH of 6.0 to 7.0.

[0015] In another aspect, in some embodiments, the active ingredient in the pharmaceutical composition is present as particles, and the particle size D90 of the active ingredient particles is less than 7 μm, and is within the range of 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.10 μm, 3.11 μm, 3.12 μm, 3.13 μm, 3.14 μm, 3.15 μm, 3.16 μm, 3.17 μm, 3.18 μm, 3.19 μm, 3.20 μm, 3.21 μm, 3.22 μm, 3.23 μm, 3.24 μm, 3.25 μm, 3.26 μm, 3.27 μm, 3.28 μm, 3.29 μm, 3.30 μm, 3.31 μm, 3.32 μm, 3.33 μm, 3.34 μm, 3.35 μm, 3.36 μm, 3.37 μm, 3.38 μm, 3.39 μm, 3.40 μm, 3.41 μm, 3.42 μm, 3.43 μm, 3.44 μm, 3.45 μm, 3.46 μm, 3.47 μm, 3.48 μm, 3.49 μ The thickness may be selected from, but is not limited to, 7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, 4.1 μm, 4.2 μm, 4.3 μm, 4.4 μm, 4.5 μm, 4.6 μm, 4.7 μm, 4.8 μm, 4.9 μm, 5.0 μm, or a value between any two of these values.

[0016] In some embodiments, the particle size D90 of the active ingredient particles in the pharmaceutical composition is 2.0 to 4.0 μm.

[0017] In some embodiments, the particle size D90 of the active ingredient particles in the pharmaceutical composition is 2.0 to 3.5 μm.

[0018] In some embodiments, the particle size D90 of the active ingredient particles in the pharmaceutical composition is 3.0 μm or 3.2 μm.

[0019] In some other embodiments, the particle size D50 of the active ingredient particles in the pharmaceutical composition is 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, or a value between any two of these values.

[0020] In some embodiments, the particle size D50 of the active ingredient particles in the pharmaceutical composition is 2.0 to 3.0 μm.

[0021] In some embodiments, the particle size D50 of the active ingredient particles in the pharmaceutical composition is 1.0 to 2.0 μm.

[0022] In some embodiments, the particle size D50 of the active ingredient particles in the pharmaceutical composition is 1.6 μm or 1.8 μm.

[0023] In another aspect, the particle size D10 of the active ingredient particles in the pharmaceutical compositions provided in some embodiments is 0.1 μm, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, or a value between any two of these values.

[0024] In another aspect, the particle size D[4,3] is the average particle size by volume. In some embodiments, the particle size D[4,3] of the active ingredient particles in the pharmaceutical composition provided is 1.0 to 4 μm, including, but not limited to, 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.1 μm, 2.2 μm, 2.3 μm, 2.4 μm, 2.5 μm, 2.6 μm, 2.7 μm, 2.8 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, 3.9 μm, 4.0 μm, or any value between any two of these values.

[0025] In some embodiments, the particle size D[4,3] of the active ingredient particles in the pharmaceutical composition is 1.6 or 1.7 μm.

[0026] In another aspect, the pharmaceutical composition according to the present disclosure further comprises a sorbitan fatty acid ester.

[0027] In some embodiments, the concentration of the sorbitan fatty acid ester in the pharmaceutical composition is 0.01 to 0.5 mg / mL, including, but not limited to, 0.01 mg / mL, 0.02 mg / mL, 0.04 mg / mL, 0.06 mg / mL, 0.08 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, or any value between any two of the data points.

[0028] In another aspect, the present disclosure further provides a pharmaceutical composition comprising particles of an active ingredient, 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicamentable salt thereof, wherein the particle size D90 of the active ingredient particles is less than 7 μm.

[0029] In some embodiments, the particle size D90 of the active ingredient particles in the pharmaceutical composition is 2.0 to 4.0 μm, for example, 3.0 μm or 3.2 μm.

[0030] In some embodiments, the particle size D50 of the active ingredient particles in the pharmaceutical composition is 1.6 μm or 1.8 μm.

[0031] In some embodiments, the particle size D[4,3] of the active ingredient particles in the pharmaceutical composition is 1.6 or 1.7 μm.

[0032] Additionally, the pharmaceutical composition further comprises a tonicity modifier. In some embodiments, the tonicity modifier in the pharmaceutical composition is sodium chloride.

[0033] In some embodiments, the concentration of the tonicity adjusting agent in the pharmaceutical composition is 2 to 8 mg / mL, and is 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 3.2 mg / mL, 3.4 mg / mL, 3.6 mg / mL, 3.8 mg / mL, 4.0 mg / mL, 4.2 mg / mL, 4.4 mg / mL, 4.6 mg / mL, 4.8 mg / mL mL, 5.0 mg / mL, 5.2 mg / mL, 5.4 mg / mL, 5.6 mg / mL, 5.8 mg / mL, 6.0 mg / mL, 6.2 mg / mL, 6.4 mg / mL, 6.6 mg / mL, 6.8 mg / mL, 7.0 mg / mL, 7.2 mg / mL, 7.4 mg / mL, 7.6 mg / mL, 7.8 mg / mL, 8.0 mg / mL or values ​​between any two data points.

[0034] In some embodiments, the pharmaceutical composition comprises 0.05 to 40 mg / mL of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof, and 0.05 to 5.0 mg / mL of polysorbate 80.

[0035] In some embodiments, the pharmaceutical composition comprises 0.05 to 40 mg / mL of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof, and 0.05 to 5.0 mg / mL of polysorbate 80, wherein the active ingredient is present as particles.

[0036] In some embodiments, the pharmaceutical composition comprises: a) 0.05 to 40 mg / mL of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicament salt thereof; b) 0.05 to 5.0 mg / mL of polysorbate 80; c) 1 to 50 mM buffer; Includes:

[0037] In some embodiments, the pharmaceutical composition comprises: a) 0.05 to 40 mg / mL of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicament salt thereof; b) 0.05 to 5.0 mg / mL of polysorbate 80; c) a 1 to 50 mM buffer solution in which the active ingredient is present as particles; Includes:

[0038] In some embodiments, the pharmaceutical composition comprises: a) 0.05 to 40 mg / mL of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicament salt thereof; b) 0.05 to 5.0 mg / mL of polysorbate 80; c) a 1 to 50 mM buffer solution in which the active ingredient is present as particles and the particle size D90 of the particles is less than 7 μm; Includes:

[0039] In some embodiments, the pharmaceutical composition comprises: a) 0.05 to 40 mg / mL of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicament salt thereof; b) 0.05 to 5.0 mg / mL of polysorbate 80; c) 1 to 50 mM buffer; d) 0.01 to 0.5 mg / mL of a sorbitan fatty acid ester in which the active ingredient is present as particles and the particle size D90 of the particles is less than 7 μm; Includes.

[0040] Pharmaceutically acceptable salts of the active ingredients described herein include, but are not limited to, fumarate, sulfate, and hydrochloride salts. In some embodiments, the pharmaceutically acceptable salt is a fumarate salt.

[0041] In some embodiments, the pharmaceutical compositions described herein are suitable for administration by a nebulizer, e.g., the pharmaceutical compositions are delivered via a special device to the respiratory tract for local or systemic effect.

[0042] The present disclosure further provides a method for preparing the above pharmaceutical composition, which comprises milling, wet-milling, homogenizing, precipitating or shearing 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, from a process and economic perspective, it is generally possible to first co-mill the active ingredient and all or a portion of the polysorbate 80 to form a concentrated suspension of the active ingredient, which is then diluted to a suitable dilute suspension. The remaining surface stabilizer can be mixed with the composition during the dilution process to maintain the stability of the diluted liquid. In another aspect, to obtain acceptable D90 particles in embodiments of the present disclosure, particles of the appropriate size are first obtained by micronization, mixed with the polysorbate 80, and then milled to form a suspension.

[0044] In an alternative embodiment, the preparation method further comprises mixing with a buffer or / and a tonicity adjusting agent.

[0045] In another aspect, the pharmaceutical compositions of the present disclosure can be further freeze-dried to obtain solid compositions such as lyophilized powder injections. In some embodiments, the pharmaceutical compositions are stored in vials.

[0046] In some embodiments, the freeze-drying comprises the steps of pre-freezing, primary drying, and secondary drying, in that order.

[0047] The present disclosure further provides a lyophilized composition obtained by freeze-drying the pharmaceutical composition, which is then reconstituted or redissolved in a liquid medium to obtain a pharmaceutical composition, and the liquid medium used for reconstitution or redissolution is selected from water for injection.

[0048] The present disclosure further provides a pharmaceutical composition comprising: a lyophilized composition prepared from the pharmaceutical composition; and a reconstituted solution obtained after the lyophilized composition is further reconstituted or reconstituted in a liquid medium, wherein the pharmaceutical composition comprises 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicament salt thereof.

[0049] In another aspect, the present disclosure further provides use of the above pharmaceutical composition, lyophilized composition or reconstituted solution in the preparation of a medicament for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism, preferably obstructive pulmonary disease.

[0050] The present disclosure further provides a pharmaceutical composition in a medicament for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism, preferably obstructive pulmonary disease.

[0051] term "Buffer" refers to a buffer that resists changes in pH by the action of its acid-base conjugate components. Examples of buffers that control pH within an appropriate range include, but are not limited to, citrate and phosphate.

[0052] A "phosphate buffer" is a buffer containing phosphate ions. Examples of phosphate buffers include disodium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate-potassium dihydrogen phosphate, etc., and a preferred phosphate buffer is disodium hydrogen phosphate-sodium dihydrogen phosphate.

[0053] A "citrate buffer" is a buffer containing acetate ions. Examples of citrate buffers include citric acid-sodium citrate, etc. A preferred citrate buffer is citric acid-sodium citrate buffer.

[0054] An "acetate buffer" is a buffer containing acetate ions. Examples of acetate buffers include acetic acid-sodium acetate, etc. A preferred acetate buffer is acetic acid-sodium acetate buffer.

[0055] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. A pharmaceutical composition is intended to maintain the stability of an active ingredient, facilitate administration to a living body, and contribute to the absorption of the active ingredient to further exert its biological activity. As used herein, the terms "pharmaceutical composition" and "formulation" are not mutually exclusive.

[0056] "Lyophilized formulation" refers to a pharmaceutical composition or formulation obtained after the step of freeze-drying under vacuum a liquid or solution form of the pharmaceutical composition or a solution formulation.

[0057] In this disclosure, "D10" refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 10%. "D50" refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 50%. "D90" refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 90%.

[0058] In this disclosure, "D[4,3]" refers to the average particle size by volume. It is generally called "mass-to-volume average particle size" and abbreviated as volume average diameter. It is calculated by averaging the particle size values ​​at both ends of each particle size interval, multiplying it by the particle size distribution percentage corresponding to that interval, and then accumulating the products: D[4,3] = (f1·D1 + f2·D2 + f3·D3 + ...).

[0059] In this disclosure, the content percentage (%) of the total substance refers to the weight-to-volume ratio, and the "weight-to-volume ratio" described in this disclosure refers to the weight (unit: g) of the above component contained per 100 mL of the liquid system, i.e., g / 100 mL.

[0060] The values ​​in this disclosure are measured by instruments and have a certain degree of error, and generally, ±10% is within a reasonable error range. Of course, the context in which the value is used must be taken into consideration. For example, in the case of the particle size of an active ingredient, the value has an error of ±10% or less after measurement, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, and preferably ±5%.

[0061] The generally accepted stability criteria for the present disclosure are as follows: When measured by HPLC, the change in content during storage is usually less than about 10%, preferably less than about 5% of the active ingredient is decomposed. HPLC conditions: Octadecylsilane-bonded silica gel is used as the packing material, and phosphate, triethylamine phosphate buffer / acetonitrile is used as the mobile phase, with gradient elution. [Brief explanation of the drawings]

[0062] [Figure 1] Inhibitory effect on immune cell counts in BALF (#p<0.01 vs normal control group, **p<0.01, *p<0.05 vs model control group). [Figure 2] Inhibitory effect on TNFα in BALF (**p<0.01, *p<0.05 vs. model control group). DETAILED DESCRIPTION OF THE INVENTION

[0063] The following are specific embodiments of the present disclosure. The examples are not intended to limit the present disclosure but are intended to further illustrate the present disclosure. Any technical solutions equivalent to the present disclosure are within the scope of the claims of the present disclosure. Example 1

[0064] Preparation of 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (Compound 1) (prepared with reference to the method in WO2022228544) [ka]

[0065] Preparation of Intermediate 1a: 1-(2-chloroethyl)-imidazolin-2-one

[0066] At 0°C, 1-(2-hydroxyethyl)imidazolinone (3.5 g, 26.9 mmol) was slowly added with chlorosulfoxide (5 mL), heated to 45°C, and stirred until the reaction was complete. The reaction was quenched by adding saturated sodium chloride solution, adjusted to pH 7 with 10% NaOH solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give intermediate 1a (3.5 g, 88.4% yield). MS(ESI) m / z 149.1 [M+H] + .

[0067] Preparation of Intermediate 1b: 1-(3,4-Dimethoxyphenethyl)urea

[0068] 2-(3,4-Dimethoxyphenyl)ethylamine hydrochloride (4.3 g, 19.8 mmol) was dissolved in water (25 mL) at room temperature, heated to 50 °C, and potassium cyanate (1.8 g, 21.8 mmol) was added in several portions. The mixture was stirred until the reaction was complete, cooled to 0 °C, filtered, and the filter cake was washed with ice water and dried to give Intermediate 1b (4.1 g, 93.8% yield). MS (ESI) m / z 225.1 [M+H] + .

[0069] Preparation of Intermediate 1c: 1-[2-(3,4-dimethoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione

[0070] Add sodium ethanol (3.8 g, 55.8 mmol) in several portions to anhydrous ethanol (50 mL) under ice-bath conditions. After addition is complete, heat to reflux, add diethyl malonate (5.9 g, 36.6 mmol) dropwise, and continue stirring for 0.25-0.5 h. Add intermediate 1b (4.1 g, 18.3 mmol) in ethanol (30 mL) dropwise, stir until reaction is complete, cool to 0 °C, add 5% HCl solution dropwise to adjust the pH to 6, add 300 mL of water, filter, wash the filter cake with ice water, and dry to obtain intermediate 1c (3.9 g, 77.1% yield). MS (ESI) m / z 293.1 [M+H] + .

[0071] Preparation of Intermediate 1d: 2-Chloro-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one

[0072] Intermediate 1c (3.9 g, 13.4 mmol) was added to phosphorus oxychloride (120 mL) at room temperature, heated to 110 °C, and stirred until the reaction was complete. The mixture was then cooled and concentrated. The solid was poured into ice water, and saturated NaOH solution was added dropwise to adjust the pH to 10. The mixture was filtered, and the filter cake was washed with ice water and dried to give Intermediate 1d (2.4 g, 62.4% yield). MS (ESI) m / z 293.1 [M+H] + .

[0073] Preparation of Intermediate 1e: 9,10-Dimethoxy-2-(2,4,6-trimethyl-phenylimino)-2,3,6,7-tetrahydropyrimido[6,1-a]isoquinolin-4-one

[0074] Intermediate 1d (2.4 g, 8.2 mmol) was suspended in isopropanol (30 mL) at room temperature, 2,4,6-trimethylaniline (4.5 g, 24.6 mmol) was added, and the mixture was heated to 90 °C and stirred until the reaction was complete. The mixture was then cooled and filtered. The filter cake was washed with ice water and dried to give Intermediate 1e (3.0 g, 92.1% yield). MS (ESI) m / z 392.2 [M+H] + .

[0075] Preparation of Compound 1: 9,10-Dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one

[0076] Intermediate 1e (0.72 g, 1.8 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and potassium tert-butoxide (0.42 g, 3.6 mmol) was added under a nitrogen atmosphere. After the addition was complete, the mixture was heated to 65 °C and stirred for 48 h. The mixture was then cooled to 25 °C, and intermediate 1a (0.82 g, 5.5 mmol) was added. After the addition was complete, the mixture was heated to 80 °C and stirred until the reaction was complete. The reaction was quenched by the addition of saturated sodium chloride solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (n-heptane / ethyl acetate) to obtain target compound 1 (0.21 g, 46.5% yield).

[0077] 1 H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H), 6.69 (s, 1H), 6.64 (s, 1H), 5.39 (s, 1H), 4.61 (s, 1H), 4.22-4.15 (m, 2H), 4.08-3.99 (m, 2H), 3.93 (s, 3H), 3.77-3.69 (m, 5H), 3.55-3.46 (m, 2H), 3.38-3.42 (t, J = 6.8 Hz, 2H), 2.88-2.92 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 2.18 (s, 6H).

[0078] MS(ESI) m / z 504.4 [M+H] + .

[0079] Test Example 1 In vitro PDE4B enzyme activity detection experiment: detection based on the IMAP FP analytical method 1. Experimental materials [Table 1] 2. Experimental procedure

[0080] The compounds were diluted 5-fold in DMSO to obtain different concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of compounds at different concentrations were taken and placed in 384-well plates (n=2), and at the same time, two aliquots of 200 μL of DMSO were placed in 384-well plates (n=2) as blank controls. 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP Reaction buffer and 1 mM DTT) was then added to the 384-well plate, and 10 μL of blank buffer without PDE4B1 enzyme was added to one of the blank controls, and incubated with shaking at room temperature for 15 minutes. 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1 mM 5*IMAP Reaction buffer and 1 mM DTT) was then added thereto, and incubated with shaking at room temperature for 30 minutes, after which 60 μL of detection solution (0.5625 mM 5*IMAP Progressive Binding buffer A, 0.1875 mM 5*IMAP Progressive Binding buffer A, 0.1875 mM 5*IMAP Progressive Binding buffer B) was added. The cells were incubated with shaking at room temperature for 60 minutes, and data were collected. The formula for calculating the inhibition rate was: inhibition rate = M / (MM control ) × 100, and the IC was calculated from the fitting curve of the concentration and inhibition rate. 50 The values ​​were calculated. In this experiment, RPL554 was used as a positive control.

[0081] Examples of the present disclosure measure the inhibition of PDE4B1 enzyme activity in vitro using the above test, and the measured IC 50 =50nM.

[0082] Test Example 2 In vitro PDE3A enzyme activity detection experiment: detection based on the analytical method of IMAP FP 1. Experimental materials [Table 2] 2. Experimental procedure

[0083] The compounds were diluted 5-fold in DMSO to obtain different concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of compounds at different concentrations were taken and placed in 384-well plates (n=2), and at the same time, two aliquots of 200 μL of DMSO were placed in 384-well plates (n=2) as blank controls. 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP Reaction buffer and 1 mM DTT) was then added to the 384-well plate, and 10 μL of blank buffer without PDE3A enzyme was added to one of the blank controls, and incubated with shaking at room temperature for 15 minutes. 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1 mM 5*IMAP Reaction buffer and 1 mM DTT) was then added thereto, and incubated with shaking at room temperature for 30 minutes, after which 60 μL of detection solution (0.5625 mM 5*IMAP Progressive Binding buffer A, 0.1875 mM 5*IMAP Progressive Binding buffer A, 0.1875 mM 5*IMAP Progressive Binding buffer B) was added. The cells were incubated with shaking at room temperature for 60 minutes, and data were collected. The formula for calculating the inhibition rate was: inhibition rate = M / (MM control ) × 100, and the IC was calculated from the fitting curve of the concentration and inhibition rate. 50 The values ​​were calculated. In this experiment, RPL554 was used as a positive control.

[0084] Examples of the present disclosure measure the inhibition of PDE3A enzyme activity in vitro using the above test, and the measured IC 50 =0.13nM. Example 2

[0085] 9,10-Dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one (Compound A) and the additives in Table 1 were prepared into different formulations according to the following steps:

[0086] Step 1: Preparation of buffer solution: The prescribed amounts of polysorbate 20, Span 20, polysorbate 80, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium chloride were weighed out and dissolved in an appropriate amount of water by stirring.

[0087] Step 2: The prescribed amount of compound A was added, and the buffer solution obtained in Step 1 was diluted to 1 / 20 of the total preparation volume. The mixture was stirred uniformly and sheared using a high-speed shearing machine T50 (shearing speed: approximately 5000 rpm) for 2 to 6 minutes, then sterilized to produce a thick suspension.

[0088] Step 3: The buffer solution obtained in Step 1 was added to the thick suspension of Step 2, mixed, adjusted to volume, and sheared for 10 to 30 minutes using a high-speed shearing machine T50.

[0089] The mixture was filled, dispensed into polyester / aluminum / polyethylene pharmaceutical composite bags, and stored in a sealed container. [Table 3] The stability of the above formulations 1 to 5 was examined under different conditions, and the data are shown in Table 2. [Table 4-1] [Table 4-2]

[0090] Note: d is in days and M is in months.

[0091] Conclusion: The Four General Rules of the Chinese Pharmacopoeia for Inhalation Preparations stipulate that the particle size of the active ingredient in an inhalant should generally be controlled below 10 μm, with the majority being 5 μm. Formulations 1 and 2 showed a significant increase in the particle size of the active ingredient in the composition under long-term or accelerated storage conditions, e.g., the D90 value was greater than 5 μm and even greater than 10 μm. Compared with polysorbate 20, the formulation containing polysorbate 80 maintained stable particle size under either accelerated conditions or long-term storage at 25°C, demonstrating better composition storage stability.

[0092] Using a breathing simulator (model number: Copley BRS2100) and a spray pump (model number: PARI TurboBOY), adult breathing (simulation parameters: tidal volume 500 mL, breathing frequency 15 cycles / min, respiratory waveform sinusoidal, respiratory ratio 1:1) was simulated and measured, and the FPF (fine particle fraction) of Formulation 5 was 52.64%. Example 3

[0093] 9,10-Dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one (Compound A) and the additives in Table 3 were prepared into different formulations according to the steps of Example 2. [Table 5-1] [Table 5-2] The stability of the above formulations 6 to 9 was investigated under different conditions, and the data are shown in Table 4. [Table 6-1] [Table 6-2] Example 4

[0094] Step 1: Preparation of buffer solution: The prescribed amounts of polysorbate 80, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium chloride were weighed out and dissolved in an appropriate amount of water by stirring.

[0095] Step 2: The prescribed amount of compound A was added, and the buffer solution obtained in Step 1 was diluted to 1 / 20 of the total preparation volume. The mixture was stirred uniformly and sheared using a high-speed shearing machine T50 (shearing speed: approximately 5000 rpm) for 2 to 6 minutes, then sterilized to produce a thick suspension.

[0096] Step 3: The buffer solution obtained in Step 1 was added to the thick suspension of Step 2, mixed, adjusted to volume, and sheared for 10 to 30 minutes using a high-speed shearing machine T50. [Table 7]

[0097] The stability of each of the above formulations was examined under conditions of 40°C ± 2°C / 25% RH ± 5% RH, and the data are shown in Table 6. [Table 8-1] [Table 8-2] Example 5: Study of drug efficacy in an LPS-induced mouse acute lung inflammation model

[0098] This study used an LPS-induced acute lung inflammation model in BALB / c mice to evaluate the inhibitory effects of compounds on lung inflammation by measuring immune cell counts and TNFα cytokine levels in bronchoalveolar lavage fluid (BALF). Mice were divided into six groups of eight mice each: a normal control group, a model control group, an RPL554 group (1.0 mg / kg), and low, medium, and high doses of Compound A (0.3, 1.0, and 3.0 mg / kg). The mice were challenged with LPS nebulization 1 h after intratracheal nebulization to establish the model. BALF samples were collected 6 h after the model establishment, and total cells, neutrophils, and eosinophils in the BALF were counted, along with the levels of the pro-inflammatory cytokine TNFα.

[0099] The results of cell counts in BALF are shown in Figure 1. The model control animals had significantly higher total cell counts, neutrophil counts, and eosinophil counts in BALF than the normal control group. After administration of 1.0 mg / kg of RPL554 to the positive control group, the total cell counts, neutrophil counts, and eosinophil counts in BALF were all significantly lower than those in the model group. Compound A 0.3, 1.0, and 3.0 mg / kg groups all showed significantly lower neutrophil and eosinophil counts than the model group. Compound A 0.3 mg / kg had a similar efficacy to RPL554 1 mg / kg. The 1.0 and 3.0 mg / kg groups both showed significantly lower total cell counts, with the 0.3 mg / kg group showing a tendency toward a decrease.

[0100] The results of TNFα level detection in BALF are shown in Figure 2. In the model control group, the TNFα level in BALF was significantly higher than in the normal control group. After administration of 1.0 mg / kg, the TNFα level in BALF of the RPL554 positive control group tended to be lower than that of the model group. All dose groups of Compound A could reduce the TNFα level, and the reduction in the 0.3 and 1.0 mg / kg groups compared to the model group was significant. Example 6

[0101] 9,10-Dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one (Compound A), sodium carboxymethylcellulose, polysorbate 20, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride were weighed according to the dosages in Table 7, and a pharmaceutical composition was prepared by the following steps: [Table 9]

[0102] Step 1: Preparation of buffer solution: The prescribed amounts of polysorbate 20, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium chloride were weighed out and dissolved in an appropriate amount of water by stirring.

[0103] Step 2: The prescribed amount of compound A was added, and the buffer solution obtained in Step 1 was diluted to 1 / 20 of the total preparation volume. The mixture was stirred uniformly and sheared using a high-speed shearing machine T50 (shearing speed: approximately 5000 rpm) for 2 to 6 minutes, then sterilized to produce a thick suspension.

[0104] Step 3: The buffer solution obtained in Step 1 was added to the thick suspension of Step 2, mixed, adjusted to volume, and sheared for 10 to 30 minutes using a high-speed shearing machine T50.

[0105] The stability of the above formulations 12 to 14 was investigated under different conditions, and the data are shown in Table 8. [Table 10-1] [Table 10-2]

[0106] Note: Data for this batch may vary widely and may not be accurate.

[0107] Using a breathing simulator (model: Copley BRS2100) and a spray pump (model: PARI TurboBOY), we simulated adult breathing (simulation parameters: tidal volume 500 mL, respiratory frequency 15 cycles / min, respiratory waveform sinusoidal, respiratory ratio 1:1) and measured the FPF of prescription 12, which was 44.1%.

Claims

1. The active ingredient is 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof, and polysorbate 80. Pharmaceutical compositions.

2. The concentration of the active ingredient is 0.01 to 40 mg / mL, preferably 0.05 to 20 mg / mL; The pharmaceutical composition of claim 1.

3. The method further comprises a buffer solution, and the buffer solution is preferably a citrate buffer solution, a phosphate buffer solution, or an acetate buffer solution, more preferably a phosphate buffer solution, and most preferably a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution. The pharmaceutical composition according to claim 1 or 2.

4. The concentration of polysorbate 80 is 0.05 to 5.0 mg / mL, preferably 0.08 to 0.5 mg / mL. The pharmaceutical composition according to any one of claims 1 to 3.

5. The concentration of the buffer solution is 1 to 50 mM, preferably 5 to 30 mM. The pharmaceutical composition according to any one of claims 1 to 4.

6. the pH of the composition is 3.0 to 8.0; The pharmaceutical composition according to any one of claims 1 to 5.

7. Further comprising a sorbitan fatty acid ester, The pharmaceutical composition according to any one of claims 1 to 6.

8. the active ingredient is present as particles, the particles having a particle size D90 of less than 7 μm, preferably 1.0 to 5.0 μm, for example 3.0 μm or 3.2 μm; The pharmaceutical composition according to any one of claims 1 to 7.

9. 1. A pharmaceutical composition comprising: a) 0.05 to 40 mg / mL of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof; b) 0.05 to 2.0 mg / mL of polysorbate 80; and c) 1 to 50 mM buffer; Pharmaceutical compositions.

10. The present invention comprises particles of the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicament salt thereof, wherein the particle size D90 of the active ingredient particles is less than 7 μm, preferably 1.0 to 5.0 μm, for example, 3.0 μm or 3.2 μm; Pharmaceutical compositions.

11. further comprising a tonicity adjusting agent, preferably sodium chloride; The pharmaceutical composition according to any one of claims 1 to 10.

12. Suitable for administration by nebulizer, The pharmaceutical composition according to any one of claims 1 to 11.

13. A method for preparing the pharmaceutical composition according to any one of claims 1 to 12, comprising the steps of milling, wet-milling, homogenizing, precipitating or shearing the active ingredient 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof; method.

14. A method for preparing a lyophilized formulation comprising 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof, the method comprising the step of lyophilizing the pharmaceutical composition according to any one of claims 1 to 12. method.

15. 15. The pharmaceutical composition of claim 14, comprising 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof. Lyophilized formulation.

16. 16. A method for preparing a reconstituted solution containing 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a medicament salt thereof, comprising the step of reconstituting the lyophilized formulation according to claim 15, wherein the liquid medium used for reconstitution is preferably water for injection. method.

17. 17. The pharmaceutical composition of claim 16, comprising 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]-isoquinolin-4-one or a pharmaceutically acceptable salt thereof. Reconstitution solution.

18. The pharmaceutical composition according to any one of claims 1 to 12, the lyophilized formulation according to claim 15, or the reconstituted solution according to claim 17. Nebulizer.

19. Use of the pharmaceutical composition according to any one of claims 1 to 12, the lyophilized formulation according to claim 15 or the reconstituted solution according to claim 17 in the preparation of a medicament for the prevention and / or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism, preferably obstructive pulmonary disease. use.

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