CN-121987634-A - Preparation containing heterocyclic compound or compound formed by heterocyclic compound and pharmaceutically acceptable salt, preparation method and application thereof

CN121987634ACN 121987634 ACN121987634 ACN 121987634ACN-121987634-A

Abstract

The invention relates to a preparation containing heterocyclic compounds or a compound formed by the heterocyclic compounds and pharmaceutically acceptable salts, a preparation method and application thereof. The preparation comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the content of the active ingredient is 1-50wt%, the active ingredient is a compound shown in a formula I-3B or a compound thereof, and the compound shown in the formula I-3B is a compound formed by the compound shown in the formula I-3B and pharmaceutically acceptable acid. The application comprises the preparation of a 15-PGDH inhibitor and/or the preparation of a medicament, a pharmaceutical composition or a preparation for preventing and/or treating 15-PGDH related diseases. 。

Inventors

WANG WEI
PAN XIAOLING
WU YUNJIE
Zong qiao
LIU LIFEI
AN DAN
YIN SHANSHAN

Assignees

湖北生物医药产业技术研究院有限公司

Dates

Publication Date: 20260508
Application Date: 20251107
Priority Date: 20241107

Claims (10)

1. A preparation containing heterocyclic compound or a complex formed by the heterocyclic compound and pharmaceutically acceptable salt is characterized by comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the content of the active ingredient is 1-50 wt%; ; the active ingredient is a compound shown in the formula I-3B or a compound thereof, and the compound shown in the formula I-3B is a compound formed by the compound shown in the formula I-3B and pharmaceutically acceptable acid.
2. Formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 1, characterized in that it fulfils one or more of the following conditions: (1) The pharmaceutically acceptable acid is hydrochloric acid, phosphoric acid, fumaric acid, tartaric acid, malic acid, ethanedisulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or oxalic acid, preferably fumaric acid, and (2) The compound shown in the formula I-3B or the compound thereof is amorphous or a crystal form thereof; (3) The formulation is for use in the treatment or prophylaxis of a 15-PGDH-associated disease, preferably idiopathic pulmonary fibrosis, liver regeneration, liver injury or inflammatory bowel disease, preferably crohn's disease or ulcerative colitis, crohn's disease being selected from one or more of ileitis, gastroduodenal crohn's disease, jejunum ileitis and crohn's disease granulomatous colitis, ulcerative colitis preferably being selected from one or more of ulcerative proctitis, ulcerative proctositis, left half-colitis and full colitis.
3. The preparation containing a heterocyclic compound or a compound formed by the heterocyclic compound and a pharmaceutically acceptable salt according to claim 1, wherein the compound shown in the formula I-3B is a compound fumaric acid compound shown in the formula I-3B, and the mol ratio of fumaric acid to the compound shown in the formula I-3B is preferably 1:1, and preferably the compound shown in the formula I-3B is fumaric acid eutectic.
4. A formulation comprising a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described in claim 1 or 3, wherein the complex of the compound of formula I-3B is a crystalline form of the fumaric acid complex of the compound of formula I-3B, which satisfies one or more of the following conditions: (1) The crystal form of the fumaric acid compound shown in the formula I-3B has diffraction peaks at 20.5+/-0.2 o, 15.9+/-0.2 o, 26.6+/-0.2 o, 18.9+/-0.2 o and 22.5+/-0.2 o by using Cu-K alpha radiation and an X-ray powder diffraction pattern expressed in terms of a2 theta angle; Preferably, there are diffraction peaks at one or more of 22.3.+ -. 0.2o, 26.4.+ -. 0.2o, 10.8.+ -. 0.2o, 17.4.+ -. 0.2o and 17.5.+ -. 0.2o; Further preferably, there are diffraction peaks at 20.5.+ -. 0.2o, 15.9.+ -. 0.2o, 26.6.+ -. 0.2o, 18.9.+ -. 0.2o, 22.5.+ -. 0.2o, 22.3.+ -. 0.2o and 26.4.+ -. 0.2 o; Still more preferably, there are diffraction peaks at 20.5.+ -. 0.2o, 15.9.+ -. 0.2o, 26.6.+ -. 0.2o, 18.9.+ -. 0.2o, 22.5.+ -. 0.2o, 22.3.+ -. 0.2o, 26.4.+ -. 0.2o, 10.8.+ -. 0.2o, 17.4.+ -. 0.2o and 17.5.+ -. 0.2 o; for example, having diffraction peaks as shown in the following table: ; further for example, the X-ray powder diffraction pattern thereof is shown in fig. 2; (2) The crystalline form of the fumaric acid compound shown in the formula I-3B has a differential scanning calorimetric curve with a starting point of an endothermic peak at 165.2+/-3 ℃ and/or can reach the peak value of the endothermic peak at 167.2 +/-3 ℃; for example, the differential scanning calorimetric curve thereof is shown in fig. 3; (3) The crystal form of the fumaric acid compound shown in the formula I-3B has a thermogravimetric analysis curve with weight loss of 0.36% in the temperature range of 26.2+/-3 ℃ to 120+/-3 ℃; For example, the thermogravimetric analysis curve is shown in fig. 3; (4) The crystalline form of the compound fumaric acid complex of formula I-3B has the following unit cell parameters of orthorhombic system, space group P2 1 2 1 2 1 , a= 6.4400 (4) A, alpha=90°, b= 11.9376 (8) A, beta=90°, c= 33.139 (2) A, gamma=90°, unit cell volume= 2547.7 (3) A 3 , asymmetric unit number Z=4 in unit cell, crystal density of 1.451 mg/m 3 , and (5) The crystal form of the compound fumaric acid complex shown in the formula I-3B is a single crystal of the compound fumaric acid complex shown in the formula I-3B.
5. Formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 1, characterized in that it fulfils one or more of the following conditions: (1) The active ingredient is present in an amount of 8wt% to 10wt%, for example 9wt% or 9.03wt%; (2) D90 of the active ingredient is less than or equal to 100 μm, for example d90=76.3 to 87 μm; (3) The pharmaceutically acceptable carrier comprises a first filler, preferably one or more of microcrystalline cellulose, lactose and pregelatinized starch, the first filler being present in an amount of 5wt% to 30wt%, preferably 15wt% to 25wt%, for example 20wt%; (4) The pharmaceutically acceptable carrier comprises a second filler, preferably selected from one or more of mannitol, lactose and pregelatinized starch, the second filler being present in an amount of 10wt% to 80wt%, preferably 60wt% to 70wt%, for example 61.47wt%, 61.5wt% or 61.97 wt%; (5) The pharmaceutically acceptable carrier comprises a binder, preferably one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone, preferably in an amount of 1wt% to 5wt%, for example 3wt%; (6) The pharmaceutically acceptable carrier may comprise a disintegrant, preferably one or more selected from croscarmellose sodium, crospovidone, croscarmellose calcium and sodium carboxymethyl starch, preferably in an amount of 2wt% to 8wt%, for example 5wt%; (7) The pharmaceutically acceptable carrier comprises a lubricant, preferably one or more selected from magnesium stearate, stearic acid, sodium stearyl fumarate, docusate sodium and calcium stearate, preferably in an amount of 0.5wt% to 2wt%, more preferably 1wt% to 2wt%, for example 1wt% or 1.5wt%, and (8) The preparation of the preparation containing the heterocyclic compound or the compound formed by the heterocyclic compound and the pharmaceutically acceptable salt is tablet or capsule.
6. The formulation comprising a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described in claim 5, which satisfies the following conditions: (1) The composition comprises the following components, by weight, 1% -50% of active ingredients, 5% -30% of first filler, 10% -80% of second filler, 1% -5% of adhesive, 2% -8% of disintegrating agent and 1% -2% of lubricant; (2) The compound comprises 9.03 weight percent of fumaric acid eutectic of a compound shown in a formula I-3B, 20 weight percent of microcrystalline cellulose, 61.47 weight percent of mannitol, 3 weight percent of hydroxypropyl cellulose, 5 weight percent of croscarmellose sodium and 1.5 weight percent of magnesium stearate; (3) The compound comprises 9.03wt% of fumaric acid eutectic crystal of a compound shown in a formula I-3B, 20wt% of microcrystalline cellulose, 61.97wt% of mannitol, 3wt% of hydroxypropyl cellulose, 5wt% of croscarmellose sodium and 1wt% of magnesium stearate.
7. A method for preparing a formulation comprising a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described in any one of claims 1 to 6, which comprises the steps of: S1, mixing a first mixture and a second mixture under a first stirring state to obtain a granulating mixture, wherein the first mixture comprises a first filler, a disintegrating agent, an active ingredient and a second filler, and the second mixture comprises a binder and water; s2, granulating the granulating mixture in a second stirring state, and then drying to obtain dry granules; S3, filling a third mixture into the hollow capsule, wherein the third mixture comprises a lubricant and the dry particles.
8. The method for preparing a formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 7, wherein one or more of the following conditions are satisfied: (1) In the step S1, the stirring speed in the first stirring state is 100-300 r/min, for example 180 r/min; (2) In the step S1, the cutter speed in the first stirring state is 500-2500 r/min, for example 1000 r/min; (3) In step S1, the active ingredient is as defined in any one of claims 1 to 5; (4) In step S1, the first filler is as defined in claim 5; (5) In step S1, the second filler is as defined in claim 5; (6) In step S1, the disintegrant is as defined in claim 5; (7) In step S1, the adhesive is as defined in claim 5; (8) In the step S2, the stirring speed of the second stirring state is 100-300 r/min, for example 200 r/min; (9) In the step S2, the cutter speed in the second stirring state is 500-2500 r/min, for example 1500 r/min; (10) In step S2, the granulation time is 0.5-3 min, e.g. 1 min; (11) In the step S2, the drying is carried out by adopting a fluidized bed, the inlet air temperature of the drying is preferably 50-80 ℃, such as 65 ℃, and the fluidization air quantity of the drying is preferably 20-140 m 3 /h; (12) In the step S2, the material is dried until the LOD of the material is less than or equal to 3.0 percent; (13) In the step S2, wet granule finishing can be performed before drying, wherein the wet granule finishing is preferably performed by using a screen of 5.0 mm ×5.0 mm, and the vibration frequency of the wet granule finishing is preferably 25+ -10 Hz; (14) In step S2, the drying may be followed by a dry granule finishing, wherein the dry granule finishing is preferably performed by using a 0.8-1.2 mm screen, for example, a 1.2 mm and/or 1 mm and/or 0.8 mm screen, and the vibration frequency of the dry granule finishing is preferably 25+/-10 Hz; (15) In step S3, the content of the third mixture is 95.0% -105.0% of the marked amount based on HPLC method and calculated as C 22 H 22 F 2 N 6 O 2 ; (16) In step S3, the lubricant is as defined in claim 5; (17) In step S3, the filling is carried out in an amount of 63-77 mg/granule, preferably 65.1-74.9 mg/granule or 325.5-374.5 mg/granule, and (18) In the step S3, the filling speed is 5000-20000 grains/hour.
9. Use of a formulation comprising a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described in any one of claims 1-6, in the preparation of a 15-PGDH inhibitor and/or in the preparation of a medicament, pharmaceutical composition or formulation for the prophylaxis and/or treatment of a 15-PGDH-associated disease.
10. The use of a formulation comprising a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 9, wherein the 15-PGDH-associated disease is idiopathic pulmonary fibrosis, liver regeneration, liver injury or inflammatory bowel disease, preferably crohn's disease or ulcerative colitis, crohn's disease being selected from one or more of ileitis, gastroduodenal type crohn's disease, jejunum ileitis and crohn's disease granulomatous colitis, ulcerative colitis preferably being selected from one or more of ulcerative proctitis, left half-colitis and ulcerative colitis.

Description

Preparation containing heterocyclic compound or compound formed by heterocyclic compound and pharmaceutically acceptable salt, preparation method and application thereof Technical Field The invention relates to a preparation containing heterocyclic compounds or a compound formed by the heterocyclic compounds and pharmaceutically acceptable salts, a preparation method and application thereof. Background The 15-hydroxy prostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4, 4q 34-q 35, with a span of about 31kb, 7 exons in total, and a molecular weight of 29kD.15-PGDH consists of 266 amino acids, belongs to the family of short-chain dehydrogenases (SDR-chain dehydrogenases), and consists of two identical subunits forming a dimer, but it is also considered that it is enzymatically active in the presence of monomers. 15-PGDH is a key enzyme for degradation and inactivation of Prostaglandins (PGs) and related eicosanoids, and is widely found in normal tissues such as the lung, kidney, gastrointestinal tract, thyroid gland, prostate gland and placenta of humans and mammals, and can catalyze the oxidation of active 15-hydroxy Prostaglandins to 15-keto Prostaglandins with greatly reduced activity on the one hand, and degrade polycyclic aromatic hydrocarbons other than Prostaglandins in the presence of NAD + coenzyme factors, and reduce the generation of carcinogens and pro-carcinogens under physiological or pathological conditions through oxidation reactions. Chinese patent application number 202211449273.5 describes heterocyclic compounds having 15-PGDH inhibitory activity: 。 The heterocyclic compound is chemically named as 7- (6- (4, 4-difluoropiperidine-1-carbonyl) -1,1a,2,7 b-tetrahydro-3H-cyclopropa [ c ] [1,8] naphthyridin-3-yl) -2-methyl- [1,2,4] triazolyl [4,3-a ] pyridin-3 (2H) -one (numbered I-3), and the structure comprises the following 2 isomers: 。 The chinese patent application 202410557122.4 describes fumaric acid complexes of heterocyclic compounds with 15-PGDH inhibitory activity, on the basis of which it is necessary to develop suitable dosage forms in order to obtain products suitable for development and industrialization, on the basis of good biological activity. Disclosure of Invention The invention provides a preparation containing heterocyclic compounds or a compound formed by the heterocyclic compounds and pharmaceutically acceptable salts, a preparation method and application thereof, and aims to solve the defects in the prior art. In order to achieve the above purpose, the present invention adopts the following technical scheme: in a first aspect, the invention provides a preparation containing heterocyclic compounds or complexes formed by the heterocyclic compounds and pharmaceutically acceptable salts, which comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the content of the active ingredient is 1-50 wt%; 。 The active ingredient is a compound shown in the formula I-3B or a compound thereof, and the compound is a compound formed by the compound shown in the formula I-3B and pharmaceutically acceptable acid. In the preparation containing the heterocyclic compound or the compound formed by the heterocyclic compound and the pharmaceutically acceptable salt, the content weight percent of each substance refers to the ratio of the weight of the substance to the total weight of the preparation. In the present invention, the pharmaceutically acceptable acid is hydrochloric acid, phosphoric acid, fumaric acid, tartaric acid, malic acid, ethanedisulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or oxalic acid, preferably fumaric acid. In the present invention, the preparation may be a preparation for treating or preventing 15-PGDH-related diseases, preferably idiopathic pulmonary fibrosis, liver regeneration, liver injury or inflammatory bowel disease, preferably Crohn's disease or ulcerative colitis, crohn's disease is selected from one or more of ileitis, gastroduodenal Crohn's disease, jejunum's disease and Crohn's disease granulomatous colitis, and ulcerative colitis is preferably selected from one or more of ulcerative proctitis, ulcerative proctositis, left half-colitis and full colitis. In the present invention, the compound represented by the formula I-3B or a complex thereof may be amorphous or a crystalline form thereof. In the invention, the compound shown in the formula I-3B is the compound fumaric acid compound shown in the formula I-3B. In the fumaric acid compound of the formula I-3B, the molar ratio of the compound of the formula I-3B to fumaric acid is preferably 1:1. The compound fumaric acid compound shown in the formula I-3B is preferably a compound fumaric acid eutectic shown in the formula I-3B. In the invention, the compound shown in the formula I-3B is a crystal form of a fumaric acid compound shown in the formula I-3B. The crystal form of the compound fumaric acid compound shown in the formula I