Solid formulation of nk3r antagonist

Abstract

The present invention provides a solid dispersion of compound 1 or a pharmaceutical salt thereof, comprising the compound 1 or the pharmaceutical salt thereof as an active ingredient and a carrier material, wherein the carrier material is selected from one, two, or more of polyvinylpyrrolidone (PVP), copovidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose, polyethylene glycol, and ethyl cellulose, enabling the drug to have good stability, dissolution, and therapeutic effects. The formulation of the present invention provides rapid drug release and can reduce the oral burden of large-dose tablets on menopausal patients, thereby improving treatment compliance and treatment efficiency.

Description

A solid dosage form of an NK3R antagonist

[0001] This invention claims priority to the prior art applications filed by the applicant with the China National Intellectual Property Administration on December 23, 2024, with patent application number 202411906831.5 entitled "A Solid Formulation of an NK3R Antagonist" and patent application number 202511812318.4 filed with the China National Intellectual Property Administration on December 3, 2025, both entitled "A Solid Formulation of an NK3R Antagonist", the contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to a solid dosage form of an NK3R antagonist. Background Technology

[0003] Hot flashes are a common problem for menopausal women worldwide. Hot flashes are primarily caused by a decline in estrogen levels, and traditional first-line treatments like hormone replacement therapy (HRT) have low patient acceptance due to their slow onset of action and potential side effects. Non-hormonal drug therapies, such as selective serotonin reuptake inhibitors (SSRIs) and other medications, while existing, have also been limited in their use due to side effects and efficacy issues. Therefore, there is a significant unmet clinical need for the treatment of hot flashes. NK3R antagonists, as non-hormonal small molecules, regulate body temperature by blocking NK3R receptors on overactivated KNDy neurons in the median preoptic nucleus, offering a novel approach to treating hot flashes.

[0004] WO2022222963A1 discloses a class of potent NK3R antagonists, specifically compound 1. Pharmacological studies show that this compound exhibits good drug-like properties. The structure of compound 1 is shown below:

[0005] WO2024083150A1 discloses the crystal form of compound 1, which is a crystalline powder with low solubility in water and at physiological pH conditions. This characteristic poses a significant challenge to its bioavailability as an oral drug.

[0006] Therefore, developing a formulation containing compound 1 or its pharmaceutical salt with good solubility and stability is a key problem that needs to be solved. Summary of the Invention

[0007] To solve the above-mentioned technical problems, the present invention provides a solid dispersion of compound 1 or its pharmaceutical salt, comprising compound 1 or its pharmaceutical salt as the active ingredient and a carrier material, wherein the carrier material is selected from one, two or more of polyvinylpyrrolidone (PVP), copovidone (CoPVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), and ethyl cellulose (EC); wherein the structure of compound 1 is shown below:

[0008] According to an embodiment of the present invention, the carrier material is preferably one, two or more of PVP-VA, HPMCAS, and Soluplus.

[0009] According to an embodiment of the present invention, when the carrier material is a combination of two materials, the carrier material is a combination of HPMCAS and Soluplus, a combination of PVP-VA and HPMCAS, or a combination of PVP-VA and Soluplus.

[0010] In some implementations, PVP-VA is selected from PVP-VA 64, and HPMCAS is selected from HPMCAS-HG or HPMCAS-MG;

[0011] According to an embodiment of the present invention, when the carrier material is a combination of two materials, the weight ratio of the two carrier materials is 1:5 to 5:1, for example, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1.

[0012] According to embodiments of the present invention, the weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 10:1 to 1:10. In some embodiments, the weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 1:1 to 1:9, for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9; in some embodiments, the weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 1:2 to 1:9; in some embodiments, the weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 1:2 to 1:4.

[0013] According to an embodiment of the present invention, the solid dispersion further includes a surfactant.

[0014] According to an embodiment of the present invention, the surfactant includes one, two or more of poloxamer, sodium dodecyl sulfate (SDS), polyethylene glycol eurotin succinate (TPGS), and Tween.

[0015] According to an embodiment of the present invention, the surfactant is preferably one or both of SDS and TPGS.

[0016] According to an embodiment of the invention, the surfactant has a weight percentage of 0.5% to 15% in the solid dispersion, preferably 2% to 8%, for example 2%, 3%, 4%, 5%, 6%, 7%, or 8%.

[0017] According to an embodiment of the present invention, the active ingredient compound 1 or its pharmaceutical salt in the solid dispersion is in an amorphous form.

[0018] The present invention provides a solid dispersion of compound 1 or its pharmaceutical salt, comprising compound 1 or its pharmaceutical salt as an active ingredient and a carrier material, wherein the carrier material is selected from hydroxypropyl methylcellulose succinate (HPMCAS), and the weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 1:2 to 1:9.

[0019] The present invention provides a solid dispersion of compound 1 or its pharmaceutical salt, comprising compound 1 or its pharmaceutical salt as an active ingredient and a carrier material, wherein the carrier material is selected from hydroxypropyl methylcellulose succinate (HPMCAS), and the weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 1:2 to 1:4.

[0020] This invention provides a solid dispersion of compound 1 or its pharmaceutical salt, comprising compound 1 or its pharmaceutical salt as an active ingredient, a carrier material, and a surfactant, wherein the carrier material is selected from hydroxypropyl methylcellulose succinate (HPMCAS), and the surfactant is selected from sodium dodecyl sulfate (SDS) or polyethylene glycol eurotin succinate (TPGS). The weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 1:2 to 1:4, and the surfactant accounts for 0.5% to 15% of the weight of the solid dispersion.

[0021] This invention provides a solid dispersion of compound 1 or its pharmaceutical salt, comprising compound 1 or its pharmaceutical salt as the active ingredient, a carrier material, and a surfactant, wherein the carrier material is selected from hydroxypropyl methylcellulose succinate (HPMCAS), and the surfactant is selected from sodium dodecyl sulfate (SDS) or polyethylene glycol succinate (TPGS). The weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 1:2 to 1:4, and the surfactant accounts for 2 to 8% of the weight of the solid dispersion.

[0022] In another aspect, the present invention also provides a method for preparing the solid dispersion, including hot melt extrusion or spray drying, preferably spray drying.

[0023] According to an embodiment of the present invention, the spray drying method comprises: dissolving compound 1 or its pharmaceutical salt and carrier material in a solvent, stirring until dissolved, removing the solvent and drying to obtain a solid dispersion.

[0024] In some embodiments, compound 1 or its pharmaceutical salt is amorphous;

[0025] In some embodiments, compound 1 is a crystal form, which may be selected from crystal form A, as disclosed in patent document WO2024083150A1.

[0026] According to an embodiment of the present invention, the A crystal form uses Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 10.40±0.20, 11.79±0.20, 19.51±0.20, and 20.81±0.20.

[0027] Preferably, the A crystal form uses Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 10.40±0.20, 11.79±0.20, 15.92±0.20, 16.92±0.20, 19.51±0.20, 20.81±0.20, 21.19±0.20, and 22.91±0.20.

[0028] Preferably, the A-type crystal uses Cu-Ka radiation, and the X-ray powder diffraction, expressed in 2θ angles, also has characteristic peaks at 3.17±0.20, 8.50±0.20, 13.24±0.20, 15.15±0.20, 19.03±0.20, 25.03±0.20, and / or 26.95±0.20.

[0029] In some embodiments of the present invention, the A crystal form has an XRPD pattern that is essentially as shown in Figure 1 of WO2024083150A1.

[0030] In some embodiments of the present invention, the XRPD spectral analysis data of the A crystal form are shown in the following table:

[0031] According to an embodiment of the present invention, the spray drying method further includes dissolving the surfactant in a solvent, stirring until dissolved, removing the solvent, and drying.

[0032] According to an embodiment of the present invention, the method for preparing the solid dispersion further includes vacuum drying the spray-dried solid powder after spray drying; preferably, the vacuum drying temperature is 30-70°C and the time is 15-30h, more preferably, the vacuum drying temperature is 40-60°C, such as 40°C, 45°C, 50°C, 55°C, or 60°C, and the time is 15-25h, such as 15h, 18h, 20h, 22h, or 25h.

[0033] According to an embodiment of the present invention, the solvent in the spray drying method is selected from one or more of methanol, ethanol, acetone, dichloromethane, isopropanol, acetonitrile, tetrahydrofuran, and cyclohexane, preferably one or more of methanol, acetone, and dichloromethane, such as methanol, acetone, dichloromethane, a mixed solvent of methanol and dichloromethane, a mixed solvent of acetone and dichloromethane, or a mixed solvent of methanol and acetone.

[0034] According to an embodiment of the present invention, the solvent in the spray drying method is further preferably a mixture of dichloromethane and methanol, with a volume ratio of 1:1 to 4:1, for example 1:1, 2:1, 3:1, 4:1, preferably 2:1.

[0035] According to an embodiment of the present invention, the mass-to-volume ratio of the crystal form of compound 1 or its pharmaceutical salt to the solvent in the spray drying method is 1g:30-100mL, preferably 1g:40-90mL, more preferably 1g:40-80mL, for example 1g:40mL, 1g:50mL, 1g:60mL, 1g:70mL, 1g:80mL.

[0036] According to an embodiment of the present invention, the inlet temperature of the spray drying method is 75-90°C, such as 75°C, 80°C, 85°C, or 90°C.

[0037] In another aspect, the present invention also provides a solid dispersion obtained by the preparation method described above.

[0038] According to an embodiment of the present invention, the particle size distribution D of the solid dispersion particles prepared by the spray drying method is... 50 The range is 2–80 μm, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 μm, D 90Within the range of 20–200 μm, for example, 20, 25, 30, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 μm. D is preferred. 50 The range is 8–50 μm, D 90 Between 20 and 100 μm.

[0039] In another aspect, the present invention also provides a pharmaceutical preparation comprising a solid dispersion of the compound 1 or a pharmaceutical salt thereof, and pharmaceutically acceptable excipients.

[0040] According to embodiments of the present invention, the pharmaceutically acceptable excipients include one, two or more of the following: diluents, disintegrants, lubricants, binders, flow aids, antioxidants, stabilizers, and coating materials.

[0041] According to embodiments of the present invention, the pharmaceutically acceptable excipients include one, two or more of the following: diluents, disintegrants, lubricants, flow aids, and coating materials.

[0042] According to an embodiment of the present invention, the diluent is selected from one or more of microcrystalline cellulose, lactose (such as lactose monohydrate or anhydrous lactose), mannitol, corn starch, sorbitol, and pregelatinized starch, preferably one, two, or more of microcrystalline cellulose, lactose, and mannitol.

[0043] According to an embodiment of the present invention, the disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and dry starch, preferably one, two or more of sodium crospovidone carboxymethyl cellulose, crospovidone, and sodium carboxymethyl starch.

[0044] According to an embodiment of the present invention, the lubricant is selected from one, two or more of magnesium stearate, stearic acid, sodium stearate fumarate, micronized silica gel, calcium stearate, and hydrogenated vegetable oil, preferably one, two or more of magnesium stearate, stearic acid, and sodium stearate fumarate.

[0045] According to an embodiment of the present invention, the flow aid is selected from one, two or more of silica, talc, and polyethylene glycol, preferably silica.

[0046] According to an embodiment of the present invention, the coating material is selected from one, two or more of ethyl cellulose, polyacrylic resins, and gastrointestinal film coating powder.

[0047] According to an embodiment of the present invention, the pharmaceutical preparation is a tablet, capsule, granule, or sustained-release tablet.

[0048] According to embodiments of the present invention, the pharmaceutical formulation is an oral tablet, wherein the solid dispersion of compound 1 or its pharmaceutical salt constitutes 1-50% of the tablet by weight, for example, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40%. In some embodiments, the solid dispersion of compound 1 or its pharmaceutical salt constitutes 2-40% of the tablet by weight; in some embodiments, the solid dispersion of compound 1 or its pharmaceutical salt constitutes 2-35% of the tablet by weight.

[0049] According to an embodiment of the invention, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipient includes a diluent, wherein the weight percentage of the diluent in the tablet is 40-95%, preferably 50-90%, for example 50%, 60%, 70%, 80%, or 90%.

[0050] According to an embodiment of the present invention, the pharmaceutical preparation is an oral tablet, wherein the diluent is selected from microcrystalline cellulose and lactose, and the ratio of microcrystalline cellulose to lactose is 1:0.2 to 1:2, preferably 1:0.25 to 1:1, for example 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0051] According to an embodiment of the present invention, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipient includes a disintegrant, the disintegrant being present in a weight ratio of 1 to 10% of the tablet, preferably 2 to 6%, for example 2%, 3%, 4%, 5%, 6%.

[0052] According to an embodiment of the present invention, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipients include retention aids, and the flow aids are present in the tablet at a weight ratio of 0.2-5%, preferably 0.5-2%, for example 0.5%, 1%, 1.5%, 2%.

[0053] According to an embodiment of the present invention, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipient includes a lubricant, and the lubricant is present in the tablet at a weight ratio of 0.2-5%, preferably 0.5-2%, for example 0.5%, 1%, 1.5%, 2%.

[0054] According to an embodiment of the present invention, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipient includes a coating material, and the weight ratio of the coating material to the uncoated tablet is 1-10%, preferably 2-5%, for example 2%, 3%, 4%, 5%.

[0055] According to an embodiment of the present invention, the oral tablets can be prepared by one or more of the following processes: wet granulation, dry granulation, fluidized bed granulation, and direct mixing tableting. Dry granulation is preferred, and the tablets are further compressed and coated after dry granulation to obtain oral tablets.

[0056] According to an embodiment of the present invention, the active ingredient compound 1 or its pharmaceutical salt in the pharmaceutical preparation is in an amorphous form.

[0057] According to an embodiment of the present invention, the active ingredient compound 1 or its pharmaceutical salt in the oral tablet is in an amorphous form.

[0058] According to embodiments of the present invention, the present invention also provides the use of the pharmaceutical preparation in the preparation of medicaments for the prevention and / or treatment of diseases.

[0059] According to embodiments of the present invention, the present invention also provides a method for preventing and / or treating a disease, comprising administering a therapeutically effective amount of the pharmaceutical preparation to a patient.

[0060] According to an embodiment of the present invention, the disease is a sex hormone-dependent disease.

[0061] According to embodiments of the present invention, the sex hormone-dependent diseases include, but are not limited to, benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibroids, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysmenorrhea (PMDD), HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with luteinized theca cells in the ovarian stroma), other manifestations of high intraovarian androgen concentrations (e.g., follicular arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (virilizing ovarian tumors or adrenal tumors), menorrhagia, and / or adenomyosis.

[0062] According to an embodiment of the present invention, the disease is a menopausal syndrome-related disease; preferably, the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness, and / or obesity.

[0063] According to an embodiment of the present invention, the disease is vasomotor syndrome. Beneficial effects

[0064] The solid formulation of this invention ensures good stability, dissolution, and therapeutic efficacy of the drug, making it suitable for the clinical application of compound 1 or its pharmaceutical salts. The formulation of this invention provides rapid drug release, reducing the burden of high-dose oral tablets for menopausal patients, thereby improving treatment adherence and efficacy. Attached Figure Description

[0065] Figure 1 shows the XRPD spectra of crystalline active pharmaceutical ingredient compound 1 and formulation 1 ASD in Example 4;

[0066] Figure 2a shows the DSC and TGA spectra of crystalline active pharmaceutical ingredient compound 1 in Example 5;

[0067] Figure 2b shows the TGA spectrum of formulation 1ASD in Example 5;

[0068] Figure 3 shows the XRPD spectra of formulations 1-3, 7-9, 11, and 12 in the stability study of Example 7;

[0069] Figure 4 shows the XRPD spectrum of packaged Formulation 1ASD in Example 10 during the stability test;

[0070] Figure 5 shows the powder dissolution results of different ASDs in Example 13. Detailed Implementation

[0071] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0072] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0073] Unless otherwise specified, % in this invention represents wt%.

[0074] Solid dispersions are abbreviated as ASD below.

[0075] Substance Definitions: HPMCAS: Hydroxypropyl methylcellulose acetate succinate; Soluplus: Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; PVP-VA: Polyvinylpyrrolidone-vinyl acetate copolymer; SDS: Sodium lauryl sulfate; TPGS: Polyethylene glycol succinate (vitamin E); HPC: Hydroxypropyl cellulose; HPMC: Hydroxypropyl methylcellulose

[0076] The compound 1 raw material involved in the examples, when in crystalline state, was obtained by referring to Example 1 of WO2024083150A1, “Preparation of the crystal form of compound A shown in formula (I)”.

[0077] Compound 1 has the following structure:

[0078] Example 1: Solvent Screening for Solid Dispersions

[0079] To screen for suitable spray drying solvents, the solubility of crystalline active pharmaceutical ingredient compound 1 in various organic solvents at room temperature (25°C) was determined.

[0080] Table 1

[0081] The solubility results in the table above show that the crystalline active pharmaceutical ingredient compound 1 has the highest solubility in dichloromethane:methanol = 2:1. Therefore, dichloromethane:methanol = 2:1 (v / v) was selected as the solvent for the preparation of the solid dispersion.

[0082] Example 2: Screening of carrier materials for solid dispersions

[0083] 2.1 Test Object

[0084] (1) Preparation of samples (No. 2-9) Crystalline drug substance compound 1 + carrier material

[0085] Weigh approximately 10 mg of crystalline active pharmaceutical ingredient compound 1 and 40 mg of carrier material and transfer them to 40 mL glass bottles respectively. Then add 1 mL of dichloromethane:methanol (2:1, v / v) solvent and shake continuously to completely dissolve the contents, obtaining a solution with a drug loading of 20%. Then transfer the solution to an 80 °C oven until the solvent has completely evaporated (approximately 1 hour), resulting in a transparent or translucent film.

[0086] (2) Prepare sample (No. 0-1) as a comparison.

[0087] No. 0 refers to crystalline active pharmaceutical ingredient compound 1;

[0088] No. 1: Weigh about 10 mg of crystalline raw material compound 1, add 1 mL of dichloromethane:methanol (2:1, v / v) solvent and shake continuously to dissolve completely, then transfer to an 80°C oven until the solvent is completely evaporated (about 1 hour) to obtain amorphous compound 1.

[0089] 2.2 Test Method

[0090] The samples No. 0-9 prepared above were subjected to dynamic solubility tests at different time points in biological media (FaSSIF, pH 6.52) to evaluate the effect of different carrier materials on the dissolution effect of compound 1 in biological media. The results are shown in Table 2.

[0091] Table 2

[0092] The results showed that, within the first 30 minutes, Soluplus, HPMCAS-HG, and HPMCAS-MG exhibited relatively better dissolution results compared to the crystalline active pharmaceutical ingredient, Compound 1. Considering that HPMCAS-HG and HPMCAS-MG, although different in type, have similar physicochemical properties, Soluplus and HPMCAS-HG were initially selected as the preferred carrier materials for the preparation of the solid dispersion of Compound 1.

[0093] Example 3: Preparation of solid dispersions

[0094] The solid dispersion of compound 1 was prepared according to the composition ratios shown in Table 3. The corresponding proportions of carrier material and surfactant were weighed and added to 100 mL of dichloromethane:methanol (2:1, v / v) solvent. The mixture was stirred continuously until completely dissolved, and then 2.0 g of the crystalline active pharmaceutical ingredient compound 1 was added. Stirring continued until completely dissolved. Spray drying was performed using a Buchi B290 spray dryer with the inlet temperature set at 85°C. The collected spray-dried solid powder was then dried under vacuum at 50°C for approximately 20 h.

[0095] Table 3

[0096] Example 4: XRPD Characterization

[0097] X-ray powder diffraction was used to characterize the crystalline active pharmaceutical ingredient (API) compound 1 powder and the solid dispersion powders prepared by formulations 1-12 in Example 3. The crystalline API compound 1 powder, formulations 4, 5, 6 and 10 all showed obvious API crystalline characteristic peaks, while the remaining formulations were in an amorphous state.

[0098] The XRPD patterns of the crystalline active pharmaceutical ingredient compound 1 powder and the ASD powder of formulation 1 are shown in Figure 1. The XRPD pattern of the crystalline active pharmaceutical ingredient compound 1 powder shows that it has crystalline characteristics. The XRPD pattern of the ASD powder prepared by formulation 1 does not show the characteristic crystalline peaks of the drug, indicating that the drug has been completely converted into an amorphous form in ASD.

[0099] Example 5: DSC and TGA detection

[0100] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to analyze the crystalline active pharmaceutical ingredient (API) compound 1 powder and the ASD powder prepared from formulation 1. The results are shown in Figures 2a and 2b. In Figure 2a, the crystalline API compound 1 showed two melting peaks at 249.79℃ and 270.88℃, while in Figure 2b, the ASD powder prepared from formulation 1 showed no crystalline melting peaks, indicating that the drug had been converted to an amorphous form in the ASD.

[0101] Example 6: Dissolution Performance Study

[0102] The solid dispersions prepared by formulations 1-3, 7-9, 11, and 12, as well as the starting crystalline active pharmaceutical ingredient compound 1, were used as controls for in vitro release performance testing. The drug concentration in the supernatant at predetermined time points was determined by a two-step dissolution assay (FaSSGF-FaSSIF). The experimental results are shown in Table 4.

[0103] Two-step dissolution test conditions and procedures: ASD and crystalline drug substance compound 1 were weighed into 40 mL glass vials, and 5 mL of FASSGF (target API concentration of 2 mg / mL) was added. After stirring at 37°C and 500 rpm for 0.5 hours, 5 mL of 2*FaSSIF (target API concentration of 1 mg / mL) was immediately added to the suspension, and stirring was continued for 1.5 hours. At predetermined time points (0.25, 0.5, 0.75, 1.0, 1.5, and 2.0 h), 350 μL of the suspension was collected, centrifuged at 14000 rpm for 5 min, and the supernatant was diluted 7-fold before UPLC analysis. Furthermore, the final pH value of the suspension was determined after the solubility test.

[0104] Table 4

[0105] The results showed that all formulations significantly improved the solubility of compound 1, with formulations 1, 2, 3, and 11 exhibiting superior solubility. Compared to the crystalline active pharmaceutical ingredient compound 1, the solubility of the four ASDs described in formulations 1-3 and 11 was increased by approximately 2-9 times in FaSSGF solution and by 6-19 times in FaSSIF solution.

[0106] Example 7: Stability Study (1 week)

[0107] The ASDs prepared from formulations 1-3, 7-9, 11, and 12, as well as the starting crystalline active pharmaceutical ingredient compound 1, were used as controls for stability testing.

[0108] Test method: ASD powder or crystalline raw material compound 1 was placed in an open glass bottle and placed in a constant temperature and humidity chamber at 40℃ / 75%RH for 1 week. The content and related substances were determined by HPLC and characterized by XRPD. The test results are shown in Table 5 and Figure 3.

[0109] Table 5

[0110] The one-week stability results show that, compared with the crystalline active pharmaceutical ingredient compound 1, the ASD samples prepared from formulations 1-3, 7-9, 11, and 12 exhibited good chemical stability after one week, with no significant increase in impurities. The XRPD characterization results are shown in Figure 3. Formulations 8, 9, 11, and 12 underwent crystal transformation, indicating poor physical stability. Formulations 1, 2, 3, and 7 did not undergo crystal transformation and showed good physical stability.

[0111] Example 8: Stability Study (2 / 4 weeks)

[0112] The ASD obtained from formulations 1-3 and 7, and the starting crystalline active pharmaceutical ingredient compound 1 were used as controls for two-week and four-week stability tests.

[0113] Test method: The storage conditions were 30℃ / 65%RH and 40℃ / 75%RH. Samples were taken at two weeks and four weeks, and the content and related substances were determined by HPLC and characterized by XRPD. The test results are shown in Table 6.

[0114] Table 6

[0115] As shown in Table 6, compared with the crystalline active pharmaceutical ingredient compound 1, the four ASD samples exhibited good chemical stability, with a total impurity content of 0.48% under various conditions. No significant impurity growth was observed during the stability test. XRPD characterization results indicate that the four ASD samples have good physical stability, and no crystal transformation was observed during the stability test.

[0116] Example 9: In vivo pharmacokinetic evaluation

[0117] Test sample: ASD prepared according to prescriptions 1, 2, and 3.

[0118] Reference standard: crystalline active pharmaceutical ingredient compound 1.

[0119] Experimental animals: Rats, 6-8 weeks old, females weighing 180±10g and males weighing 230±10g, 6 rats per group, 3 females and 3 males, original source: Experimental Animal Management Department of Shanghai Institute of Family Planning Science.

[0120] Experimental steps:

[0121] (1) Grouping and experimental design

[0122] Two dosages were set: 30 mg / kg and 300 mg / kg. Six animals were given each dose, three males and three females, as detailed in Table 7 below.

[0123] Table 7 *PO: Oral administration

[0124] (2) Sample collection

[0125] Rats were administered the drug via gavage, and blood samples were collected at the following time points: pre-dose, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h, 24 h, and 48 h post-dose. Blood was collected via the jugular vein or other suitable vein at a rate of 0.2 mL per time point, anticoagulated with K2-EDTA. Plasma was obtained by centrifugation within 1 h of blood sample collection (centrifugation conditions: 6800 g, 6 min, 2-8 °C). Samples were stored at -80 °C before analysis.

[0126] The results of in vivo pharmacokinetic tests are shown in Table 8.

[0127] Table 8

[0128] As shown in Table 8, compared with the crystalline active pharmaceutical ingredient compound 1, the ASDs prepared by formulations 1 to 3 above can significantly improve the in vivo absorption of the drug. At the same time, there may be some differences in the absorption of the drug in male and female rats.

[0129] Example 10: Crystal form stability test

[0130] The ASD prepared according to Formula 1 was packaged in double-layered polyethylene bags with the bags sealed, a desiccant packet placed between the two layers, and then placed in an aluminum foil bag. The crystal stability of the packaged Formula 1 ASD powder was investigated using XRPD to determine whether crystal transformation had occurred. The stability test conditions were 40±2℃ / 75±5%RH and 25±2℃ / 60±5%RH for 3 months. The results are shown in Figure 4. During the 3-month stability test, the drug in the ASD remained amorphous and no crystal transformation occurred.

[0131] Example 11: Further Study of Solid Dispersions

[0132] According to the prescription in Table 9, a solid dispersion was prepared using crystalline active pharmaceutical ingredient compound 1 and carrier material HPMCAS-HG as raw materials, referring to the preparation method of Example 3.

[0133] The physicochemical properties of the ASD powders prepared according to formulations 1, 13, and 14 are shown in Table 9. XRPD was used to detect the drug crystal form in the samples to determine whether an amorphous structure was formed. The results showed that the solid dispersions with different drug loadings were all amorphous, and the particle size results were basically the same.

[0134] Table 9

[0135] Example 12: Crystal form stability test

[0136] Sample 1 of Formulation 1 was stored under accelerated conditions (40±2℃ / 75±5%RH) for 6 months and under long-term conditions (25±2℃ / 60±5%RH) for 24 months. No significant changes were observed in the properties, content, total impurities, moisture content, and crystal form. The results of the accelerated condition test are shown in Table 10, and the results of the long-term condition test are shown in Table 11.

[0137] Formulation 14 prepared in Example 11 was subjected to a 4-week stability test under closed-cell conditions at 25°C / 60%RH and open-cell or closed-cell conditions at 40°C / 75%RH. The results are shown in Table 12. The results show that the high-drug-loaded formulation 14 sample did not show a significant increase in impurities under both 25°C / 60%RH and 40°C / 75%RH conditions, indicating good chemical stability. The samples under both open and closed-cell conditions remained amorphous after 4 weeks, demonstrating good physical stability.

[0138] Table 10 N / A: Not applicable

[0139] Table 11 N / A: Not applicable

[0140] Table 12 " / " indicates that no detection was performed.

[0141] Example 13: Evaluation of ASD powder dissolution

[0142] Samples of prescription 1, prescription 13, and prescription 14 underwent a two-step dissolution test in simulated gastrointestinal fluid.

[0143] Two-step dissolution test conditions and procedures: Following the second method (paddle method) of the Dissolution and Release Determination Method in Chinese Pharmacopoeia 0931 (2025 edition), 900 ml of FaSSGF (pH 1.6) to FaSSIF (pH 6.5) medium was used at a rotation speed of 50 rpm. The theoretical API concentration was 0.033 mg / mL. Samples were taken at predetermined time points (5, 10, 15, 30, 60, and 90 min), and HPLC was used to determine the dissolution rate. Furthermore, the pH value of the dissolution solution was measured after sampling at 90 min of dissolution.

[0144] As shown in Table 13 and Figure 5, in the two-step dissolution experiment in simulated biological media, the dissolution rates of ASD with three different drug loadings were basically the same, and complete release could be achieved in FaSSIF.

[0145] Table 13

[0146] Example 14: Dissolution evaluation of ASD-corresponding tablets

[0147] The solid dispersions 33% ASD, 25% ASD, and 20% ASD prepared in Example 11 were used to prepare tablets 1, 2, and 3 according to the tablet formulation composition described in Table 14. The tablet preparation process included premixing, sieving, dry granulation, total mixing, and tableting.

[0148] Table 14 " / " indicates that it is not applicable.

[0149] Dissolution tests were conducted on the tablets listed in Table 14. The experimental procedures and conditions are as follows:

[0150] According to the second method (paddle method) of the Dissolution and Release Determination Method of Chinese Pharmacopoeia 0931 in 2025, the dissolution test was carried out using 900 ml of pH 6.8 phosphate buffer and a rotation speed of 75 rpm. After the tablets were added, samples were taken at predetermined time points (5, 10, 15, 30, 45, 60, and 90 min) and the dissolution rate was calculated by HPLC.

[0151] The experimental results are shown in Table 15. The results show that ASD with different drug loadings can be dissolved by more than 95% within 15 minutes.

[0152] Table 15

[0153] Example 15: Animal pharmacokinetic evaluation of ASD-corresponding tablets

[0154] For tablets 1-3 prepared in Example 14, the pharmacokinetic parameters of different formulation tablets were investigated.

[0155] Experimental animals: 9 Beagle dogs, washed-out males, 9-10 months old, purchased from Jiangsu Mas Biotechnology Co., Ltd. All animals were fasted overnight before administration and fed 4 hours after administration.

[0156] Experimental steps:

[0157] The grouping and experimental design are shown in Table 16. After overnight fasting, beagle dogs were given intramuscular injection of pentagastrin (6 μg / kg, 0.08 mL / kg) according to the dosage and route of administration in Table 16. The pH value of the gastric juice was measured 25 min after injection. Animals with a pH value between 1 and 3 were immediately given the test tablet orally. Plasma samples were collected at predetermined time points and analyzed. The experiment was conducted in three cycles, with a washout period of at least 7 days between each two cycles.

[0158] Based on plasma drug concentration-time data and animal dosage, the pharmacokinetic parameters of compound 1 in plasma were calculated using a non-compartmental model with WinNonlin 8.2 software, including the area under the drug-time curve (AUC) and elimination half-life (t). 1 / 2 Peak concentration C max Peak Time Tmax , etc. Pharmacokinetic parameters C were analyzed using Microsoft Excel 2016. max AUC last and AUC INF Perform a T-test.

[0159] The experimental results are shown in Tables 17 and 18. According to the results, the C-value of tablets with three different ASD loadings administered to beagle dogs was [not specified]. max AUC last and AUC INF There were no statistically significant differences (P > 0.05).

[0160] Table 16 *: Fasting refers to fasting overnight before administration and feeding 4 hours after administration.

[0161] Table 17

[0162] Table 18

[0163] The exemplary embodiments of the present invention have been described above. However, the scope of protection of this application is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A solid dispersion of compound 1 or its pharmaceutical salt thereof, comprising compound 1 or its pharmaceutical salt as the active ingredient and a carrier material, wherein the carrier material is selected from one, two or more of polyvinylpyrrolidone (PVP), copovidone (CoPVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), and ethyl cellulose (EC); wherein the structure of compound 1 is shown below: Preferably, the carrier material is selected from one, two or more of PVP-VA, HPMCAS, and Soluplus; Preferably, the carrier material PVP-VA is selected from PVP-VA 64, and HPMCAS is selected from HPMCAS-HG or HPMCAS-MG; Preferably, when the carrier material is a combination of two materials, the carrier material is a combination of HPMCAS and Soluplus, a combination of PVP-VA and HPMCAS, or a combination of PVP-VA and Soluplus; Preferably, when the carrier material is a combination of two materials, the weight ratio of the two carrier materials is 1:5 to 5:1; Preferably, the weight ratio of compound 1 or its pharmaceutical salt to the carrier material is 10:1 to 1:10, more preferably 1:1 to 1:9, and even more preferably 1:2 to 1:

9.

2. A solid dispersion of Compound 1 or a pharmaceutically acceptable salt thereof according to claim 1, wherein The solid dispersion also includes a surfactant; Preferably, the surfactant includes one, two or more of poloxamer, sodium dodecyl sulfate (SDS), polyethylene glycol eurotin succinate (TPGS), and Tween; Preferably, the surfactant has a weight percentage of 0.5% to 15% in the solid dispersion, more preferably 2% to 8%.

3. A solid dispersion of a compound 1 according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The active ingredient compound 1 or its pharmaceutical salt in the solid dispersion is in an amorphous form.

4. A process for preparing a solid dispersion of a compound 1 or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized by, The preparation method includes hot melt extrusion or spray drying, with spray drying being preferred; Preferably, the spray drying method comprises: dissolving compound 1 or its pharmaceutical salt and carrier material in a solvent, stirring until dissolved, removing the solvent and drying to obtain a solid dispersion; Preferably, compound 1 is in crystalline form; Preferably, the crystal form is A crystal form, and the X-ray powder diffraction, expressed in 2θ angles using Cu-Kα radiation, has characteristic peaks at 10.40±0.20, 11.79±0.20, 19.51±0.20, and 20.81±0.

20. Preferably, the A crystal form uses Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 10.40±0.20, 11.79±0.20, 15.92±0.20, 16.92±0.20, 19.51±0.20, 20.81±0.20, 21.19±0.20, and 22.91±0.

20.

5. A process for preparing a solid dispersion of Compound 1 or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that, The spray drying method further includes dissolving the surfactant in a solvent, stirring until dissolved, removing the solvent, and then drying. Preferably, the method for preparing the solid dispersion further includes vacuum drying the spray-dried solid powder after spray drying; preferably, the vacuum drying temperature is 30-70°C and the time is 15-30 h, more preferably, the vacuum drying temperature is 40-60°C and the time is 15-25 h; Preferably, the solvent in the spray drying method is selected from one or more of methanol, ethanol, acetone, dichloromethane, isopropanol, acetonitrile, tetrahydrofuran, and cyclohexane, and more preferably one or more of methanol, acetone, and dichloromethane, such as methanol, acetone, dichloromethane, a mixed solvent of methanol and dichloromethane, a mixed solvent of acetone and dichloromethane, or a mixed solvent of methanol and acetone. In the spray drying method, the solvent is further preferably a mixture of dichloromethane and methanol, with a volume ratio of 1:1 to 4:

1. Preferably, the mass-to-volume ratio of the crystal form of compound 1 or its pharmaceutical salt to the solvent in the spray drying method is 1g:30-100mL, more preferably 1g:40-90mL, and even more preferably 1g:40-80mL.

6. The solid dispersion obtained by the preparation method according to claim 4 or 5; Preferably, the particle size distribution D of the solid dispersion particles prepared by the spray drying method is... 50 The range is 2–80 μm, D 90 Within the range of 20–200 μm, D is preferred. 50 The range is 8–50 μm, D 90 Between 20 and 100 μm.

7. A pharmaceutical preparation comprising a solid dispersion of compound 1 as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients; Preferably, the pharmaceutically acceptable excipients include one, two or more of the following: diluents, disintegrants, lubricants, binders, flow aids, antioxidants, stabilizers, and coating materials; Preferably, the pharmaceutical preparation is a tablet, capsule, granule, or sustained-release tablet; Preferably, the pharmaceutical preparation is an oral tablet, wherein the solid dispersion of compound 1 or its pharmaceutical salt is 1-50% by weight in the tablet, preferably 2-35%; Preferably, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipient includes a diluent, wherein the weight percentage of the diluent in the tablet is 40–95%, preferably 50–90%; Preferably, the pharmaceutical preparation is an oral tablet, wherein the diluent is selected from microcrystalline cellulose and lactose, and the ratio of microcrystalline cellulose to lactose is 1:0.2 to 1:2, preferably 1:0.25 to 1:1; Preferably, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipient includes a disintegrant, and the disintegrant accounts for 1 to 10% by weight in the tablet, preferably 2 to 6%. Preferably, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipients include retention aids, and the weight percentage of the glidant in the tablet is 0.2-5%, preferably 0.5-2%; Preferably, the pharmaceutical formulation is an oral tablet, wherein the pharmaceutically acceptable excipient includes a lubricant, and the lubricant accounts for 0.2-5% by weight of the tablet, preferably 0.5-2%. Preferably, the pharmaceutical preparation is an oral tablet, wherein the pharmaceutically acceptable excipients include coating materials, and the weight ratio of the coating material to the uncoated tablet is 1-10%, preferably 2-5%.

8. The method of preparing a pharmaceutical preparation according to claim 7, characterized by, The oral tablets can be prepared by one or more of the following processes: wet granulation, dry granulation, fluidized bed granulation, and direct mixing tableting. Dry granulation is preferred. After dry granulation, the tablets are further compressed and coated to obtain oral tablets. Preferably, the active ingredient compound 1 or its pharmaceutical salt in the pharmaceutical preparation is in an amorphous form; Preferably, the active ingredient compound 1 or its pharmaceutical salt in the oral tablet is in an amorphous form.

9. The use of a solid dispersion of compound 1 or its pharmaceutical salt according to claim 1 or 2, or the pharmaceutical preparation according to claim 7, in the preparation of a medicament for the prevention and / or treatment of a disease, wherein the disease is a sex hormone-dependent disease. Preferably, the sex hormone-dependent diseases include, but are not limited to, benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibroids, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysmenorrhea (PMDD), HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with luteinized theca cells in the ovarian stroma), other manifestations of high intraovarian androgen concentrations (e.g., follicular arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (virilizing ovarian tumors or adrenal tumors), menorrhagia, and / or adenomyosis; Preferably, the disease is a menopausal syndrome-related disease; preferably, the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness, and / or obesity; Preferably, the disease is vasomotor syndrome.

10. A method of preventing and / or treating a disease, comprising administering to a patient a therapeutically effective amount of a solid dispersion of compound 1 of claim 1 or 2 or a pharmaceutical salt thereof, or a pharmaceutical preparation of claim 7. Preferably, the disease is a sex hormone-dependent disease. Preferably, the sex hormone-dependent diseases include, but are not limited to, benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibroids, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysmenorrhea (PMDD), HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with luteinized theca cells in the ovarian stroma), other manifestations of high intraovarian androgen concentrations (e.g., follicular arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (virilizing ovarian tumors or adrenal tumors), menorrhagia, and / or adenomyosis; Preferably, the disease is a menopausal syndrome-related disease; preferably, the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness, and / or obesity; Preferably, the disease is vasomotor syndrome.

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