X842 formulations

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

[0001] This divisional application is a divisional application based on the Chinese patent application with application number 202380010889.9, application date March 23, 2023, and invention name “X842 preparation”, which is the Chinese national phase of the international application with international application number PCT / CN2023 / 083375. Technical Field

[0002] The present disclosure relates to the field of treating gastrointestinal inflammatory diseases or gastric acid-related diseases, and in particular to a solid dispersion (SD) of X842 developed for this purpose. Background Art

[0003] 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, generally referred to as X842, is a potent inhibitor of gastric secretion.

[0004] X842 has the following structural formula:

[0005]

[0006] 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.

[0007] However, the solubility of X842 is very low, which makes it difficult to prepare an effective oral formulation of X842. Summary of the invention

[0008] It is an object of the present disclosure to overcome the solubility problem of X842, thereby facilitating effective treatment using the drug.

[0009] The present inventors have found that this object is achieved by a solid dispersion of X842 and a carrier, in which the X842 has an amorphous form.

[0010] Accordingly, this disclosure provides an itemized listing of the following embodiments.

[0011] 1. A pharmaceutical preparation for oral administration, comprising a solid dispersion containing amorphous X842 and a water-soluble amphiphilic carrier.

[0012] 2. The pharmaceutical preparation according to item 1, wherein the carrier is a polymer carrier.

[0013] 3. The pharmaceutical formulation according to item 2, wherein the polymer carrier comprises vinyl caprolactam.

[0014] 4. The pharmaceutical formulation according to item 2 or 3, wherein the polymer carrier comprises vinyl acetate.

[0015] 5. The pharmaceutical formulation according to any one of items 2 to 4, wherein the average molecular weight of the polymer carrier is in the range of 40,000-250,000 g / mol when determined by gel permeation chromatography.

[0016] 6. The pharmaceutical formulation according to item 5, wherein the average molecular weight of the polymer carrier is in the range of 80,000-150,000 g / mol when determined by gel permeation chromatography.

[0017] 7. The pharmaceutical formulation according to any of the preceding clauses, wherein the dry weight ratio of X842 to the carrier is between 2:1 and 1:20, such as between 1:2 and 1:10, such as between 1:1 and 1:10, such as between 1:2 and 1:7, such as between 1:3 and 1:7, such as between 1:3 and 1:5.

[0018] 8. The pharmaceutical formulation according to any one of the preceding clauses, wherein the solid dispersion is formed by spray drying.

[0019] 9. The pharmaceutical formulation according to item 8, wherein the solid dispersion is obtained by spray drying a solution of X842 and the carrier.

[0020] 10. The pharmaceutical formulation according to item 9, wherein the solid dispersion is obtained by spray drying X842 and the carrier solution in an organic solvent. The organic solvent is any solvent suitable for spray drying X842, preferably anhydrous ethanol, methanol, acetone, tetrahydrofuran, dimethyl sulfoxide and chloroform.

[0021] 11. The pharmaceutical preparation according to any one of the preceding clauses, which is in the form of a unit dose.

[0022] 12. The pharmaceutical formulation according to item 11, wherein the amount of amorphous X842 in the unit dose is 10-100 mg, such as 10-60 mg, such as 10-40 mg, such as 10-25 mg, such as 10-24 mg.

[0023] 13. The pharmaceutical formulation according to any one of items 1 to 12, for use in a method of treating a gastrointestinal inflammatory disease or a gastric acid-related disease such as erosive gastroesophageal reflux disease (eGERD).

[0024] 14. A solid dispersion comprising amorphous X842 and a water-soluble amphiphilic carrier, wherein the solid dispersion is obtainable by spray drying a solution of X842 and the carrier.

[0025] 15. The solid dispersion according to item 14, wherein the solution is X842 and the carrier solution in an organic solvent. The organic solvent is any solution suitable for spray drying X842, preferably anhydrous ethanol, methanol, acetone, tetrahydrofuran, dimethyl sulfoxide and chloroform.

[0026] 16. The solid dispersion according to item 14 or 15, wherein the nozzle temperature during the spray drying is in the range of 55-99°C, such as in the range of 65-95°C, such as in the range of 70-85°C.

[0027] 17. A solid dispersion according to any of items 14 to 16, wherein the temperature of the solution fed to the nozzle during spray drying is in the range of 25-99°C, such as 55-99°C, such as in the range of 65-95°C, such as in the range of 70-85°C.

[0028] 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 longer, preferably 6 months or longer, more preferably 12 months or longer.

[0029] 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 18, which has an oral bioavailability higher than that of crystalline X842.

[0030] 20. The pharmaceutical formulation according to any one of items 1 to 13 or the solid dispersion according to any one of items 14 to 18, wherein the oral bioavailability (eg AUC or C max ) is 1.2 times or more, 1.5 times or more, 2 times or more, preferably 3 times or more, more preferably 6 times or more, the oral bioavailability of crystalline X842.

[0031] 21. The solid dispersion according to any one of items 14 to 20, for use in a method of treating a gastrointestinal inflammatory disease or a gastric acid related disease such as erosive gastroesophageal reflux disease (eGERD).

[0032] 22. A tablet or capsule comprising the pharmaceutical formulation according to any one of items 1 to 13 and 18 to 20 or the solid dispersion according to any one of items 14 to 20.

[0033] 23. The tablet or capsule according to item 22, further comprising a disintegrant such as polyvinylpolypyrrolidone.

[0034] 24. A tablet or capsule according to item 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, such as at least 2:1, such as at least 2.8:1.

[0035] 25. The tablet or capsule according to any one of items 22-24, further comprising a cellulosic excipient such as microcrystalline cellulose (MCC).

[0036] 26. The tablet or capsule according to any one of items 22-25, further comprising lactose.

[0037] 27. The tablet or capsule according to any one of items 22-26, wherein the tablet or capsule has a shelf life of 3 months or longer, preferably 6 months or longer, more preferably 12 months or longer.

[0038] 28. A tablet or capsule according to any one of items 22 to 27, having an oral bioavailability greater than that of an X842 capsule comprising crystalline X842.

[0039] 29. A tablet or capsule according to any one of items 22 to 28, wherein the oral bioavailability (e.g. AUC or C max ) is 1.2 times or more, 1.5 times or more, 2 times or more, preferably 3 times or more, more preferably 6 times or more, the oral bioavailability of X842 capsules containing crystalline X842.

[0040] 30. Use of a pharmaceutical formulation according to any one of items 1 to 13 and 18 to 20 for the preparation of a medicament for treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as erosive gastroesophageal reflux disease (eGERD).

[0041] 31. Use of the solid dispersion according to any one of items 14 to 20 for the preparation of a medicament for treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as erosive gastroesophageal reflux disease (eGERD). BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The solubility of X842 in mixtures or solid dispersions (formed by a solvent method) of different carriers having different mass ratios is shown (see Example 1 below).

[0043] Figure 2X842 solubility measurements of different solid dispersions and physical mixtures are shown. "Sol" refers to Soluplus.

[0044] Figure 3 Shown are the PXRD diffraction patterns of three different solid dispersions (one prepared by spray drying, one by hot melt extrusion (HME) and another by a solvent process), a physical mixture, Soluplus and X842.

[0045] Figure 4 and Figure 5 PXRD diffraction patterns of samples 3.1-3.11 are shown (the preparation of these samples is described in the Examples section below).

[0046] Figure 6 and Figure 7 PXRD diffraction patterns of samples 3.12-3.18 are shown (the preparation of these samples is described in the Examples section below).

[0047] Figure 8 The X842 solubility measurements are shown for samples 3.12, 3.13, 3.16, 3.17 (solid dispersions formed by spray drying), samples 3.15 and 3.18 (physical mixtures).

[0048] Fig. 9 The dissolution of X842 from tablets formed from Compositions 1-4 (the preparation of these tablets is described in the Examples section below) and from a reference capsule is shown.

[0049] Fig.10 The figure shows the stability test results of the solid dispersion powder at room temperature for 6 months.

[0050] Fig.11 The stability test results of the solid dispersion tablets placed at room temperature for 3 months are shown.

[0051] Fig.12 and Fig.13 The pharmacokinetic parameter results of the solid dispersion tablet and the reference capsule in beagle dogs are shown. DETAILED DESCRIPTION

[0052] In the context of the present invention, "shelf life" means the life cycle of a drug during which 10% or less of the drug is degraded.

[0053] In the context of the present invention, "crystalline X842" means a state in which X842 exists in a stable crystalline form, as opposed to an amorphous state. Such "crystalline X842" is, for example, forms A and B disclosed in US2022002297A1, in particular form A.

[0054] As a first aspect of the present disclosure, a pharmaceutical preparation for oral administration is provided. The preparation comprises a solid dispersion containing amorphous X842 and a water-soluble amphiphilic carrier. This preparation promotes the rapid dissolution of X842 and can therefore be regarded as an immediate release pharmaceutical preparation.

[0055] 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.

[0056] The average molecular weight of the polymer carrier (determined by gel permeation chromatography) is preferably in the range of 40,000-250,000 g / mol, more preferably in the range of 80,000-150,000 g / mol.

[0057] An example of a polymer carrier comprising vinylcaprolactam and vinyl acetate and having an average molecular weight (determined by gel permeation chromatography) in the range of 80,000 - 150,000 g / mol is Soluplus from BASF.

[0058] The dry weight ratio of X842 to the carrier is preferably between 2:1 and 1:20, preferably between 1:1 and 1:10, more preferably between 1:1 and 1:10, more preferably between 1:2 and 1:7, more preferably between 1:3 and 1:7, and most preferably between 1:3 and 1:5.

[0059] 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 the carrier. The solution may be, for example, an ethanol solution. Further embodiments of the spray drying are discussed below in conjunction with the third aspect.

[0060] The pharmaceutical preparation of the first aspect may, for example, be in the form of a unit dose. In such a unit dose, the amount of amorphous X842 may be 10-100 mg, such as 10-60 mg, such as 10-40 mg, such as 10-25 mg, such as 10-24 mg. The efficient dissolution of X842 means that the amount of X842 may be relatively low.

[0061] As a second aspect of the present disclosure, there is provided a pharmaceutical preparation according to the first aspect, which is used in a method for treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as erosive gastroesophageal reflux disease (eGERD). In the method, the pharmaceutical preparation is designed for oral administration.

[0062] As a third aspect of the present disclosure, a solid dispersion comprising amorphous X842 and a water-soluble amphiphilic carrier is provided, wherein the solid dispersion can be obtained by spray-drying a solution of X842 and the carrier, such as an ethanol solution.

[0063] During the spray drying, the nozzle temperature may be, for example, in the range of 55-99° C., such as in the range of 65-95° C., such as in the range of 70-85° C. In addition, the temperature of the solution fed to the nozzle during the spray drying may be in the range of 25-99° C., such as in the range of 55-99° C., such as in the range of 65-95° C., such as in the range of 70-85° C. When the solution is an ethanol solution, the nozzle temperature and the temperature of the solution fed to the nozzle are preferably in the range of 65-78° C., more preferably in the range of 65-75° C.

[0064] Apart from this, the embodiments and examples of the first aspect apply to the third aspect mutatis mutandis.

[0065] As a fourth aspect of the present disclosure, there is provided the solid dispersion of the third aspect, which is used in a method for treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as eGERD. In the method, the solid dispersion is designed for oral administration.

[0066] As a fifth aspect of the present disclosure, provided is a tablet or a capsule, comprising the pharmaceutical preparation of the first aspect or the solid dispersion of the third aspect.

[0067] The tablet or capsule may further comprise a disintegrant, such as a non-cellulose disintegrant. A preferred example of a non-cellulose disintegrant is polyvinylpolypyrrolidone. The dry weight ratio of disintegrant to X842 is typically at least 1.1:1, such as at least 1.4:1, preferably at least 1.7:1, such as at least 2:1, such as at least 2.8:1. The upper limit of the dry weight ratio may be 4:1.

[0068] In one embodiment, the tablet or capsule further comprises a cellulose excipient and / or lactose. The cellulose excipient may be, for example, MCC.

[0069] The amount of amorphous X842 in the tablet or capsule may be 10-100 mg, such as 10-60 mg, such as 10-40 mg, such as 10-25 mg, such as 10-24 mg.

[0070] As a sixth aspect of the present disclosure, there is provided a tablet or capsule according to the fifth aspect, which is used in a method for treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as eGERD. In the method, the tablet or capsule is designed for oral administration.

[0071] The subject of the treatment methods discussed above is preferably a human.

[0072] As the seventh aspect of the present disclosure, provided is the use of the pharmaceutical preparation of the first aspect, the solid dispersion of the third aspect, or the tablet or capsule of the fifth aspect for preparing a medicament for treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as erosive gastroesophageal reflux disease (eGERD).

[0073] As an eighth aspect of the present disclosure, after the solid dispersion powder of the third aspect is left at room temperature for 3 months or longer, preferably 6 months or longer, more preferably 12 months or longer, its PXRD shows that it is still amorphous and remains stable.

[0074] As a ninth aspect of the present disclosure, after the solid dispersion tablet or capsule of the fifth aspect is placed at room temperature for 3 months or longer, preferably 6 months or longer, more preferably 12 months or longer, its dissolution rate is substantially the same as before, and it remains stable.

[0075] As a tenth aspect of the present disclosure, after oral administration of the solid dispersion tablet or capsule of the fifth aspect, its oral bioavailability (e.g. AUC or C max ) is higher than the oral bioavailability of the X842 capsule containing crystalline X842. For example, the oral bioavailability of the solid dispersion tablet or capsule of the fifth aspect is 1.2 times or more, 2 times or more, preferably 3 times or more, more preferably 6 times or more of the oral bioavailability of the X842 capsule. For example, the AUC of the solid dispersion tablet or capsule of the fifth aspect is 1.2 times or more, 2 times or more, preferably 3 times or more, more preferably 6 times or more of the AUC of the X842 capsule. For example, the C842 capsule of the solid dispersion tablet or capsule of the fifth aspect is 1.2 times or more, 2 times or more, preferably 3 times or more, more preferably 6 times or more of the AUC of the X842 capsule. max C for the X842 capsule max 1.2 times or more, 2 times or more, preferably C of the X842 capsule max 3 times or more, more preferably 6 times or more.

[0076] Example

[0077] Example 1

[0078] Solid dispersions of X842 and different carriers (at different ratios) were prepared by a solvent method, and their solubility at pH 6.8 was determined.

[0079] X842 (API) and carrier were added to a 250 mL beaker, followed by about 150 mL of anhydrous ethanol. 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(vinyl pyrrolidone-co-vinyl acetate) from BASF), PVP K30 (polyvinyl pyrrolidone K30 ((C 6 H 9 NO) n )), Affinisol-15 LV (HPMC), plasdone TM S-630 (60:40 linear random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate), PEG6000, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PEG 6000: vinyl caprolactam: vinyl acetate = 13:57:30) from BASF) or Klucel EF (hydroxypropyl cellulose (HPC)). The API was completely dissolved in ethanol using ultrasound.

[0080] The solution was added to a porcelain dish and placed in a water bath at 80°C to evaporate the solvent. The solid residue was then placed in a vacuum drying oven at 40°C for 24 hours. The dried residue was finely ground through a 65 mesh sieve.

[0081] As a reference, a physical mixture of API and each carrier was prepared at a dry weight ratio of 1:10.

[0082] The API solubility of 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 an oscillator at 25°C (oscillator speed: 130 r / min) for 24 h. Then, an appropriate amount of liquid was taken from the tube and passed through a 0.22 μm microporous membrane. Finally, the solubility of X842 was determined using HPLC (n=3). The results are presented in Tables 1 and 2 below. Figure 1 Table 1. Solubility (μg / mL) of X842 in various physical mixtures (M) and solid dispersions (SD) in phosphate buffer (pH 6.80)

[0083]

[0084] Notably, Table 1 shows that the Soluplus carrier was ineffective in physical mixtures with the API (as was also the case when compared to most other carriers), but outperformed all other carriers in solid dispersions independent of ratio (see also Figure 1 ).

[0085] Example 2.1

[0086] A solid dispersion was prepared from X842 (17 wt.%) and Soluplus (83 wt.%) according to the following steps:

[0087] 1g X842 and 5g Soluplus are fully mixed to obtain a physical mixture. The hot melt extruder is turned on and the extrusion temperature is set to 160°C (twin screw speed is 100rpm). When the temperature is reached and stabilized for half an hour, the physical mixture is hot melt extruded to obtain an extruded strip. The hot melt extruded strip is cooled and crushed through a 65 mesh sieve to obtain a solid dispersion.

[0088] The solid dispersion was analyzed using powder X-ray diffraction (PXRD). In addition, the X842 solubility of the solid dispersion was tested. This is described below.

[0089] Example 2.2

[0090] A solid dispersion was prepared from X842 (17 wt.%) and Soluplus (83 wt.%) according to the following steps:

[0091] 1g X842 and 5g Soluplus were fully mixed to obtain a physical mixture. The hot melt extruder was turned on and the extrusion temperature was set to 120°C (twin screw speed was 100 rpm). After reaching the temperature and stabilizing for half an hour, the physical mixture was hot melt extruded to obtain an extruded strip. The hot melt extruded strip was cooled and crushed through a 65 mesh screen to obtain a solid dispersion.

[0092] Solid dispersions of X842 were tested for solubility. This is described below.

[0093] Example 2.3

[0094] A solid dispersion was prepared from X842 (17 wt.%), polymer carrier polyvinyl alcohol (66 wt.%) and sorbitol (17 wt.%) according to the following steps:

[0095] 1g X842, 4g polyvinyl alcohol (PVOH) and 1g sorbitol were fully mixed to obtain a physical mixture. The hot melt extruder was turned on and the extrusion temperature was set to 190°C (twin screw speed was 75rpm). When the temperature was reached and stabilized for half an hour, the physical mixture was hot melt extruded to obtain an extruded strip. The hot melt extruded strip was cooled and crushed through a 65 mesh screen to obtain a solid dispersion.

[0096] Solid dispersions of X842 were tested for solubility. This is described below.

[0097] Example 2.4

[0098] A solid dispersion was prepared from X842 (17 wt.%), polymer carrier polyvinyl alcohol (41.5 wt.%) and sorbitol (41.5 wt.%) according to the following steps:

[0099] 1g X842, 2.5g polyvinyl alcohol (PVOH) and 2.5g sorbitol were fully mixed to obtain a physical mixture. The hot melt extruder was turned on and the extrusion temperature was set to 190°C (twin screw speed was 75rpm). When the temperature was reached and stabilized for half an hour, the physical mixture was hot melt extruded to obtain an extruded strip. The hot melt extruded strip was cooled and crushed through a 65 mesh screen to obtain a solid dispersion.

[0100] Solid dispersions of X842 were tested for solubility. This is described below.

[0101] Example 2.5

[0102] A solid dispersion was prepared from X842 (17 wt.%) and Soluplus (83 wt.%) using spray drying according to the following steps:

[0103] 0.5 g X842 and 2.5 g Soluplus were added to anhydrous ethanol, which was heated to 70° C. in a water bath to completely dissolve X842. The spray drying equipment was turned on and the nozzle temperature was set to 75° C. When the temperature was reached, the solution was pumped into the nozzle by a peristaltic pump (5-20 rpm) for spray drying.

[0104] The solid dispersion was analyzed using powder X-ray diffraction (PXRD). In addition, the X842 solubility of the solid dispersion was tested. This is described below.

[0105] Example 2.6 (Solubility Determination)

[0106] The solid dispersions prepared in Examples 2.1-2.5 and the X842 / Soluplus solid dispersion formed by the solvent method (1:5 dry weight ratio, see Example 1) were tested for X842 solubility. As a reference, a physical mixture of X842 and a carrier was also tested.

[0107] 25 mg (measured as X842) of solid dispersion or physical mixture is added to 25 mL of phosphate buffer at pH 6.8 to prepare a suspension containing about 1 mg / mL X842. The suspension is shaken in an oscillator (oscillator speed: 130 rpm). After 1, 2, 4, 8 and 24 hours, 2 mL samples are taken and filtered through a 0.22 μm microporous membrane. Methanol is added to reach a 2 or 10-fold dilution (thereby reaching a concentration within the assay range). 10 μL are injected into HPLC to determine solubility.

[0108] The results are presented in Figure 2 It shows that the solid dispersion prepared according to Example 2.5 is significantly better than other solid dispersions and physical mixtures.

[0109] Example 2.7 (PXRD)

[0110] PXRD was performed to compare the solid dispersion of Example 2.5 (which has excellent X842 solubility) with the solid dispersion of Example 2.1 (prepared by hot melt extrusion at 160° C.). In addition, PXRD was performed on the X842 / Soluplus solid dispersion formed by the solvent method (1:5 dry weight ratio, see Example 1), the X842 / Soluplus physical mixture (1:5 dry weight ratio), and Soluplus alone and X842 alone were also analyzed to provide further reference.

[0111] For the PXRD experiments, the instrument was Nippon Science Smartlab9kw, and the conditions were as follows: Cu target, Kα radiation (λ=0.15406nm), operating voltage and current were 45kV and 100mA, respectively, and scanned in the 2θ range of 5 to 40° at a rate of 4° / min.

[0112] The obtained PXRD diffraction pattern is shown in Figure 3 In, it is shown that the crystallinity of X842 is retained in solid dispersions formed by hot melt extrusion and solvent methods as well as in physical mixtures. In addition, Figure 2 These forms were shown to have poor X842 solubility compared to the solid dispersion formed by spray drying (Example 2.5). Figure 3 It was shown that X842 was amorphous in the solid dispersion formed by spray drying. Figure 2 and Figure 3 The fact that X842 in the solid dispersion is amorphous is critical to the solubility of X842.

[0113] Example 3.1 (PXRD)

[0114] A second PXRD run was performed. This run included the following samples:

[0115] 3.1 - spray-dried (nozzle temperature = 75 °C) solid dispersion of X842 and Soluplus in a ratio of 1:3;

[0116] 3.2 - solid dispersion of Example 2.5;

[0117] 3.3 – Soluplus only;

[0118] 3.4 – hot melt extruded (T = 175 °C, 50 rpm) solid dispersion of X842 and Soluplus in a ratio of 1:5;

[0119] 3.5—solid dispersion of X842, Soluplus and mannitol in a ratio of 1:3:2 by hot melt extrusion (T=175°C, 50 rpm);

[0120] 3.6—solid dispersion of X842 and PVP / VA64 in a ratio of 1:5 by hot melt extrusion (T=160°C, 30rpm);

[0121] 3.7 – physical mixture of X842 and Soluplus in a ratio of 1:5;

[0122] 3.8 – X842 only;

[0123] 3.9—spray-dried (nozzle temperature = 60° C., ethanol) solid dispersion of X842 and Soluplus in a ratio of 1:3;

[0124] 3.10—spray dried (nozzle temperature = 90° C., ethanol) solid dispersion of X842 and Soluplus in a ratio of 1:3; and

[0125] 3.11 - Spray dried (nozzle temperature = 75°C, methanol) solid dispersion of X842 and Soluplus in a ratio of 1:3.

[0126] The obtained PXRD diffraction pattern is shown in Figure 4 and 5 , it is again shown that spray drying of the X842 / Soluplus solution produced a solid dispersion comprising amorphous X842, whereas the hot melt extruded solid dispersion contained crystalline X842.

[0127] Example 3.2 (PXRD)

[0128] A third PXRD run was performed. This run included the following samples:

[0129] 3.12 - Spray dried (nozzle temperature = 75°C) solid dispersion of X842 and Soluplus in a ratio of 1:3;

[0130] 3.13 – X842, Soluplus and SiO in a ratio of 1:1:1 2 A solid dispersion of spray drying (nozzle temperature = 75°C);

[0131] 3.14 – SiO only 2 ;

[0132] 3.15 – X842, Soluplus and SiO in a ratio of 1:1:1 2 Physical mixture

[0133] 3.16 - spray dried (nozzle temperature = 75°C) solid dispersion of X842 and Soluplus in a ratio of 1:1; and

[0134] 3.17—spray-dried (nozzle temperature = 75° C.) solid dispersion of X842 and Soluplus in a ratio of 1:5;

[0135] 3.18 – Physical mixture of X842 and Soluplus in a ratio of 1:5

[0136] The obtained PXRD diffraction pattern is shown in Figure 6 and 7 , it is shown again that spray drying of X842 / Soluplus solutions not only at a ratio of 1:5, but also at ratios of 1:3 and 1:1, yields solid dispersions comprising amorphous X842.

[0137] Example 3.3 (Solubility Determination)

[0138] The solubility of X842 was measured for samples 3.12, 3.13, 3.15, 3.16 and 3.17 as follows:

[0139] 25 mg (measured in X842) of sample material was added to 25 mL of phosphate buffer at pH 6.8 to prepare a suspension containing approximately 1 mg / mL X842. The suspension was shaken in an oscillator (oscillator speed = 130 rpm; temperature = 25 °C). After 1, 2, 4, 8 and 24 hours, 2 mL of the suspension sample was filtered through a 0.22 μm microporous membrane. Methanol was added to 0.5 mL of the filtrate to achieve a 2 or 10-fold dilution (thereby reaching a concentration within the assay range). 10 μL of injections were injected into the HPLC to determine solubility.

[0140] The results are presented in Figure 8 , which shows that solid dispersions containing amorphous X842 have dramatically increased X842 solubility compared to physical mixtures containing crystalline X842. Figure 8 It was further shown that a ratio of X842 to Soluplus of 1:5 or 1:3 was more effective than a ratio of X842 to Soluplus of 1:1, and that of the ratios tested, both 1:3 and 1:5 were very effective.

[0141] Example 4.1 (Preparation of Tablets)

[0142] Tablets were prepared from compositions comprising various solid dispersions of X842 and Soluplus prepared by spray drying or hot melt extrusion. The weight of each tablet was 350 mg and the amount of X842 in each tablet was 25 mg.

[0143] Composition 1 was prepared by the following method: a solid dispersion (by Spray drying Preparation), MicroceLac 100 (microcrystalline cellulose and lactose in a ratio of 1:3) and silicon dioxide were placed in a self-sealing bag and mixed thoroughly, and then directly tableted (tablet thickness = 0.8-1.0 mm; tableting pressure = 4-6 kN; tablet hardness 60-80 N).

[0144]

[0145] Composition 2 was prepared by the following method: a solid dispersion (by Hot Melt Extrusion Preparation), MicroceLac 100 (microcrystalline cellulose and lactose in a ratio of 1:3) and silicon dioxide were placed in a self-sealing bag and mixed thoroughly, and then directly tableted (tabletting pressure = 18-20 kN; tablet hardness 60-70 N).

[0146]

[0147] Composition 3 was prepared by the following method: a solid dispersion (by Spray drying Preparation), MicroceLac 100 (microcrystalline cellulose and lactose in a ratio of 1:3) and silicon dioxide were placed in a self-sealing bag and mixed thoroughly, and then directly tableted (tablet thickness = 0.8-1.0 mm; tableting pressure = 4-6 kN; tablet hardness 60-80 N).

[0148]

[0149] Composition 4 was prepared by the following method: a solid dispersion (by Spray drying Preparation), MicroceLac 100 (microcrystalline cellulose and lactose in a ratio of 1:3) and silicon dioxide were placed in a self-sealing bag and mixed thoroughly, and then directly tableted (tablet thickness = 0.5-0.8 mm; tableting pressure = 5-8 kN; tablet hardness 50-80 N).

[0150]

[0151] Example 4.2 (Dissolution Determination)

[0152] According to the dissolution determination method (Chinese Pharmacopoeia 2020 edition Four-way Rule 0931 second method paddle method), two tablets of each composition (corresponding to about 50mg of X842) are placed in a cup, and 900mL of pH 6.8 phosphate buffer (dissolution medium) is added to the cup to prepare a suspension. The suspension is shaken in a shaking table (shaking table speed = 100rpm). After 0.5, 1, 2, 4, 6, 8 and 10 hours, 5mL suspension samples are taken (supplemented with the same volume of medium at the same time) and filtered through a 0.22μm microporous membrane. The filtrate is diluted twice with methanol, then filtered again and injected into HPLC to determine the solubility by measuring the peak area.

[0153] As a reference, capsules containing a composition comprising crystalline X842 (e.g., Form A disclosed in US2022002297) were suspended and analyzed in the same manner.

[0154] The obtained dissolution rates of X842 are presented in Tables 2 and Fig. 9 , which shows that tablets containing a solid dispersion of amorphous X842 (i.e., tablets formed from Compositions 1, 3, and 4) perform better than tablets containing a solid dispersion of crystalline X842 (Composition 2) and an X842 capsule reference (also containing crystalline X842).

[0155] Table 2. X842 SD tablet test - based on the average of 3 parallel tests, dissolution medium: pH 6.8

[0156]

[0157] Example 5 (Stability Test of Solid Dispersion Powder)

[0158] The X842 ASD powder prepared by spray drying was placed in a ziplock bag and stored at room temperature for about 6 months, and its PXRD pattern was collected using the method described above.

[0159] The PXRD pattern of X842 ASD powder is shown in Fig.10 It is shown in , which shows that X842 ASD powder has good stability and is still amorphous after storage at room temperature for about 6 months.

[0160] Example 6 (Stability Test of Solid Dispersion Tablets)

[0161] For the tablets containing the solid dispersions (Composition 1 and Composition 2) prepared above, after being stored at room temperature for at least 3 months, the dissolution stability of the tablets after storage was measured according to the dissolution determination method mentioned in Example 4.2.

[0162] The dissolution stability test results of the tablets are shown in Tables 3 and Fig.11 It was shown that the dissolution rate after storage was essentially the same as that at the time of initial tableting, indicating that the tested tablets had good stability.

[0163] Table 3. X842 SD tablet stability test - based on the average of 3 parallel tests, dissolution medium: pH 6.8

[0164]

[0165] Example 7 (In vivo pharmacokinetic study)

[0166] Experimental method: 6 beagles weighing between 8kg and 12kg were raised in a standard animal breeding room for 1 week before testing. After fasting for 24 hours before the test, they were divided into two groups; a single-dose self-crossover test was used, with a dose of 50 mg / dog; a total of 4 groups were administered, including X842 spray-dried excipient physical mixture, X842 spray-dried ASD (composition 1) tablets, X842 hot-melt extruded SD (composition 2) and X842 capsules, and the washout period for each group was 7 days. 1.5mL of blood was collected at 11 time points before and after administration, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h. The blood was centrifuged at 5000rpm for 10 minutes, the upper plasma was separated at 2-8°C, and the collected plasma samples were stored in a -80°C refrigerator before analysis. After analysis, the remaining plasma samples continued to be stored in a -80°C refrigerator. After taking out the plasma sample, place it at room temperature, vortex and mix evenly (if necessary, the blank sample can be centrifuged before use), place 80 μL of the sample in a 1.5 mL centrifuge tube, add 40 μL of methanol and 360 μL of internal standard solution (for the blank sample, add the same volume of methanol instead of the internal standard), vortex and mix, centrifuge for 5 minutes (14000 rpm), and take a certain amount of supernatant for LC-MS / MS sample analysis. Analyze and record the peak areas of X842, active metabolite TX07 (8-[(2,6-dimethylbenzyl)amino]-N-(3-hydroxypropyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide, linarasen, AZD0865) and internal standard, and use DAS software for data processing.

[0167] The following chromatographic conditions were used: chromatographic column model: Thermo AQUASIL C18, 4.6 μm, 50 mm x 2.1 mm; mobile phase: A is 0.1% formic acid in water, B is 0.1% formic acid in methanol; needle washing solution: 50% methanol in water; mobile phase gradient elution program is shown in the following table:

[0168] Time (min) 0.5 2.5 2.51 3.5 Phase B (%) 40 95 40 stop

[0169] 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.

[0170] Mass spectrometry conditions: LCMS-8060 mass spectrometer, ESI source, positive ion MRM scan

[0171] As an experimental result, the plasma concentration-time curves of 4 groups including X842 spray-dried excipient physical mixture, X842 spray-dried ASD (composition 1) tablets, X842 hot melt extruded SD (composition 2) and X842 capsules are shown in Fig.12 and 13 Some PK parameters are shown in Tables 3 and 4.

[0172] Table 3. X842 PK parameters

[0173]

[0174] Table 4. PK parameters of TX07 (active metabolite of X842)

[0175]

[0176] According to the measurement results of the prototype drug X842 shown in Table 3, the AUC (0-24h) of the X842 spray-dried ASD (Composition 1) tablet group was the largest, which was 269.61 ng / mL*h; the X842 capsule group was 34.69 / mL*h; the X842 hot-melt extruded SD (Composition 2) tablet group was 7.95 ng / mL*h; the X842 spray-dried excipient physical mixture tablet group was the smallest, which was 4.99 ng / mL*h; the X842 spray-dried ASD (Composition 1) tablet group was 7.77, 33.91 and 54.03 times that of the other three groups, respectively.

[0177] According to the analysis results of the active metabolite TX07 shown in Table 4: the AUC (0-24h) of the X842 spray-dried ASD (Composition 1) tablet group was the largest, which was 2422.70 ng / mL*h; the X842 spray-dried excipient physical mixture tablet group was 900.72 g / mL*h; the X842 capsule group was 745.29 ng / mL*h; the X842 hot-melt extruded SD (Composition 2) tablet group was the smallest, which was 342.42 ng / mL*h; the X842 spray-dried ASD (Composition 1) tablet group was 2.39, 3.25 and 7.08 times that of the other three groups, respectively.

[0178] The above results showed that both X842 and the active metabolite TX07 were measured at much higher concentrations for the X842 spray-dried ASD group, indicating that their bioavailability was significantly improved compared to the other groups.

[0179] In beagle dogs, the blood concentration of the X842 solid dispersion (spray drying method) tablets of the present invention is higher than that of the X842 capsules, which proves that the X842 amorphous solid dispersion of the present invention can better maintain the supersaturated concentration of X842 in the stomach and intestines, thereby improving its oral bioavailability.

[0180] Each technical feature of the above embodiments can be arbitrarily combined. In order to make the description concise, all possible combinations of each technical feature in the above embodiments are not described. However, as long as the combination of these technical features does not cause conflict, they should be regarded as within the scope of the present invention.

[0181] The above embodiments only express several implementation methods of the present invention, and their descriptions are relatively specific and detailed, but they cannot be interpreted as limiting the scope of the invention patent. It should be pointed out that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and they all belong to the protection scope of the present invention. Therefore, the patent protection scope of the present invention should be based on the attached claims.

Claims

1. A pharmaceutical preparation for oral administration, comprising a solid dispersion containing amorphous X842 and a water-soluble amphiphilic carrier.

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

3. The pharmaceutical formulation of claim 2, wherein the polymer carrier comprises vinyl caprolactam.

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, wherein the carrier is selected from poly(vinyl pyrrolidone-co-vinyl acetate), polyvinyl pyrrolidone K30, Soluplus, hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC).

6. The pharmaceutical formulation according to any one of claims 2 to 5, wherein the average molecular weight of the polymer carrier is in the range of 40,000-250,000 g / mol, preferably in the range of 80,000-150,000 g / mol, when determined by gel permeation chromatography.

7. A pharmaceutical formulation according to any one of the preceding claims, wherein the dry weight ratio of X842 to the carrier is between 2:1 and 1:20, such as between 1:1 and 1:10, such as between 1:2 and 1:10, such as between 1:2 and 1:7, such as between 1:3 and 1:7, such as between 1:3 and 1:

5.

8. A pharmaceutical formulation according to any one of the preceding claims, wherein the solid dispersion is formed by spray drying.

9. A pharmaceutical formulation according to any one of the preceding claims in the form of a unit dose.

10. The pharmaceutical formulation according to claim 8, wherein the amount of amorphous X842 in the unit dose is 10-100 mg, such as 10-60 mg, such as 10-40 mg, such as 10-25 mg, such as 10-24 mg.

11. The pharmaceutical formulation according to any one of the preceding claims, which has a shelf life of 3 months or more, preferably 6 months or more, more preferably 12 months or more.

12. A pharmaceutical formulation according to any one of the preceding claims, wherein the oral bioavailability (e.g. AUC or C max ) is higher than the oral bioavailability of crystalline X842, for example, 1.2 times or more, 1.5 times or more, 2 times or more, preferably 3 times or more, more preferably 6 times or more, of the oral bioavailability of crystalline X842.

13. A pharmaceutical formulation according to any one of the preceding claims for use in a method of treating an inflammatory disease of the gastrointestinal tract 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, wherein the solid dispersion can be obtained by spray drying a solution of X842 and the carrier, such as an ethanol solution of X842 and the carrier.

15. The solid dispersion according to claim 14, for use in a method for treating gastrointestinal inflammatory diseases or gastric acid related diseases such as erosive gastroesophageal reflux disease (eGERD).

16. A tablet or capsule comprising the pharmaceutical formulation according to any one of claims 1 to 12 or the solid dispersion according to any one of claims 14 to 15.

17. The tablet according to claim 16, further comprising a disintegrant such as polyvinylpolypyrrolidone.

18. A tablet or capsule according to claim 16 or 17, 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, such as at least 2:1, such as at least 2.8:1.

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