X842 Preparation

Abstract

The present disclosure provides a pharmaceutical formulation for oral administration comprising a solid dispersion comprising amorphous X842 and a water-soluble amphiphilic carrier.

Description

[Technical field]

[0001] The present disclosure relates to the field of treatment of gastrointestinal inflammatory or gastric acid related diseases, and in particular to a solid dispersion (SD) of X842 developed for this purpose. [Background technology]

[0002] WO 2010 / 063876 discloses that the compound 5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid, often referred to as X842, is a potent inhibitor of gastric secretion.

[0003] X842 has the following formula: [ka] has.

[0004] US2022002297 discloses two crystalline forms of X842 and states that for use in pharmaceutical formulations, it is desirable for the active pharmaceutical ingredient (API) to be in a highly crystalline form.

[0005] However, the solubility of X842 is very low, making it difficult to prepare an effective oral formulation of X842. Summary of the Invention

[0006] It is an object of the present disclosure to overcome the solubility problems of X842, thereby facilitating effective treatment with this agent.

[0007] The inventors have found that this objective is achieved by a solid dispersion of X842 and a carrier, wherein the solid dispersion X842 has an amorphous morphology.

[0008] Accordingly, this disclosure provides the following itemized list of embodiments: 1. A pharmaceutical formulation for oral administration comprising a solid dispersion comprising amorphous X842 and a water-soluble amphiphilic carrier. 2. The pharmaceutical formulation described in item 1, wherein the carrier is a polymeric carrier. 3. The pharmaceutical formulation described in item 2, wherein the polymer carrier comprises vinylcaprolactam. 4. The pharmaceutical formulation of paragraph 2 or 3, wherein the polymeric carrier comprises vinyl acetate. 5. The pharmaceutical formulation according to any one of items 2 to 4, wherein the average molecular weight of the polymeric carrier is in the range of 40,000 to 250,000 g / mol as determined by gel permeation chromatography. 6. The pharmaceutical formulation according to item 5, wherein the average molecular weight of the polymer carrier is in the range of 80,000 to 150,000 g / mol as determined by gel permeation chromatography. 7. The pharmaceutical formulation according to any one of the preceding claims, wherein the dry weight ratio of X842 to the carrier is from 2:1 to 1:20, such as from 1:2 to 1:10, for example from 1:1 to 1:10, such as from 1:2 to 1:7, for example from 1:3 to 1:7, for example from 1:3 to 1:5. 8. The pharmaceutical formulation of any one of the preceding claims, wherein the solid dispersion is formed by spray drying. 9. The pharmaceutical formulation according to item 8, obtained by spray drying a solution of X842 and said carrier. 10. The pharmaceutical formulation according to item 9, wherein the solid dispersion is obtained by spray drying a solution of X842 and a carrier in an organic solvent. The organic solvent is any solvent suitable for spray drying X842, preferably absolute ethanol, methanol, acetone, tetrahydrofuran, dimethylsulfoxide and chloroform. 11. A pharmaceutical formulation according to any preceding claim, which is in unit dose form. . 12. The pharmaceutical formulation according to item 11, wherein the amount of amorphous X842 in a unit dose is 10 to 100 mg, for example 10 to 60 mg, for example 10 to 40 mg, for example 10 to 25 mg, for example 10 to 24 mg. 13. The pharmaceutical formulation according to any one of items 1 to 12, for use in a method for treating a gastrointestinal inflammatory disease or a gastric acid-related disease, such as erosive gastroesophageal reflux disease (eGERD). 14. A solid dispersion comprising amorphous X842 and a water-soluble amphiphilic carrier, the solid dispersion being obtained by spray drying a solution of X842 and the carrier. 15. The solid dispersion according to item 14, wherein the solution is a solution of X842 and a carrier in an organic solvent. The organic solvent is any solvent suitable for spray drying X842, preferably absolute ethanol, methanol, acetone, tetrahydrofuran, dimethylsulfoxide and chloroform. 16. The solid dispersion according to item 14 or 15, wherein the nozzle temperature is in the range of 55 to 99°C, for example, in the range of 65 to 95°C, for example, in the range of 70 to 85°C, during the spray drying. 17. The solid dispersion according to any one of items 14 to 16, wherein the temperature of the solution supplied to the nozzle during spray drying is in the range of 25 to 99°C, for example, in the range of 55 to 99°C, for example, in the range of 65 to 95°C, for example, in the range of 70 to 85°C. 18. The pharmaceutical formulation according to any one of items 1 to 13 or the solid dispersion according to any one of items 14 to 17, which has a shelf life of 3 months or more, preferably 6 months or more, more preferably 12 months or more. 19. The pharmaceutical formulation according to any one of items 1 to 13 or the solid dispersion according to any one of items 14 to 17, which has a higher oral bioavailability than crystalline X842. 20. AUC or C max The pharmaceutical formulation according to any one of Items 1 to 13 or the solid dispersion according to any one of Items 14 to 17, wherein the oral bioavailability of the pharmaceutical formulation according to any one of Items 1 to 13 is 1.2-fold or more, 1.5-fold or more, 2-fold or more, preferably 3-fold or more, more preferably 6-fold or more than that of crystalline X842. 21. The solid dispersion according to any one of items 14 to 20, for use in a method for treating a gastrointestinal inflammatory disease or a gastric acid-related disease, such as erosive gastroesophageal reflux disease (eGERD). 22. A tablet or capsule comprising the pharmaceutical formulation according to any one of items 1 to 13 and items 18 to 20 or the solid dispersion according to any one of items 14 to 20. 23. The tablet or capsule according to claim 22, further comprising a disintegrant, such as polyvinylpolypyrrolidone. 24. A tablet or capsule according to paragraph 22 or 23, wherein the dry weight ratio of disintegrant to X842 is at least 1.1:1, such as at least 1.4:1, such as at least 1.7:1, for example at least 2:1, such as at least 2.8:1. 25. The tablet or capsule of any one of paragraphs 22 to 24, further comprising a cellulose excipient, such as microcrystalline cellulose (MCC). 26. The tablet or capsule according to any one of items 22 to 25, further comprising lactose. 27. The tablet or capsule according to any one of items 22 to 26, wherein the tablet or capsule has a shelf life of 3 months or more, preferably 6 months or more, more preferably 12 months or more. 28. The tablet or capsule according to any one of items 22 to 27, having a higher oral bioavailability than a X842 capsule containing crystalline X842. 29. AUC or C max The tablet or capsule according to any one of items 22 to 28, wherein the oral bioavailability of the compound is 1.2 times or more, 1.5 times or more, 2 times or more, preferably 3 times or more, and more preferably 6 times or more, of the compound containing crystalline X842 in the X842 capsule. 30. Use of the pharmaceutical formulation according to any one of paragraphs 1 to 13 and 18 to 20 in the manufacture of a medicament for treating a gastrointestinal inflammatory disease or a gastric acid-related disease, such as erosive gastroesophageal reflux disease (eGERD). 31. Use of the solid dispersion according to any one of paragraphs 14 to 20 in the preparation of a medicament for treating a gastrointestinal inflammatory disease or a gastric acid-related disease, such as erosive gastroesophageal reflux disease (eGERD). [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows the solubility of X842 in mixtures or solid dispersions (formed by the solvent method) containing different carriers at different mass ratios (see Example 1 below).

[0010] [Diagram 2] Figure 2 shows the X842 solubility measurements of various solid dispersions and physical mixtures. "Sol" means Soluplus.

[0011] [Diagram 3] FIG. 3 shows the PXRD diffractograms of three different solid dispersions (prepared by spray drying, hot melt extrusion (HME) and solvent methods), the physical mixture, Soluplus and X842.

[0012] [Figure 4] Figures 4 and 5 are PXRD diffractograms of Samples 3.1-3.11 (the preparation of these samples is described in the Examples section below).

[0013] [Diagram 5] Figures 4 and 5 are PXRD diffractograms of Samples 3.1-3.11 (the preparation of these samples is described in the Examples section below).

[0014] [Figure 6] Figures 6 and 7 are PXRD diffractograms of samples 3.12-3.18 (the preparation of these samples is described in the Examples section below).

[0015] [Figure 7] Figures 6 and 7 are PXRD diffractograms of samples 3.12-3.18 (the preparation of these samples is described in the Examples section below).

[0016] [Figure 8] FIG. 8 shows the X842 solubility measurements for samples 3.12, 3.13, 3.16, 3.17 (solid dispersions formed by spray drying), and samples 3.15 and 3.18 (physical mixtures).

[0017] [Figure 9] FIG. 9 shows the dissolution of X842 from tablets formed from Compositions 1-4 (the preparation of these tablets is described in the Examples section below) and a reference capsule.

[0018] [Figure 10] FIG. 10 shows the results of a stability experiment in which the solid dispersion powder was left to stand at room temperature for six months.

[0019] [Figure 11] FIG. 11 shows the results of a stability experiment in which solid dispersion tablets were left to stand at room temperature for three months.

[0020] [Figure 12] FIG. 12 and FIG. 13 show the pharmacokinetic parameter results of the solid dispersion tablet and the reference capsule in beagle dogs.

[0021] [Figure 13] FIG. 12 and FIG. 13 show the pharmacokinetic parameter results of the solid dispersion tablet and the reference capsule in beagle dogs.

[0022] Detailed Description In the context of the present invention, "shelf life" means the shelf life of a drug during which 10% or less of the drug is degraded.

[0023] In the context of the present invention, "crystalline X842" refers to the state in which X842 exists in a stable crystalline form, as opposed to an amorphous state, and such "crystalline X842" is, for example, Forms A and B, particularly Form A, as disclosed in US2022002297A1.

[0024] As a first aspect of the present disclosure, a pharmaceutical formulation for oral administration is provided.The formulation comprises a solid dispersion comprising amorphous X842 and a water-soluble amphiphilic carrier.This formulation promotes the rapid dissolution of X842, and therefore can be referred to as an immediate release pharmaceutical formulation.

[0025] The carrier is typically a polymer. In one embodiment, the polymer carrier comprises vinyl caprolactam and / or vinyl acetate. Preferably, the polymer carrier comprises vinyl caprolactam and vinyl acetate.

[0026] The average molecular weight of the polymer carrier (measured by gel permeation chromatography) is preferably in the range of 40,000 to 250,000 g / mol, more preferably in the range of 80,000 to 150,000 g / mol.

[0027] An example of a polymeric support comprising vinyl caprolactam and vinyl acetate and having an average molecular weight in the range of 80,000 to 150,000 g / mol (as determined by gel permeation chromatography) is Soluplus from BASF.

[0028] The dry weight ratio of X842 to the carrier is preferably 2:1 to 1:20, preferably 1:1 to 1:10, more preferably 1:1 to 1:10, more preferably 1:2 to 1:7, more preferably 1:3 to 1:7, and most preferably 1:3 to 1:5.

[0029] In an embodiment of the first aspect, the solid dispersion is formed by spray drying.Typically, the solid dispersion is obtained by spray drying a solution of X842 and carrier.The solution can be, for example, an ethanol solution.Further embodiments of spray drying are described below in relation to the third aspect.

[0030] The pharmaceutical preparation of the first aspect can be, for example, in the form of a unit dose. In such a unit dose, the amount of amorphous X842 can be 10-100 mg, for example 10-60 mg, for example 10-40 mg, for example 10-25 mg, for example 10-24 mg. Efficient dissolution of X842 means that the amount of X842 is relatively small.

[0031] In a second aspect of the present disclosure, the pharmaceutical formulation of the first aspect is provided for use in a method for treating a gastrointestinal inflammatory disease or a gastric acid-related disease, such as erosive gastroesophageal reflux disease (eGERD), in which the pharmaceutical formulation is intended to be administered orally.

[0032] As a third aspect of the present disclosure, there is provided a solid dispersion comprising amorphous X842 and a water soluble amphiphilic carrier, said solid dispersion being obtained by spray drying a solution of X842 and the carrier, such as an ethanol solution.

[0033] During the spray drying, the nozzle temperature may be, for example, in the range of 55 to 99° C., for example, in the range of 65 to 95° C., for example, in the range of 70 to 85° C. Furthermore, the temperature of the solution supplied to the nozzle during the spray drying is in the range of 25 to 99° C., for example, in the range of 55 to 99° C., for example, in the range of 65 to 95° C., for example, in the range of 70 to 85° C. When the solution is an ethanol solution, the nozzle temperature and the temperature of the solution supplied to the nozzle are preferably in the range of 65 to 78° C., more preferably in the range of 65 to 75° C.

[0034] Additionally, the embodiments and examples of the first aspect also apply mutatis mutandis to the third aspect.

[0035] In a fourth aspect of the present disclosure, the solid dispersion of the third aspect is provided for use in a method of treating a gastrointestinal inflammatory disease or a gastric acid-related disease, such as eGERD, wherein said solid dispersion is intended to be administered orally.

[0036] In a fifth aspect of the present disclosure, there is provided a tablet or capsule comprising the pharmaceutical formulation of the first aspect or the solid dispersion of the third aspect.

[0037] Said tablet or capsule may comprise disintegrant, for example non-cellulose disintegrant.Preferred example of non-cellulose disintegrant is polyvinylpolypyrrolidone.The dry weight ratio of disintegrant to X842 is typically at least 1.1:1, for example at least 1.4:1, preferably at least 1.7:1, for example at least 2:1, for example at least 2.8:1.The upper limit of this dry weight ratio may be 4:1.

[0038] In one embodiment, the tablet or capsule further comprises a cellulose excipient and / or lactose. The cellulose excipient may be, for example, MCC.

[0039] The amount of amorphous X842 in the tablet or capsule may be from 10 to 100 mg, such as from 10 to 60 mg, for example from 10 to 40 mg, for example from 10 to 25 mg, for example from 10 to 24 mg.

[0040] As a sixth aspect of the present disclosure, the tablet or capsule of the fifth aspect is provided for use in a method for treating a gastrointestinal inflammatory disease or a gastric acid-related disease, such as eGERD. The method of treatment of the present invention contemplates oral administration of the tablet or capsule.

[0041] The subject of the above-mentioned therapeutic methods is preferably a human.

[0042] As a seventh aspect of the present disclosure, there is provided use of the pharmaceutical formulation of the first aspect or the solid dispersion of the third aspect, or the tablet or capsule of the fifth aspect for preparing a medicament for treating a gastrointestinal inflammatory disease or a gastric acid related disease, such as erosive gastroesophageal reflux disease (eGERD).

[0043] In an eighth aspect of the present disclosure, after leaving the solid dispersion powder of the third aspect at room temperature for 3 months or more, preferably 6 months or more, more preferably 12 months or more, its PXRD shows that it remains amorphous and stable.

[0044] In a ninth aspect of the present disclosure, after a tablet or capsule of the solid dispersion of the fifth aspect is left at room temperature for 3 months or more, preferably 6 months or more, more preferably 12 months or more, its dissolution rate remains essentially the same and stable.

[0045] In a tenth aspect of the present disclosure, a tablet or capsule of the solid dispersion of the fifth aspect is orally administered, followed by measuring the AUC or C max The oral bioavailability of the solid dispersion tablet or capsule is higher than that of the X842 capsule containing crystalline X842. For example, the oral bioavailability of the solid dispersion tablet or capsule is 1.2 times or more than that of the X842 capsule, 2 times or more than that of the X842 capsule, preferably 3 times or more than that of the X842 capsule, more preferably 6 times or more than that of the X842 capsule. For example, the AUC of the solid dispersion tablet or capsule of the fifth embodiment is 1.2 times or more than that of the X842 capsule, 2 times or more than that of the X842 capsule, preferably 3 times or more than that of the X842 capsule, more preferably 6 times or more than that of the X842 capsule. For example, the C of the solid dispersion tablet or capsule of the fifth embodiment is 1.2 times or more than that of the X842 capsule, 2 times or more than that of the X842 capsule, preferably 3 times or more than that of the X842 capsule, more preferably 6 times or more than that of the X842 capsule. max is 1.2 times or more, 2 times or more, preferably 3 times or more, more preferably 6 times or more than that of X842 capsule. EXAMPLES

[0046] Example 1 Solid dispersions of X842 and different carriers (in different ratios) were prepared by the solvent method and the solubility at pH 6.8 was measured.

[0047] X842 (API) and carrier were placed in a 250 mL beaker, and then about 150 mL of absolute ethanol was added. The amount of API was about 70 mg, and the dry weight ratio of API to carrier was 1:3, 1:5, or 1:10. The carriers were PVP / VA64 (Poly-(vinylpyrrolidone-co-vinyl acetate) from BASF), PVP K30 (Polyvinylpyrrolidone K30 ((C6H9NO) from BASF). n )), Affinisol-15 LV(HPMC), plasdone TM The APIs were dissolved in ethanol using ethanol as the bases, and the APIs were dissolved in ethanol as the bases. The APIs were dissolved in ethanol using ethanol as the bases. The ...

[0048] The solution was added to a porcelain dish and placed in an 80° C. water bath to evaporate the solvent. The solid residue was placed in a vacuum drying oven at 40° C. for 24 h. The dried residue was finely ground through a 65 mesh sieve.

[0049] As a reference, physical mixtures of API and each carrier were prepared in a dry weight ratio of 1:10.

[0050] The solubility of API in each solid dispersion and mixture was measured according to the following protocol. The solid dispersion / mixture was added to a 50 mL centrifuge tube, 20 mL of pH 6.80 phosphate buffer was added, and then shaken in a shaker at 25°C for 24 h (shaking speed: 130 r / min). Then, an appropriate amount of liquid was taken from the centrifuge tube and passed through a 0.22 μm microporous membrane. Finally, the solubility of X842 was determined using HPLC (n=3). The results are shown in Table 1 below and Figure 1.

[0051] [Table 1]

[0052] Notably, Table 1 shows that the Soluplus carrier is ineffective (compared to most other carriers) in physical mixtures with the API, but is superior to all other carriers in ratio-independent solid dispersions (see also Figure 1).

[0053] Example 2.1 A solid dispersion was prepared from X842 (17 wt.%) and Soluplus (83 wt.%) as follows:

[0054] 1 g of X842 and 5 g of Soluplus were mixed well to obtain a physical mixture. The hot melt extruder was opened and the extrusion temperature was set to 160°C (twin screw speed 100 rpm). After reaching temperature and stabilizing for 30 minutes, the physical mixture was hot melt extruded to obtain an extrusion strip. The hot melt extrusion strip was cooled and milled through a 65 mesh sieve to obtain a solid dispersion.

[0055] The solid dispersion was analyzed using powder X-ray diffraction (PXRD). Additionally, the solubility of X842 in the solid dispersion was tested, as described below.

[0056] Example 2.2 A solid dispersion was prepared from X842 (17 wt.%) and Soluplus (83 wt.%) as follows:

[0057] 1 g of X842 and 5 g of Soluplus were mixed well to obtain a physical mixture. The hot melt extruder was opened and the extruder temperature was set to 120° C. (twin screw speed 100 rpm). After reaching temperature and stabilizing for 30 minutes, the physical mixture was hot melt extruded to obtain extruded strips. The hot melt extruded strips were cooled and milled through a 65 mesh sieve to obtain a solid dispersion.

[0058] The solubility of X842 in solid dispersions was tested and is described below.

[0059] Example 2.3 A solid dispersion was prepared from X842 (17 wt.%), the polymer carrier polyvinyl alcohol (66 wt.%) and sorbitol (17 wt.%) as follows:

[0060] 1g of X842, 4g of polyvinyl alcohol (PVOH) and 1g of sorbitol were mixed well to obtain a physical mixture. The hot melt extruder was opened and the extrusion temperature was set to 190°C (twin screw speed 75 rpm). After reaching temperature and stabilizing for 30 minutes, the physical mixture was hot melt extruded to obtain an extrusion strip. The hot melt extrusion strip was cooled and milled through a 65 mesh sieve to obtain a solid dispersion.

[0061] The solubility of X842 in solid dispersions was tested and is described below.

[0062] Example 2.4 A solid dispersion was prepared from X842 (17 wt.%), the polymer carrier polyvinyl alcohol (41.5 wt.%), and sorbitol (41.5 wt.%) as follows:

[0063] 1g of X842, 4g of polyvinyl alcohol (PVOH) and 1g of sorbitol were mixed well to obtain a physical mixture. The hot melt extruder was opened and the extrusion temperature was set to 190°C (twin screw speed 75 rpm). After reaching temperature and stabilizing for 30 minutes, the physical mixture was hot melt extruded to obtain an extrusion strip. The hot melt extrusion strip was cooled and milled through a 65 mesh sieve to obtain a solid dispersion.

[0064] The solubility of X842 in solid dispersions was tested and is described below.

[0065] Example 2.5 A solid dispersion was prepared from X842 (17 wt.%) and Soluplus (83 wt.%) using spray drying method as follows:

[0066] 0.5 g of X842 and 2.5 g of Soluplus were added to absolute ethanol and heated to 70 °C in a water bath to completely dissolve the X842. The spray-drying apparatus was opened and the nozzle temperature was set to 75 °C. Once at temperature, the solution was pumped through the nozzle by a peristaltic pump (5–20 rpm) and spray-dried.

[0067] The solid dispersion was analyzed using powder X-ray diffraction (PXRD). Additionally, the solubility of X842 in the solid dispersion was tested, as described below.

[0068] Example 2.6 (Solubility Determination) The solubility of X842 was tested in the solid dispersions prepared in Examples 2.1-2.5, and in an X842 / Soluplus solid dispersion formed by the solvent method (dry weight ratio 1:5, see Example 1). A physical mixture of X842 and carrier was also tested as a reference.

[0069] 25 mg (measured as X842) of solid dispersion or physical mixture was added to 25 mL of pH 6.8 phosphate buffer to prepare a suspension containing approximately 1 mg / mL of X842. The suspension was shaken in a shaker (shaking speed: 130 rpm). 2 mL samples were taken after 1 h, 2 h, 4 h, 8 h and 24 h and filtered through a 0.22 μm micropore membrane. Methanol was added to dilute 2-fold or 10-fold (to achieve a concentration within the determined range). 10 μL was injected into the HPLC to determine the solubility.

[0070] The results, shown in Figure 2, indicate that the solid dispersion prepared according to Example 2.5 is significantly superior to other solid dispersions and physical mixtures.

[0071] Example 2.7 (PXRD) PXRD was performed to compare the solid dispersion of Example 2.5 (which has superior X842 solubility) with the solid dispersion of Example 2.1 (prepared by hot melt extrusion at 160° C.). Additionally, PXRD was also performed on the X842 / Soluplus solid dispersion formed by the solvent process (1:5 dry weight ratio, see Example 1), the X842 / Soluplus physical mixture (1:5 dry weight ratio), Soluplus alone, and X842 alone for further reference.

[0072] For the PXRD experiments, the instrument used was a Nippon Science Smartlab9kw, and the conditions were as follows: Cu target, Kα radiation (λ = 0.15406 nm), operating voltage and current were 45 kV and 100 mA, respectively, and scanning was performed at a rate of 4° / min in the 2θ range from 5° to 40°.

[0073] The resulting PXRD diffractograms shown in Figure 3 indicate that the crystallinity of X842 is preserved in the solid dispersions formed by hot melt extrusion and solvent methods, and in the physical mixtures. Furthermore, Figure 2 shows that these forms have poorer solubility of X842 compared to the solid dispersion formed by spray drying (Example 5.2). Finally, Figure 3 shows that X842 is amorphous in the solid dispersion formed by spray drying. Thus, Figures 2 and 3 show that a solid dispersion in which X842 is amorphous is key to the solubility of X842.

[0074] Example 3.1 (PXRD) A second round of PXRD was performed, which included the following samples: 3.1-Spray-dried (nozzle temperature = 75°C) solid dispersion of X842 and Soluplus in a 1:3 ratio; 3.2 - The solid dispersion of Example 2.5; 3.3 - Soluplus only; 3.4-Hot melt extrusion (T=175°C, 50 rpm) solid dispersion of X842 and Soluplus in a 1:5 ratio; 3.5-Hot melt extrusion (T=175°C, 50 rpm) solid dispersion of X842, Soluplus and mannitol in a ratio of 1:3:2; 3.6-Hot melt extrusion (T = 160°C, 30 rpm) solid dispersion of X842 and PVP / VA64 in a ratio of 1:5; 3.7-A physical mixture of X842 and Soluplus in a ratio of 1:5; 3.8-X842 only; 3.9-Spray-dried (nozzle temperature = 60°C, ethanol) solid dispersion of X842 and Soluplus in a 1:3 ratio; 3. Spray-dried (nozzle temperature = 90 °C, ethanol) solid dispersion of 10-X842 and Soluplus in a 1:3 ratio; and 3.11-Spray dried (nozzle temperature = 75°C, methanol) solid dispersion of X842 and Soluplus in a 1:3 ratio.

[0075] The resulting PXRD diffractograms, shown in Figures 4 and 5, again demonstrate that spray drying of the X842 / Soluplus solution produces a solid dispersion containing amorphous X842, whereas the hot melt extrusion solid dispersion contains crystalline X842.

[0076] Example 3.2 (PXRD) A third round of PXRD was performed, which included the following samples: 3. Spray-dried (nozzle temperature = 75°C) solid dispersion of 12-X842 and Soluplus in a 1:3 ratio; 3.13-Spray dried (nozzle temperature = 75°C) solid dispersion of X842, Soluplus and SiO2 in a 1:1:1 ratio; 3.14-SiO2 only; 3.15-X842, Soluplus and SiO2 physical mixture in a ratio of 1:1:1:1; 3. Spray-dried (nozzle temperature = 75 °C) solid dispersion of 16-X842 and Soluplus in a 1:1 ratio; and 3. Spray-dried (nozzle temperature = 75°C) solid dispersion of 17-X842 and Soluplus in a 1:5 ratio; 3. A physical mixture of 18-X842 and Soluplus in a ratio of 1:5.

[0077] The resulting PXRD diffractograms, shown in Figures 6 and 7, again demonstrate that spray drying of X842 / Soluplus solutions produces solid dispersions containing amorphous X842 not only in a 1:5 ratio, but also in ratios of 1:3 and 1:1.

[0078] Example 3.3 (Solubility Determination) The solubility of X842 in samples 3.12, 3.13, 3.15, 3.16 and 3.17 was measured according to the following:

[0079] A sample of 25 mg (measured as X842) was added to 25 mL of pH 6.8 phosphate buffer to prepare a suspension containing approximately 1 mg / mL of X842. The suspension was shaken in a shaker (shaking speed = 130 rpm, temperature = 25°C). After 1 h, 2 h, 4 h, 8 h and 24 h, 2 mL suspension samples were taken and filtered through a 0.22 μm micropore membrane. Methanol was added to 0.5 mL of the filtrate and diluted 10 or 2 times (to achieve a concentration within the determined range). 10 μL was injected into the HPLC to determine the solubility.

[0080] The results, shown in Figure 8, demonstrate that solid dispersions containing amorphous X842 dramatically improve the solubility of X842 compared to physical mixtures containing crystalline X842. Figure 8 further demonstrates that 1:5 and 1:3 ratios of X842 to Soluplus are more effective than a 1:1 ratio of X842 to Soluplus, with both the 1:3 and 1:5 ratios being highly effective among those tested.

[0081] Example 4.1 (Preparation of Tablets) Tablets were prepared from compositions containing various solid dispersions of X842 and Soluplus prepared by spray drying or hot melt extrusion, with each tablet weighing 350 mg and the amount of X842 in each tablet being 25 mg.

[0082] Composition 1 prepared by the following method: solid dispersion (prepared by spray drying), MicroceLac 100 (microcrystalline fiber and lactose in a ratio of 1:3), and silicon dioxide were placed in a self-sealing bag, mixed well, and then directly compressed into tablets (tablet thickness = 0.8-1.0 mm; tableting pressure = 4-6 kN; tablet hardness is 60-80 N). [Table 2]

[0083] Composition 2 prepared in the following manner: solid dispersion (prepared by hot melt extrusion), MicroceLac 100 (microcrystalline cellulose and lactose in a ratio of 1:3), and silicon dioxide were placed in a self-sealing bag, mixed well, and then directly compressed into tablets (compression pressure = 18-20 kN; tablet hardness is 60-70 N). [Table 3]

[0084] Composition 3 prepared in the following manner: solid dispersion (prepared by spray drying), MicroceLac 100 (microcrystalline cellulose and lactose in a ratio of 1:3), and silicon dioxide were placed in a self-sealing bag, mixed well, and then directly compressed into tablets (tablet thickness = 0.8-1.0 mm; tableting pressure = 4-6 kN; tablet hardness is 60-80 N). [Table 4]

[0085] Composition 4 prepared in the following manner: solid dispersion (prepared by spray drying), MicroceLac 100 (microcrystalline cellulose and lactose in a ratio of 1:3), and silicon dioxide were placed in a self-sealing bag, mixed well, and then directly compressed into tablets (tablet thickness = 0.5-0.8 mm; tableting pressure = 5-8 kN; tablet hardness is 50-80 N). [Table 5]

[0086] Example 4.2 (Determination of Dissolution) According to the method for determining dissolution (Chinese Pharmacopoeia 2020 edition of the four general principles 0931 second method paddle method), 2 tablets (equivalent to about 50 mg of X842) for each composition were placed in a cup, and 900 mL of phosphate buffer solution at pH 6.8 (dissolution solvent) was added to prepare a suspension. The suspension was shaken in a shaker (shaker speed = 100 rpm). 5 mL suspension samples were taken after 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 10 h (while replenishing the same amount of solvent) and filtered through a 0.22 μm microporous membrane. The filtrate was diluted 2 times with methanol, filtered again, injected into HPLC, and the solubility was determined by measuring the peak area.

[0087] As a reference, capsules containing a composition containing crystalline X842 (such as Form A disclosed in US2022002297) were suspended and analyzed similarly.

[0088] The resulting dissolution of X842, shown in Table 2 and FIG. 9, indicates that tablets containing solid dispersions of amorphous X842 (i.e., tablets formed from compositions 1, 3, and 4) are superior to tablets containing solid dispersions of crystalline X842 (composition 2) and to the X842 capsule reference (also containing crystalline X842).

[0089] [Table 6]

[0090] Example 5 (Stability test of solid dispersion powder) The X842 ASD powder prepared by spray drying was placed in a ziplock bag and stored at room temperature for approximately 6 months, and the PXRD diagram was collected by conventional methods.

[0091] As shown in FIG. 10, the PXRD diagram of X842 ASD powder indicates that the X842 ASD powder has good stability and remains amorphous after about 6 months of storage at room temperature.

[0092] Example 6 (Stability test of solid dispersion tablets) The tablets containing the above prepared solid dispersions: Composition 1 and Composition 2 were stored at room temperature for at least 3 months, and then the dissolution stability of the tablets after storage was measured according to the dissolution determination method described in Example 4.2.

[0093] As shown in Table 3 below and FIG. 11, the dissolution stability test results of the described tablets showed that the dissolution rates after the storage were essentially the same as on the first tableting day, indicating that the tested tablets have good stability.

[0094] [Table 7]

[0095] Example 7 (In vivo pharmacokinetic studies) Experimental method: Six beagle dogs weighing 8kg to 12kg were kept in a standard animal breeding room for one week and then used for the test. After fasting for 24 hours before the test, they were divided into two groups and a single-dose self-crossover test was adopted, with a dose of 50mg / dog; a total of four groups were administered with X842 spray-dried excipient physical mixture, X842 spray-dried ASD (composition 1) tablets, X842 hot melt extrusion SD (composition 2) and X842 capsules, with a washout period of 7 days for each group. 1.5mL of blood was collected at 11 time points before administration and 0.25 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration. The blood was centrifuged at 5000 rpm for 10 minutes, the upper layer of plasma was separated at 2-8℃, and the collected plasma samples were stored in a refrigerator at -80℃ before analysis. After the analysis is completed, the remaining plasma samples are stored continuously in a refrigerator at -80 °C. After the plasma samples are taken out, they are placed at room temperature and mixed well by vortexing (if necessary, blank samples can be centrifuged before use), 80 μL of the sample is placed in a 1.5 mL centrifuge tube, 40 μL of methanol and 360 μL of internal standard solution (for blank samples, add the same volume of methanol instead of the internal standard), mixed by vortexing, centrifuged for 5 minutes (14000 rpm), a certain amount of the supernatant is taken, and LC-MS / MS sample analysis is performed. The peak areas of X842, the active metabolite TX07 (8-[(2,6-dimethylbenzyl)amino]-N-(3-hydroxypropyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide, Linaprazan, AZD0865) and the internal standard are analyzed and recorded, and data processing is performed using DAS software.

[0096] The following chromatographic conditions were used: Chromatographic column model: Thermo AQUASIL C18, 4.6 μm, 50 mm × 2.1 mm; Mobile phase: A is 0.1% formic acid in water, B is 0.1% formic acid in methanol; Needle wash: 50% methanol in water; Mobile phase gradient elution is shown in the table below. [Table 8]

[0097] Initial gradient (B%): 40%; column temperature: 40 °C; flow rate: 0.6 mL / min; injection volume: 3 μL; run time: 3.5 min; autosampler temperature: 4 °C.

[0098] Mass spectrometry conditions: LCMS-8060 mass spectrometer with ESI source, positive ion MRM scan

[0099] As experimental results, the plasma concentration-time curves of four groups including X842 spray-dried excipient physical mixture, X842 spray-dried ASD (composition 1) tablets, X842 hot-melt extrusion SD (composition 2) and X842 capsules are shown in Figures 12 and 13, and some PK parameters are shown in Tables 3 and 4.

[0100] [Table 9]

[0101] [Table 10]

[0102] According to the measurement results of the prototype drug X842 shown in Table 3, the AUC(0-24h) was the highest at 269.61ng / mL*h for the X842 spray dried ASD (Composition 1) tablet group; 34.69 / mL*h for the X842 capsule group; 7.95ng / mL*h for the X842 hot melt extrusion SD (Composition 2) tablet group; and the lowest at 4.99ng / mL*h for the X842 spray dried excipient physical mixture tablet group; the X842 spray dried ASD (Composition 1) tablet group was 7.77 times, 33.91 times, and 54.03 times that of the other three groups, respectively.

[0103] According to the analysis results of the active metabolite TX07 shown in Table 4, the AUC(0-24h) was the highest in the X842 spray dried ASD (Composition 1) tablet group at 2422.70ng / mL*h, the highest in the X842 spray dried excipient physical mixture tablet group at 900.72ng / mL*h; the lowest in the X842 capsule group at 745.29ng / mL*h; and the lowest in the X842 hot melt extrusion SD (Composition 2) tablet group at 342.42ng / mL*h; the X842 spray dried ASD (Composition 1) tablet group was 2.39-fold, 3.25-fold, and 7.08-fold higher than the other three groups, respectively.

[0104] In the results above, both X842 and the active metabolite TX07 were measured at much higher concentrations in the X842 spray-dried ASD group, indicating significantly improved bioavailability compared to the other groups.

[0105] In beagle dogs, the blood concentration of the X842 solid dispersion (spray-dried) tablets of the present invention is higher than that of the X842 capsules, demonstrating that the X842 amorphous solid dispersion of the present invention can better maintain the supersaturated concentration of X842 in the stomach and intestinal tract, thereby increasing its oral bioavailability.

[0106] The technical features of the above embodiments can be combined in any manner. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as the combinations of these technical features do not cause any contradictions, they are all within the scope of the present invention.

[0107] The above examples merely show some embodiments of the present invention, and the description is relatively specific and detailed, so it does not limit the scope of the invention patent. It should be pointed out that those skilled in the art can make some modifications and improvements without departing from the concept of the present invention, all of which belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be based on the attached claims.

Claims

1. An orally administered pharmaceutical preparation comprising a solid dispersion containing amorphous 5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid (X842) and a water-soluble amphiphilic carrier.

2. The pharmaceutical formulation according to claim 1, wherein the carrier is a polymer carrier.

3. The pharmaceutical formulation according to claim 2, wherein the polymer carrier comprises vinylcaprolactam.

4. The pharmaceutical formulation according to claim 2 or 3, wherein the polymer carrier comprises vinyl acetate.

5. The pharmaceutical formulation according to claim 2 or 3, wherein the average molecular weight of the polymer support is in the range of 40,000 to 250,000 g / mol, preferably 80,000 to 150,000 g / mol, when determined by gel permeation chromatography.

6. A pharmaceutical preparation according to any one of claims 1 to 3, wherein the dry weight ratio of X842 to the carrier is 2:1 to 1:20, for example 1:1 to 1:10, for example 1:2 to 1:10, for example 1:2 to 1:7, for example 1:3 to 1:7, for example 1:3 to 1:

5.

7. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the solid dispersion is formed by spray drying.

8. A pharmaceutical preparation according to any one of claims 1 to 3, in the form of a unit dose.

9. The pharmaceutical preparation according to claim 8, wherein the amount of amorphous X842 in a unit dose is 0 to 100 mg, for example 10 to 60 mg, for example 10 to 40 mg, for example 10 to 25 mg, for example 10 to 24 mg.

10. A pharmaceutical preparation according to any one of claims 1 to 3, having an effective period of 3 months or more, preferably 6 months or more, and more preferably 12 months or more.

11. AUC or C max The pharmaceutical formulation according to any one of claims 1 to 3, wherein the oral bioavailability of such substances is higher than that of crystalline X842, for example, 1.2 times or more, 1.5 times or more, 2 times or more, preferably 3 times or more, and more preferably 6 times or more.

12. A pharmaceutical formulation according to any one of claims 1 to 3, for treating gastrointestinal inflammatory diseases or gastric acid-related diseases, such as erosive reflux disease (eGERD).

13. A solid dispersion comprising amorphous 5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid (X842) and a water-soluble amphiphilic carrier, the solid dispersion being obtained by spray-drying a solution of X842 and the carrier, for example, an ethanol solution of X842 and the carrier.

14. A solid dispersion according to claim 13 for treating gastrointestinal inflammatory diseases or gastric acid-related diseases, such as erosive reflux disease (eGERD).

15. A tablet or capsule comprising a pharmaceutical preparation according to any one of claims 1 to 3 or a solid dispersion according to claim 13.

16. The tablet or capsule according to claim 15, further comprising a disintegrant, such as polyvinylpolypyrrolidone.

17. The tablet or capsule according to claim 16, wherein the dry weight ratio of the disintegrant to X842 is at least 1.1:1, for example at least 1.4:1, for example at least 1.7:1, for example at least 2:1, for example at least 2.8:1.

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