Long-acting formulation composition of relugolix

Abstract

Disclosed in the present invention are a long-acting formulation composition of Relugolix, a preparation method therefor, and use thereof. The composition comprises an active drug and at least one suspending agent. The long-acting formulation composition of Relugolix of the present invention has an excellent sustained-release effect, can prolong the administration interval from 1 day / time to 7 days to 90 days / time, and significantly improves the bioavailability, compliance, and safety of patients. The pharmaceutical composition of the present invention has the advantages of high formulation stability, simple prescription, controllable preparation process, and scale-up capability for industrial production.

Description

Long-acting formulations of retinoic acid Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a long-acting formulation of retinoic acid, its preparation method, and its application. Background Technology

[0002] Prostate cancer is the most common malignant tumor of the male reproductive system, and its incidence increases with age. It is reported to be the second leading cause of cancer death in men, after lung cancer. In recent years, with the aging of my country's population, the incidence of prostate cancer has been increasing year by year. Currently, the main treatment method for advanced or metastatic prostate cancer is endocrine therapy.

[0003] Endocrine therapy includes castration therapy (suppressing androgen secretion from the testes) and anti-androgen therapy (blocking the binding of androgens to receptors). Castration therapy includes surgical castration (orchiectomy) and medical castration. In advanced prostate cancer, gonadotropin-releasing hormone agonists are commonly used clinically. i (gonadotropin releasing hormone agonist, GHRH-a) is a drug-based castration treatment. Commonly used GHRH-a drugs include leuprorelin, goserelin, and triptorelin.

[0004] In the early stages of treatment, GHRH-a induces the release of gonadotropins, which increases testosterone levels and worsens patient symptoms. In severe cases, it can lead to death due to spinal cord compression. This phenomenon is clinically known as the "sparkling phenomenon." To prevent the serious adverse consequences of the "sparkling phenomenon," anti-androgen drugs (such as bicalutamide) are used in combination for two weeks before or on the day of GHRH-a injection and continue for two weeks after injection. This treatment method is cumbersome and increases the burden of medication for patients.

[0005] Gonadotropin-releasing hormone antagonists, such as regrugoli, have a different mechanism of action than agonists. They can rapidly and reversibly inhibit gonadotropin secretion to achieve rapid testosterone suppression, without producing a "blink" effect. They do not induce the initial stimulation of gonadotropin release and do not require the combined use of anti-androgen drugs to suppress testosterone surges. This improves efficacy, reduces adverse reactions, lowers the burden of medication on patients, and improves patient compliance.

[0006] Relugoli, chemically named 1-(4-(1-(2,6-difluorophenyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxy-1,2,3,4-tetrahydrothiophene[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea, has the following structure:

[0007] Relugoline tablets are an oral, non-peptide gonadotropin-releasing hormone (GnRH) antagonist, developed in collaboration between Takeda Pharmaceutical Company Limited and ASKA Pharmaceutical Company Limited of Japan. It received approval from the Japanese PMDA on January 8, 2019, under the brand name Relumina. Its indications include improving symptoms caused by uterine fibroids, menorrhagia, lower abdominal pain, back pain, anemia, and pain caused by endometriosis. On December 8, 2020, Takeda Pharmaceutical Company Limited and Roivant Technologies Ltd. of the UK jointly established Myovant Scientific Biopharmaceuticals Ltd., which applied for accelerated approval from the FDA for relugoline tablets in the US, under the brand name Orgovyx. Its indications include the treatment of adult patients with advanced prostate cancer, with a loading dose of 360 mg on the first day of treatment, followed by 120 mg orally once daily. On April 29, 2022, it was launched in Europe for the treatment of adult patients with advanced hormone-sensitive prostate cancer. This drug is currently not imported into China. Because the treatment cycle for prostate cancer is long, with a typical dosing cycle of 1-3 years, long-term use of regoracin tablets leads to poor patient compliance. Improving regoracin tablets into a long-acting injectable form, with a single injection providing sustained release for 7 days or longer, can significantly improve patient compliance.

[0008] Long-acting injectable formulations are a novel type of drug delivery system. Administered via intramuscular or subcutaneous injection, they create a drug reservoir at the injection site, slowly releasing the drug and providing a therapeutic effect lasting for weeks or months with a single injection. Compared to conventional oral formulations, long-acting injectables offer significant advantages. The slow release from the drug reservoir results in less fluctuation in blood drug concentration, reducing adverse drug reactions. The slow release also reduces dosing frequency, significantly improving patient compliance. Furthermore, long-acting injectables improve bioavailability, addressing the low bioavailability issue of oral administration (relugoline is an intestinal P-gp substrate, while Orgovyx has an oral bioavailability of only about 12%). They also avoid the gastrointestinal discomfort and swallowing difficulties associated with oral administration.

[0009] In summary, long-acting injections have clinical value in reducing fluctuations in drug blood concentrations, improving bioavailability, reducing toxic side effects, prolonging the duration of drug action, and reducing the frequency of administration. The clinical advantage of modifying regoraciate tablets into a long-acting injection lies in improving drug safety and patient compliance while maintaining efficacy.

[0010] Current design strategies for long-acting injectables typically include prodrug modification, PEGylation, poorly soluble salts or esters, long-acting microsphere formulations, in-situ gels, implants, and micron suspensions.

[0011] Micron-sized suspensions, also known as microcrystalline formulations, have become a research hotspot in recent years, enabling sustained-release effects. Micron-sized suspensions use the drug itself as the delivery system, eliminating the need for a carrier. They offer high drug loading capacity and small administration volume, making them particularly suitable for large-dose intramuscular or subcutaneous injections. Micron-sized suspensions form a local drug reservoir at the injection site, utilizing the drug's low solubility to achieve slow release, thus achieving a long-lasting sustained-release effect. With a clear mechanism of action, simple formulation and manufacturing process, mature production scale-up equipment, and ease of large-scale industrialization, they are the preferred dosage form for designing long-acting formulations.

[0012] CN 116531314 A discloses a nanocrystalline oral delivery system for regrugoli. The main content of the patent is to prepare regrugoli into nanocrystalline drugs using a media milling machine, then solidify it on a blank carrier by electrostatic adsorption, further dry it, compress it into tablets, fill it into capsules, or granulate it to obtain a nanocrystalline oral delivery system.

[0013] CN 115068421 A discloses a process for obtaining regrugoli nanosuspension by mixing an aqueous phase and a drug-loaded organic phase under the action of a stabilizer, followed by sonication and removal of organic solvent. This process and formulation increase the solubility of regrugoli by 7 times and the dissolution rate by 70%, thereby improving its oral bioavailability and oral efficacy.

[0014] The two patents mentioned above, along with other existing technologies, all prepare reglucoglide into nano-suspensions to increase its solubility and bioavailability for oral administration. However, they do not achieve long-lasting effects. This invention aims to develop a long-acting reglucoglide formulation that provides sustained release for 7 days or more. Summary of the Invention

[0015] To address the shortcomings of existing technologies, the main objective of this invention is to provide a relugoline pharmaceutical composition with a long-lasting sustained-release effect. This composition is a relugoline suspension prepared using nanotechnology or further processed into a powder composition by freeze-drying. This improves the sedimentation properties and / or redispersibility of the suspension, significantly enhancing formulation stability and clinical ease of use. It can also be restored to its pre-freeze-dried state after reconstitution with a conventional injectable solution. This composition greatly enhances the sustained-release effect, extending the dosing interval from 1 day / dose to 7-90 days / dose, significantly improving patient compliance and safety. The pharmaceutical composition of this invention features a simple formulation, controllable preparation process, scalability for industrial production, and high formulation stability.

[0016] Unless otherwise specified, the percentage content of this invention is expressed in w / v, which means the number of grams of the component contained in 100 ml of water.

[0017] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0018] A long-acting composition of relugoli, characterized in that it comprises relugoli and a suspending agent, wherein the suspending agent is polyethylene glycol, or carboxymethyl cellulose or a salt thereof.

[0019] In some technical solutions, the composition further comprises a pH adjuster, preferably, the pH adjuster is one or more selected from sodium phosphate, disodium hydrogen phosphate or disodium hydrogen phosphate (monohydrate), sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate), phosphoric acid, carbonic acid, sulfuric acid, hydrochloric acid, citric acid or citric acid (monohydrate), and sodium hydroxide. In some technical solutions, the pH adjuster is one or more selected from sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate), citric acid or citric acid (monohydrate), and sodium hydroxide. In some technical solutions, the content of the pH adjuster is 0.05‰-3%, 0.75‰-2.8%, 0.75‰-1.9%, 0.75‰-1%, or 1.9%-2.8%.

[0020] In some technical solutions, the composition further comprises a wetting agent, preferably one or more selected from polysorbate, polysorbate 20, polysorbate 80, sorbitan laurate, phospholipids, polyoxyethylene castor oil, deoxycholic acid and its sodium salt, and sodium lauryl sulfate. In some technical solutions, the wetting agent is polysorbate 20 (tween 20). In some technical solutions, the content of the wetting agent is 0.1-5%, 0.24-5%, 0.4-5%, 0.4-2%, or 0.4-1%.

[0021] In some technical solutions, the composition further comprises a lyophilization protectant, preferably one or more of sucrose, lactose, glucose, mannitol, maltose, and trehalose. In some technical solutions, the lyophilization protectant is mannitol. In some technical solutions, the content of the lyophilization protectant is 0.5-20%, 4-15%, 5-18%, or 4-5%.

[0022] In some technical solutions, the regrugoli content is 10%-40%, 15%-40%, 20%-40%, or 20%-30%. In other technical solutions, the regrugoli content is 20%, 25%, or 30%.

[0023] In some technical solutions, the molecular weight of the polyethylene glycol is 1000 (i.e., polyethylene glycol 1000, PEG 1000), 1500 (i.e., polyethylene glycol 1500, PEG 1500), 3350 (i.e., polyethylene glycol 3350, PEG 3350), 4000 (i.e., polyethylene glycol 4000, PEG 4000), or 6000 (i.e., polyethylene glycol 6000, PEG 6000). In some technical solutions, the content of polyethylene glycol is 1-20%, 2-20%, 2.5-10%, or 2.5-7.5%. Preferably, the long-acting formulation composition of regoragulide further comprises a wetting agent and a pH adjuster. In some technical solutions, the wetting agent is polysorbate 20 or polysorbate 80. In some technical solutions, the wetting agent content is 0.1-5%. In some technical solutions, the pH adjuster is one or more of sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate), citric acid or citric acid (monohydrate), and sodium hydroxide. In some technical solutions, the pH adjuster content is 0.05‰-3%. In some technical solutions, the composition further comprises a lyophilization protectant. In some technical solutions, the lyophilization protectant is mannitol. In some technical solutions, the lyophilization protectant content is 0.5-20%.

[0024] In some technical solutions, the carboxymethyl cellulose or its salt is sodium carboxymethyl cellulose (i.e., CMC-NA), and in some technical solutions, it is CMC-NA (7LF) or CMC-NA (7MF). In some technical solutions, the content of CMC-NA is 0.1%-5%, 0.5%-5%, 0.7%-4%, or 0.85%-4%. Preferably, the long-acting regrugolide composition further comprises a pH adjuster. In some technical solutions, the pH adjuster is one or more of sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate), citric acid or citric acid (monohydrate), and sodium hydroxide. In some technical solutions, the content of the pH adjuster is 0.05‰-3%. Preferably, the long-acting regrugolide composition further comprises a lyophilization protectant. In some technical solutions, the lyophilization protectant is mannitol. In some technical solutions, the content of the lyophilization protectant is 0.5-20%.

[0025] In some technical solutions, the composition further comprises hyaluronic acid or its sodium salt. In some technical solutions, the molecular weight of the hyaluronic acid or its sodium salt is 100,000 to 5,000,000, preferably 800,000 to 2,000,000; in some technical solutions, the molecular weight of the hyaluronic acid or its sodium salt is 1,000,000, 1,400,000, or 2,000,000. In some technical solutions, the content of the hyaluronic acid or its sodium salt is 0.05-2%, 0.05-1%, 0.05-0.5%, 0.25-0.5%, 0.1-0.5%, or 0.25-1% or 0.25-0.1%.

[0026] In some technical solutions, the composition has a D50 of 3-25 μm. In other technical solutions, the D50 is 3-20 μm, 6-20 μm, 3-18 μm, 5-18 μm, or 7-16 μm. In this invention, D50 specifically refers to the particle size distribution.

[0027] The composition exists in the form of a suspension or a freeze-dried product. Preferably, the composition is a freeze-dried powder for injection, used for parenteral injection, intramuscular injection, or subcutaneous injection. In some technical solutions, the suspension is freeze-dried to obtain the freeze-dried powder for injection.

[0028] In some technical solutions, the composition comprises the following components: reglugoline, polysorbate, sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate), citric acid or citric acid (monohydrate); in some technical solutions, the composition comprises the following components: reglugoline, polysorbate, sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate), citric acid or citric acid (monohydrate), mannitol; preferably, in the above technical solutions, it further comprises hyaluronic acid and its sodium salt; preferably, in the above technical solutions, it further comprises sodium hydroxide.

[0029] In some technical solutions, the composition comprises the following components: relugoli, CMC-Na, sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate); preferably, the above technical solutions further comprise mannitol; preferably, the above technical solutions further comprise hyaluronic acid and its sodium salt; preferably, the above technical solutions further comprise sodium hydroxide.

[0030] The long-acting composition is used in the treatment of prostate cancer and uterine fibroids.

[0031] The preparation method of the aforementioned long-acting relugoli composition employs a media milling process and includes the following steps:

[0032] (1) Preparation of blank excipient: Add the excipient to an appropriate amount of aqueous solution for injection and stir until clear and homogeneous to obtain a blank excipient solution.

[0033] (2) Dispersion of active ingredient: The active ingredient is added to the blank excipient solution under stirring or high-speed shearing, and after uniform dispersion, a crude suspension of retinoic acid is obtained.

[0034] (3) Media grinding: The crude suspension of relugoli was placed in a media grinding machine and zirconium oxide beads were used as the grinding media to obtain the relugoli suspension.

[0035] In some technical solutions, the excipients in step (1) include wetting agents, suspending agents and / or pH adjusters and / or lyophilization protectants, etc.

[0036] In some technical solutions, the grinding bead size in step (3) is 0.8-3.0 mm. In some technical solutions, the grinding media filling rate in step (3) is 50%-90% (v / v). In some technical solutions, the media grinding mill linear speed in step (3) is 2.5-10 m / s. In some technical solutions, the grinding temperature in step (3) is 10-40℃.

[0037] In some technical solutions, the D50 of the relugoli suspension is 3-25 μm. In other technical solutions, the D50 is 3-20 μm, or 6-20 μm, or 3-18 μm, or 5-18 μm, or 7-16 μm. In this invention, D50 specifically refers to the particle size distribution.

[0038] The preparation method of the aforementioned long-acting relugoli composition is not limited to media milling, but can employ air jet milling, and includes the following steps:

[0039] (1) Air jet milling: The active ingredient regrugoli was pulverized using an air jet mill to obtain micronized regrugoli.

[0040] (2) Dispersion of active ingredients: The active ingredients are added to the blank excipient solution under stirring and dispersed evenly to obtain rilugoli suspension.

[0041] The preparation method of the aforementioned long-acting relugoli composition is not limited to media milling, but can employ a microfluidic method, including the following steps:

[0042] (1) Preparation of blank excipient: Add the excipient to an appropriate amount of aqueous solution for injection and stir until clear and homogeneous to obtain a blank excipient solution.

[0043] (2) Dispersion of active ingredients: The active ingredients are added to the blank excipient solution under stirring or high-speed shearing, and after uniform dispersion, a coarse suspension is obtained.

[0044] (3) Microjets: The crude suspension of relugoli is placed in a microjets to obtain a relugoli suspension.

[0045] In some technical solutions, the pressure in step (3) is set to 3000-10000 psi. In some technical solutions, the temperature of the liquid is controlled at 10-40℃ in step (3). In some technical solutions, the microjet process involves 2-10 cycles in step (3).

[0046] The long-acting formulation composition of this invention comprises regrugolide and a specific suspending agent, existing in the form of a suspension or lyophilized product. This significantly improves the sustained-release effect, extending the dosing interval from once a day to 7-90 days, and substantially improving bioavailability, patient compliance, and safety. The specific suspending agent improves the sedimentation properties and / or redispersibility of the suspension, greatly enhancing formulation stability and clinical ease of use. It can also be restored to its pre-lyophilized state after reconstitution with conventional injectable solutions. The pharmaceutical composition of this invention has the advantages of simple formulation, controllable preparation process, and scalability for industrial production. Attached Figure Description

[0047] Figure 1 shows the plasma concentration curves of retinoic acid in rats of groups 1-3 (RF group, TF1 group, and TF2 group) in Example 20.

[0048] Figure 2 shows the blood concentration curves of retinoic acid in cynomolgus monkeys in groups 1-2 (TF3 and TF4) in Example 21.

[0049] Figure 3 shows the blood concentration curve of retinoic acid in cynomolgus monkeys in the RF group in Example 22. Detailed Implementation

[0050] The present invention is further illustrated below with specific embodiments. However, the present invention is not limited to the following embodiments and the preparation methods used. Any simple modifications made to the present invention based on the embodiments are within the scope of protection of the present invention.

[0051] The effective particle size of this invention is expressed as volumetric diameter and is measured using a Malvern laser particle size analyzer, model Malvern Mastersizer 3000. The equipment parameters are set as follows: particle refractive index is set to 1.7, particle absorptivity is 0.01, water is used as the dispersion medium, and the test sample suspension is added until the light-blocking rate is 8%-20% before measurement.

[0052] Unless otherwise specified, the percentage content of this invention is expressed in w / v, which means the number of grams of the component contained in 100 ml of water.

[0053] Example 1: Preparation of Relugoline Suspension

[0054] Preparation process:

[0055] (1) Add polysorbate 20, sodium dihydrogen phosphate (monohydrate), citric acid monohydrate and sodium hydroxide to an appropriate amount of water for injection according to the prescription dosage, stir until clear and uniform, and then add water for injection to make up to 250 ml to obtain a blank excipient solution.

[0056] (2) Add reglugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain reglugoline crude suspension;

[0057] (3) Place the crude suspension of rilugoli in a media mill, use zirconia beads as the grinding medium, the mill speed is 1000 r / min, the grinding temperature is 10-40℃, and the mill is milled 6 times to obtain a rilugoli suspension with a D50 of 11.861 μm.

[0058] Example 2: Investigating the effect of different suspending agents on the resuspensibility of retinoic acid suspension.

[0059] (1) Solution preparation: Measure 20 ml of the liquid after grinding in Example 1 into a vial, 20 ml / vial. Weigh CMC-Na(7MF), CMC-Na(7LF), F68, HS15, PVP K12, PVP K17, and PEG-4000 according to the following table, and add 20 ml of suspension and stir to dissolve to obtain Sample 1-Sample 9.

[0060] (2) Resuspension: Samples 1-9 were placed at room temperature for 8 hours (drug particles settled at the bottom of the bottle), and the vials were inverted for 30 seconds. The redispersion of the suspension was recorded (judgment criteria: no drug particles were seen at the bottom of the bottle, indicating that it was redispersible; drug particles were seen at the bottom of the bottle, indicating that it was not redispersible). If the redispersion time was less than 30 seconds, the redispersion time was recorded. The test results are shown in Table 1.

[0061] Table 1. Redispersion times of regrugoli suspensions for samples 1-9

[0062] The redispersibility results show that, for the same amount of additive, PEG 4000 has the best redispersibility of suspension and the shortest redispersibility time. Furthermore, the redispersibility increases with the increase of PEG 4000 dosage. Therefore, formulations containing PEG4000 are beneficial for the redispersibility of clinically used drug solutions, significantly improving convenience.

[0063] Example 3: Preparation of Relugoline Suspension

[0064] Preparation process:

[0065] (1) Add sodium dihydrogen phosphate (monohydrate), mannitol and sodium hydroxide to an appropriate amount of water for injection according to the prescription dosage, add water for injection to make up to 350 ml, stir until clear and uniform to obtain a blank excipient solution.

[0066] (2) Add reglugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain reglugoline crude suspension;

[0067] (3) Place the crude suspension of rilugoli in a media mill, use zirconia beads as the grinding medium, the mill speed is 1000 r / min, the grinding temperature is 10-40℃, and the mill is milled 8 times to obtain a rilugoli suspension with a D50 of 12.333 μm.

[0068] Example 4: Investigating the effect of different suspending agents on the sedimentation of relugoli suspension.

[0069] (1) Solution preparation: Measure 50 ml of the liquid after grinding in Example 3, 50 ml / bottle, weigh CMC-Na(7MF), CMC-Na(7LF), F68, HS15, PEG 4000 according to the table below, and add 50 ml of suspension and stir to dissolve to obtain sample 10-sample 14.

[0070] (2) Sedimentation volume ratio: Take 50 ml of each of samples 10-14, and compare the effect of adding the same amount of suspending agent on sedimentation according to the sedimentation volume ratio method in Part II of the Chinese Pharmacopoeia (2020 edition). Procedure: Measure 50 ml of the test sample using a stoppered graduated cylinder, seal tightly, shake vigorously for 1 min, and record the initial height Ho of the suspension. Let it stand for 1, 2, 3, 4, 6, and 8 hours, and record the final height H of the suspension respectively. Calculate the sedimentation volume ratio using the following formula: Sedimentation volume ratio = H / Ho. The test results are shown in Table 2.

[0071] Table 2 Sedimentation volume ratio of regrugoli suspensions in samples 10-14

[0072] The sedimentation volume ratio results show that the sedimentation volume ratios of the two groups of samples with added CMC-NA were not lower than 0.9 at 3h and 8h, while the sedimentation volume ratios of the other groups were significantly lower than 0.9 at 3h. The sedimentation of the two groups of drug solutions with added CMC-NA was slower, and the formulation stability was higher.

[0073] Example 5: Preparation of Relugoline Suspension

[0074] Preparation process:

[0075] (1) Add polysorbate 20, PEG4000, sodium dihydrogen phosphate (monohydrate), citric acid monohydrate and sodium hydroxide to an appropriate amount of water for injection according to the prescription dosage and make up to 2000 ml. Stir until clear and uniform to obtain a blank excipient solution.

[0076] (2) Add retlugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain retlugoline crude suspension.

[0077] (3) Place the crude suspension of rilugoli in a media mill, use zirconia beads as the grinding medium, the mill speed is 1200 r / min, the grinding temperature is 10-40℃, and the mill is milled 2.5 times to obtain a rilugoli suspension with D50 of 3-20 μm.

[0078] Example 6: Preparation of Relugoline Suspension

[0079] Preparation process:

[0080] (1) Add polysorbate 20, PEG4000, sodium dihydrogen phosphate (monohydrate), citric acid monohydrate and sodium hydroxide to an appropriate amount of water for injection according to the prescription dosage, add water for injection to make up to 2000 ml, stir until clear and uniform to obtain a blank excipient solution.

[0081] (2) Add retlugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain retlugoline crude suspension.

[0082] (3) Place the crude suspension of rilugoli in a media mill, use zirconia beads as the grinding medium, the mill speed is 1200 r / min, the grinding temperature is 10-40℃, and the mill is milled 12 times to obtain a rilugoli suspension with D50 of 3-20 μm.

[0083] Example 7: Preparation of Relugoline Suspension

[0084] Preparation process:

[0085] (1) Add CMC-NA (7LF), sodium dihydrogen phosphate (monohydrate), sodium hydroxide, and mannitol to an appropriate amount of water for injection according to the prescription dosage, and add water for injection to make up to 2000 ml. Stir until clear and uniform to obtain a blank excipient solution.

[0086] (2) Add retlugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain retlugoline crude suspension.

[0087] (3) Place the crude suspension of rilugoli in a media mill, use zirconia beads as the grinding medium, the mill speed is 1200 r / min, the grinding temperature is 10-40℃, and the mill is milled 3 times to obtain a rilugoli suspension with D50 of 3-20 μm.

[0088] Example 8: Preparation and sedimentation volume ratio test of sodium hyaluronate relugoli suspensions with different molecular weights.

[0089] (1) Solution preparation: Weigh appropriate amounts of sodium hyaluronate (molecular weights of 1 million, 1.4 million, and 2 million respectively), and dissolve in water for injection to obtain a 10 mg / ml stock solution. Weigh 58 g of the relugoli suspension prepared in Example 5, and add 6 g of the 10 mg / ml sodium hyaluronate stock solution (molecular weights of 1 million, 1.4 million, and 2 million respectively) and water for injection. The amount of sodium hyaluronate added to the suspension is approximately 1 mg / ml, as follows:

[0090] (2) Sedimentation volume ratio: Referring to the sedimentation volume ratio method in Part II of the Chinese Pharmacopoeia (2020 edition), the ability of adding the same amount of sodium hyaluronate with different molecular weights to improve the sedimentation of suspensions was compared. Procedure: 50 ml of the test sample was measured using a stoppered graduated cylinder, sealed tightly, and shaken vigorously for 1 min. The initial height Ho of the suspension was recorded. After standing for 1, 2, 3, 4, 6, and 8 hours, the final height H of the suspension was recorded. The sedimentation volume ratio was calculated using the following formula: Sedimentation volume ratio = H / Ho. The test results are shown in Table 3.

[0091] Table 3 Sedimentation volume ratio of regrugoli suspensions in samples 15-18

[0092] The sedimentation volume ratio results show that the sedimentation volume ratio of the suspension sample without sodium hyaluronate was 0.54 after 15 and 3 hours, while the sedimentation volume ratio with the addition of 1 mg / ml sodium hyaluronate was greater than 0.9. Sodium hyaluronate can improve the sedimentation properties of the suspension and increase the stability of the sample. Moreover, the improvement effect is more obvious with the increase of molecular weight, and the sample stability is higher.

[0093] Example 9: Preparation and sedimentation volume ratio test of sodium hyaluronate relugoli suspensions with different molecular weights.

[0094] (1) Solution preparation: Weigh appropriate amounts of sodium hyaluronate (molecular weights of 1 million, 1.4 million, and 2 million respectively), and dissolve in water for injection to obtain a stock solution of 10 mg / ml. Weigh 52 g of regorafenib suspension from Example 5, and add 12 g of 10 mg / ml sodium hyaluronate stock solution with molecular weights of (1 million, 1.4 million, and 2 million) and water for injection respectively. The amount of sodium hyaluronate added to the suspension is approximately 2 mg / ml, as follows:

[0095] (2) Sedimentation volume ratio: Referring to the sedimentation volume ratio method in Part II of the Chinese Pharmacopoeia (2020 edition), the ability of adding the same amount of sodium hyaluronate with different molecular weights to improve the sedimentation of suspensions was compared. Procedure: 50 ml of the test sample was measured using a stoppered graduated cylinder, sealed tightly, and shaken vigorously for 1 min. The initial height Ho of the suspension was recorded. After standing for 1, 2, 3, 4, 6, and 8 hours, the final height H of the suspension was recorded. The sedimentation volume ratio was calculated using the following formula: Sedimentation volume ratio = H / Ho. The test results are shown in Table 4.

[0096] Table 4 shows the sedimentation volume ratios of regrugoli suspensions in samples 19-22.

[0097] The sedimentation volume ratio results show that the sedimentation volume ratio of the suspension sample 19 without sodium hyaluronate was 0.56 after 3 hours, while the sedimentation volume ratio with the addition of 2 mg / ml sodium hyaluronate was greater than 0.9. Sodium hyaluronate can improve the sedimentation properties of the suspension and enhance sample stability, and the improvement effect is more pronounced with increasing molecular weight, resulting in higher sample stability. Examples 8 and 9 demonstrate that the improvement in sedimentation volume ratio is more significant and the sample stability is higher with increasing sodium hyaluronate concentration.

[0098] Example 10: Preparation and sedimentation test of sodium hyaluronate relugoli suspensions with different molecular weights.

[0099] (1) Solution preparation: Weigh an appropriate amount of sodium hyaluronate (molecular weights of 1 million and 2 million respectively), and dissolve it in water for injection to obtain a stock solution of 10 mg / ml. Weigh 435 g of the regorafenib suspension from Example 7, and add 145 g of water for injection and the 10 mg / ml sodium hyaluronate stock solution with molecular weights of (1 million and 2 million) respectively. The amount of sodium hyaluronate added to the suspension is approximately 2.5 mg / ml, as follows:

[0100] (2) Sedimentation test: The ability of adding sodium hyaluronate of different molecular weights to improve the sedimentation of suspension was compared using appearance, particle size, and content as indicators. Procedure: Add the test sample to a 1L beaker and stir well. Let it stand and observe whether the solution separates into layers at 0h, 15min, 30min, 1h, 2h, and 4h. At the same time, take appropriate amounts of the solution from the upper, middle, and lower layers of the beaker and measure the particle size and content of the upper, middle, and lower layers at 0h, 15min, 30min, 1h, 2h, and 4h. The results are shown in Table 5.

[0101] Table 5. Sedimentation properties of regrugoli suspensions in samples 23-25

[0102] As can be seen from the table above,

[0103] 1. Appearance: Group 1 showed stratification after 1 hour, while Groups 2 and 3 did not show stratification after 2 hours, indicating that the addition of sodium hyaluronate to the solution greatly improved the stability of the samples.

[0104] 2. Particle size: In Group 1, although no stratification occurred within 30 minutes, the particle size of the upper, middle, and lower layers was significantly different. After 15 minutes, the particle size of the lower layer increased while the particle size of the upper layer decreased, indicating that the particles settled very quickly. In Group 2, the particle sizes of the upper, middle, and lower layers were not significantly different in the first 3 hours. After 4 hours, the particle size of the lower layer showed an increasing trend, indicating that the solution was stable in the first 3 hours and showed a settling trend after 4 hours. Compared with Group 1, the effect of improving particle size and settling was significant. In Group 3, the particle sizes of the upper, middle, and lower layers were not significantly different within 4 hours, indicating that the solution did not settle significantly within 4 hours and remained stable.

[0105] 3. Content: In Group 1, the content of the upper, middle, and lower layers was inconsistent at 0h, indicating that the drug solution settled too quickly and was not easy to mix evenly. This trend became more obvious as time went on. In Group 2, the content of the upper, middle, and lower layers was consistent in the first 3h, until the content of the lower layer increased at 4h, indicating that the drug solution was stable in the first 3h and sedimentation occurred at 4h. In Group 3, the content of the upper, middle, and lower layers was consistent in the first 3h, and the content of the upper layer decreased and the content of the lower layer increased at 4h, indicating that the drug solution was stable in the first 3h and sedimentation occurred at 4h. Groups 2 and 3 were significantly better than Group 1.

[0106] Conclusion: The addition of sodium hyaluronate significantly improves the uniformity of the upper, middle and lower layers of the drug solution, prevents rapid sedimentation of the drug solution, and improves sample stability.

[0107] Example 11: Preparation of Reglugoli suspension by microfluidic method

[0108] Preparation process:

[0109] (1) Add CMC-NA (7MF), sodium dihydrogen phosphate (monohydrate), and sodium hydroxide to an appropriate amount of water for injection according to the prescription dosage and make up to 500 ml. Stir until clear and uniform to obtain a blank excipient solution.

[0110] (2) Add retlugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain retlugoline crude suspension.

[0111] (3) Microjets: The crude suspension of relugoli was placed in a microjets and the pressure was set to 3000-5000 psi. Homogenization was performed for 2, 5, 10 and 14 cycles respectively to obtain a relugoli suspension with D50 of 3-15 μm.

[0112] Example 12: Preparation of Reglugoli suspension by air jet milling

[0113] Preparation process:

[0114] (1) Weigh an appropriate amount of regrugoli raw material, set the air intake pressure, pulverizing pressure and feed speed of the air jet mill, and pulverize to obtain regrugoli raw material with D50 of 3-10um.

[0115] (2) Add CMC-NA (7MF), sodium dihydrogen phosphate (monohydrate), and sodium hydroxide to an appropriate amount of water for injection according to the prescription dosage and make up to 20 ml. Stir until clear and uniform to obtain a blank excipient solution.

[0116] (3) Weigh the amount of the pulverized raw material and disperse it in the blank excipients to make derilugoli suspension.

[0117] Example 13 Preparation of lyophilized formulation of relugoline

[0118] Preparation process:

[0119] (1) Add polysorbate 20, PEG4000, sodium dihydrogen phosphate (monohydrate), citric acid monohydrate and sodium hydroxide to water for injection according to the prescription dosage and make up to 15 ml. Stir until clear and uniform to obtain blank excipient solution.

[0120] (2) Add reglugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain reglugoline crude suspension;

[0121] (3) Add an appropriate amount of regrugoli coarse suspension to a 15ml centrifuge tube, and add an appropriate amount of zirconia grinding beads to the centrifuge tube. Grind the suspension using a media grinder at 1000rpm, at a grinding temperature of 10-40℃, for 3min, 4min, and 8min respectively, to obtain a regrugoli suspension with a D50 of 10-25um. The particle size is as follows:

[0122] (4) Add freeze-drying protectant: Weigh mannitol according to the prescription dosage and add it to the suspension and stir to dissolve.

[0123] (5) Filling: Measure 4 ml of regrugoli suspension and fill it into 7 ml vials, half-stop the vials, and place them in a freeze dryer. The freeze-drying temperature and time are as follows:

[0124] Example 14: Preparation of lyophilized formulation of relugoline

[0125] Preparation process:

[0126] (1) Add CMC-NA (7LF), sodium dihydrogen phosphate (monohydrate), mannitol and sodium hydroxide to 15ml of water for injection according to the prescription dosage, and stir until clear and uniform to obtain a blank excipient solution.

[0127] (2) Add reglugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain reglugoline crude suspension;

[0128] (3) Take an appropriate amount of retinoic acid crude suspension and add it to a 15ml centrifuge tube. At the same time, add an appropriate amount of zirconia grinding beads to the centrifuge tube and grind it using a media grinder. The media grinder speed is 1000rpm, the grinding temperature is 10-40℃, and the grinding time is 5min, 10min, and 15min respectively. A retinoic acid suspension with D50 of 10-20um is obtained, and the particle size is as follows.

[0129] (2) Filling: Measure 4 ml of regrugoli suspension and fill it into 7 ml vials, half-stop the vials, and place them in a freeze dryer. The freeze-drying temperature and time are as follows:

[0130] Example 15: Preparation of lyophilized formulation of relugoline.

[0131] Preparation process:

[0132] (1) Add CMC-NA (7LF), sodium dihydrogen phosphate (monohydrate), mannitol and sodium hydroxide to water for injection according to the prescription dosage and make up to 1000 ml. Stir until clear and uniform to obtain a blank excipient solution.

[0133] (2) Add reglugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain reglugoline crude suspension;

[0134] (3) Place the crude suspension of rilugoli in a media mill, use zirconia beads as the grinding medium, the mill speed is 1200 r / min, the grinding temperature is 10-40℃, and the grinding time is 26 min to obtain a rilugoli suspension with D50 of 3-20 μm.

[0135] (4) Filling: Measure 4 ml of regrugoli suspension and fill it into 7 ml vials, half-stop, pre-freeze at -80℃ overnight, and place in a freeze dryer the next morning. The freeze-drying temperature and time are as follows:

[0136] Example 16: Preparation of lyophilized formulation of relugoline.

[0137] Preparation process:

[0138] (1) Take the suspension prepared in Example 7, add sodium hyaluronate (molecular weight: 1 million) according to the prescription amount, stir evenly to obtain a relugoli suspension containing 0.1% sodium hyaluronate;

[0139] (2) Filling: Measure 4 ml of regrugoli suspension and fill it into 7 ml vials, half-stop, pre-freeze at -80℃ overnight, and place in a freeze dryer the next morning. The freeze-drying temperature and time are as follows:

[0140] Example 17: Preparation of Relugoline Suspension

[0141] Preparation process:

[0142] (1) Add polysorbate 20, PEG4000, sodium dihydrogen phosphate (monohydrate), citric acid monohydrate and sodium hydroxide to water for injection according to the prescription dosage and make up to 350 ml. Stir until clear and uniform to obtain blank excipient solution.

[0143] (2) Add retlugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain retlugoline crude suspension.

[0144] (3) Place the crude suspension of relugoli in a media mill, using zirconia beads as the grinding medium. The mill speed is 1000 r / min and the grinding temperature is 10-40℃. Grind for 6 times and 16 times respectively to obtain relugoli suspensions with D50 of 13.676um and 6.547um respectively.

[0145] Example 18: Preparation of Relugoline Suspension

[0146] Preparation process:

[0147] (1) Add polysorbate 20, PEG4000, sodium dihydrogen phosphate (monohydrate), citric acid monohydrate and sodium hydroxide to water for injection according to the prescription dosage and make up to 300 ml. Stir until clear and uniform to obtain blank excipient solution.

[0148] (2) Add retlugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain retlugoline crude suspension.

[0149] (3) Place the crude suspension of rilugoli in a media mill, using zirconia beads as the grinding medium. The mill speed is 1200 r / min, the grinding temperature is 10-40℃, and the mill is milled twice to obtain a rilugoli suspension with a D50 of 17.775 μm. After 6 months of storage, the stability data are shown in Table 6.

[0150] Table 6. Stability data of regorafenib suspension in Example 18

[0151] As shown in the table above, the prepared retinoic acid suspension has a satisfactory appearance after 6 months, and the particle size is stable compared to day 0, indicating good formulation stability.

[0152] Example 19: Preparation of lyophilized formulation of relugoline

[0153] Preparation process:

[0154] (1) Add CMC-NA (7LF), sodium dihydrogen phosphate (monohydrate), and sodium hydroxide to water for injection according to the prescription dosage and make up to 1000 ml. Stir until clear and uniform to obtain a blank excipient solution.

[0155] (2) Add reglugoline active pharmaceutical ingredient to blank excipient solution under stirring, and disperse evenly to obtain reglugoline crude suspension;

[0156] (3) Place the crude suspension of relugoli in a media mill, use zirconia beads as the grinding medium, the mill speed is 1000 r / min, the grinding temperature is 10-40℃, and the mill is ground 2.5 times to obtain relugoli suspension sample 32 with the following particle size.

[0157] (4) Add freeze-drying protectant: Weigh mannitol according to the prescription dosage and add it to the suspension and stir to dissolve.

[0158] (5) Filling: Measure 4 ml of regrugoli suspension and fill it into 7 ml vials, half-stop, pre-freeze at -80℃ overnight, and place in a freeze dryer the next morning. The freeze-drying temperature and time are as follows:

[0159] The product was stored for 6 months, and the stability data are shown in Table 7.

[0160] Table 7. Stability data of the lyophilized formulation of relugoline in Example 19

[0161] Note: A-Class white freeze-dried lumps or powder; B-Class white to pale yellow freeze-dried lumps or powder.

[0162] Results: The prepared lyophilized formulation of retinoic acid showed good stability over a long period of 6 months.

[0163] Example 20: Pharmacokinetic Study of Long-Acting Relugoline for Injection in SD Rats

[0164] The formulation and preparation method of the long-acting retinoic acid preparation used in this experiment are the same as those in Example 15.

[0165] Experimental animals: 18 male SD rats, approximately 250g each, divided into 3 groups of 6 rats each.

[0166] Preparation of test samples: Group 1: RF group (Relumina tablets), the tablets were ground and dissolved in 10 ml of water for injection to prepare a suspension for administration; Group 2: TF1 group (long-acting formulation of relumina prepared in Example 15), 5 ml of water for injection was drawn into a syringe and added to a vial, and the vial was shaken up and down until evenly dispersed; Group 3: TF2 group (long-acting formulation of relumina prepared in Example 15), 5 ml of a solution containing sodium hyaluronate (0.25%) was drawn into a syringe and added to a vial, and the vial was shaken up and down until evenly dispersed.

[0167] Trial groups: Group 1: RF group (Relumina tablets), 12 mg / kg, orally administered by gavage, once daily for 10 consecutive days; Group 2: TF1 group, 80 mg / kg, intramuscularly administered, once daily for 28 days, as a single dose; Group 3: TF2 group, 80 mg / kg, intramuscularly administered, once daily for 28 days, as a single dose.

[0168] Blood collection points: RF1 group: D1: 0h (drug administration after blood collection), 1h, 2h, 3h, 4h, 6h, 12h, before the last administration (i.e., D10) and 1h, 2h, 3h, 4h, 6h, 12h, 24h after administration; TF1 / TF2 group: 0h, 1h, 6h, 12h, 24h before administration, 2d, 3d, 5d, 7d, 9d, 11d, 14d, 19d, 24d, 28d. Sampling site: 0.2ml of blood was collected from the jugular vein of rats and placed in a test tube containing anticoagulant (EDTA-K2 solution). The plasma was collected after centrifugation at 4℃ for 5min (6000rpm) within 1 hour and temporarily stored below -70℃. Plasma was dissolved at room temperature, centrifuged by vortexing, and the supernatant was used to detect regrugoli. The results are shown in Figure 1 (Note: The steady-state drug-time curve of rats in the RF group was predicted using the Winnonlin software nonparametric superposition method based on the average blood drug concentration over 24 hours). The p-k parameters are as follows:

[0169] As shown in the table above, the Cmax of TF1 and TF2 are 0.53 times and 0.64 times that of RF1, respectively; the AUC is 56 times and 62 times that of RF1, respectively; and the Tmax is 94 times and 70 times that of RF1, respectively.

[0170] Conclusion: Compared with the oral reference tablet group (RF), the long-acting formulation group (TF1 / TF2) had a lower Cmax, a longer Tmax, and less fluctuation in blood drug concentration, indicating better safety. The long-acting formulation group had a significantly higher AUC, indicating significantly improved bioavailability and a significant sustained-release effect, which can extend the dosing interval to more than 7 days.

[0171] Example 21: Pharmacokinetic Study of Long-Acting Relugoline Formulation in Cynomolgus Monkeys

[0172] The formulation and preparation method of the long-acting retinoic acid preparation used in this experiment are the same as those in Example 17.

[0173] Experimental animals: 12 male cynomolgus monkeys, weighing 3-5 kg, divided into 2 groups of 6 each.

[0174] Preparation of test samples: Group 1: TF3 group (long-acting formulation of retinoic acid prepared in Example 17), use a syringe to draw an appropriate amount of special diluent for injection and add it to the drug solution and mix well to make the drug solution content 96 mg / ml; Group 2: TF4 group (long-acting formulation of retinoic acid prepared in Example 17), use a syringe to draw an appropriate amount of special diluent for injection and add it to the drug solution and mix well to make the drug solution content 96 mg / ml.

[0175] Trial groups: Group 1: TF3 group, 24 mg / kg, intramuscular injection, once every 28 days, single administration; Group 2: TF4 group, 24 mg / kg, intramuscular injection, once every 28 days, single administration.

[0176] Blood collection points: TF3 / 4 group: 0h, 1h, 6h, 12h, 24h before drug administration; 2d, 3d, 5d, 7d, 9d, 11d, 14d, 19d, 24d, 28d. Sampling site: 0.6ml of blood was collected from the anterior / hind limb veins of cynomolgus monkeys and placed in a test tube containing anticoagulant (EDTA-K2 solution). The plasma was centrifuged at 4℃ for 5min (6000rpm) within 1 hour and then temporarily stored below -70℃. The plasma was thawed at room temperature, vortexed, and the supernatant was used for relugoline detection.

[0177] The test results are shown in Figure 2. As shown, TF3 releases more stably than TF4.

[0178] Example 22: Pharmacokinetic Study of Long-Acting Relugoline Formulation in Cynomolgus Monkeys

[0179] Experimental animals: 6 male cynomolgus monkeys, weighing 3-5 kg, divided into 1 group of 6.

[0180] Preparation of test sample: RF group (Relumina tablets), the tablets were ground and then dissolved in 10 ml of water for injection to prepare a suspension for administration;

[0181] Trial group: RF group (Relumina tablets), the first day's dose was 5 mg / kg, administered orally by gavage, and from the second day onwards, the daily dose was 2 mg / kg, administered orally by gavage, once a day, for 7 consecutive days.

[0182] Blood collection points: D1: 0h (drug administration after blood collection), 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h; D2-D7: before each administration, before the last administration (i.e., D8), and 0.5h, 1h, 2h, 3h, 4h, 6h, 12h, 24h, 48h, 72h, 96h after administration. Sampling site: 0.6ml of blood was collected from the anterior / hind limb veins of cynomolgus monkeys and placed in a test tube containing anticoagulant (EDTA-K2 solution). The plasma was collected after centrifugation at 4℃ for 5min (6000rpm) within 1 hour and temporarily stored below -70℃. The plasma was dissolved at room temperature, vortexed, and the supernatant was used for regrugoli detection. The detection results are shown in Figure 3 (Note: The steady-state drug-time curve of cynomolgus monkeys was predicted using the Winnonlin software nonparametric superposition method based on the average blood drug concentration over 24 hours).

[0183] The PK parameters are as follows:

[0184] It can be seen from the above table:

[0185] 1. The Cmax of TF3 and TF4 in cynomolgus monkeys after a single dose was 0.61 times and 1.10 times that of the RF group, respectively; the AUC was 26.2 times and 40.2 times that of the RF group, respectively; and the Tmax was 267 times and 307 times that of the RF group, respectively.

[0186] 2. The overall drug concentration and exposure of TF4 are higher than those of TF3.

[0187] in conclusion:

[0188] 1. Compared with the oral reference tablet group (RF), the long-acting formulation group (TF3 / TF4) showed a similar Cmax, but significantly improved AUC, significantly improved bioavailability, significantly prolonged Tmax, and obvious sustained-release effect.

[0189] 2. Particle size can significantly affect in vivo PK parameters, with TF4 (larger particle size) being released more slowly and steadily than TF3 (smaller particle size);

[0190] 3. Both of the self-made long-acting formulations TF3 and TF4 can achieve sustained release for at least 28 days, thus achieving the goal of long-acting sustained release.

[0191] The above experiments show that the long-acting formulation has higher bioavailability and a more significant sustained-release effect in vivo compared to the tablet formulation.

[0192] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A long-acting composition of relugolix, characterized in that, It contains relugoli and a suspending agent, wherein the suspending agent is polyethylene glycol, or carboxymethyl cellulose or a salt thereof.

2. The pharmaceutical composition of claim 1, wherein, The product further includes a pH adjuster, preferably one or more of sodium phosphate, disodium hydrogen phosphate or disodium hydrogen phosphate (monohydrate), sodium dihydrogen phosphate or sodium dihydrogen phosphate (monohydrate), phosphoric acid, carbonic acid, sulfuric acid, hydrochloric acid, citric acid or citric acid (monohydrate), and sodium hydroxide. Preferably, the content of the pH adjuster is 0.05‰-3%.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The product further includes a wetting agent, preferably one or more of polysorbate, sorbitan laurate, phospholipid, polyoxyethylene castor oil, deoxycholic acid and its sodium salt, and sodium dodecyl sulfate. Preferably, the content of the wetting agent is 0.1-5%.

4. The pharmaceutical composition according to any one of the preceding claims, characterized in that, It further includes a freeze-drying protectant, preferably one or more of sucrose, lactose, glucose, mannitol, maltose, and trehalose, preferably, the content of the freeze-drying protectant is 0.5-20%.

5. The pharmaceutical composition according to any one of the preceding claims, characterized in that, It further contains hyaluronic acid or its sodium salt, preferably, the content of said hyaluronic acid or its sodium salt is 0.05-2%.

6. The pharmaceutical composition according to any one of the preceding claims, characterized in that, The composition contains 10%-40% regorafenib.

7. The pharmaceutical composition according to any one of the preceding claims, characterized in that, The composition has a D50 of 3-25 μm, preferably 3-20 μm.

8. The pharmaceutical composition according to any one of the preceding claims, characterized in that, The composition exists in the form of a suspension or a freeze-dried product, preferably in the form of a freeze-dried powder for injection.

9. Use of the pharmaceutical composition according to any one of the preceding claims in the preparation of a medicament for treating prostate cancer and uterine fibroids.

10. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 8, characterized in that, The process employs media grinding, air jet milling, or microjet milling.

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