Preparation technology of controlled-release sterile relugoride injection

Abstract

The invention belongs to the technical field of medicines, and provides a preparation technology of a sterile injection of rerugolix, which comprises the following steps: redissolving freeze-dried powder consisting of raw material medicines and auxiliary materials by using sterile water for injection, slowly releasing the rerugolix within 2-8 weeks, maintaining the dynamic balance of blood concentration, and preparing the sterile injection of the rerugolix by using the freeze-dried powder to prepare the sterile injection of the rerugolix. Release of gonadotropin is effectively controlled, and the pharmaceutical composition is used for treating indications such as prostatic cancer, uterine fibroma and endometriosis.

Description

Technical Field

[0001] This patent belongs to the field of pharmaceutical research and development. Specifically, this patent is a method for preparing relugolix into a sterile injection preparation with moderate particle size through physical means. After injection, a drug reservoir is formed, and the drug enters the blood circulation through slow dissolution, maintaining a dynamic balance of blood drug concentration, and achieving controlled-release administration for the treatment of gonadotropin-releasing diseases. Background Art

[0002] N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (generic name: Relugolix) is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the treatment of adult patients with advanced prostate cancer.

[0003] Relugoli, which has the following structure, has low solubility in water (0.04 mg / mL in water at 25°C).

[0004]

[0005] Orgovyx (Rigolike) is an oral formulation of relugolix developed by Myovant Sciences and is currently the only approved formulation of this type. However, its bioavailability is extremely low, requiring daily administration to control the disease and subsequent, long-term, uninterrupted medication for hormone receptor antagonism to maintain therapeutic effects. Relugoli has extremely poor water solubility, and its solubility is directly correlated with particle size: the larger the particle size, the slower the dissolution rate. Therefore, after the nanocrystalline particles of this patented invention are injected into the body, the drug accumulates at the injection site to form a drug reservoir. Crystalline drugs of varying particle size distribution slowly dissolve in the body, continuously releasing relugolix into the bloodstream, maintaining long-term effective blood drug concentrations and effectively reducing the frequency of medication. Summary of the Invention

[0006] This patented invention uses a physical method to crush relugolix crystals in an excipient medium solution to a particle size range of 0.5 to 20 μm, and freeze-drying under the action of a lyoprotectant to obtain a freeze-dried yellow powder preparation with controllable particle size. When used, a quantitative amount of water for injection is added to prepare the freeze-dried powder into a yellow suspension solution. After the suspension is injected into the body, it accumulates at the injection site to form a drug reservoir. The crystals slowly dissolve in the body and continuously release the drug into the blood circulation, maintaining an effective blood drug concentration, thereby exerting a therapeutic effect.

[0007] The sterile lyophilized powder preparation of relugolix of the present invention is mixed with water for injection for use in injection, continuously releases the drug in the body for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks or longer, maintains an effective blood drug concentration range in the body, and is used for disease control.

[0008] The pharmaceutical preparation of the present invention comprises the following components: an active ingredient - relugolix; and a carrier of relugolix.

[0009] The sustained-release suspension obtained by mixing the patented preparation with water is injected into the body, preferably intramuscularly and subcutaneously, and the suspension releases the therapeutic dose of the drug for at least 1 week, more preferably 2 weeks, 4 weeks, 6 weeks or longer.

[0010] The patented preparation of the present invention preferably contains: relugolix; one or more suspending agents; one or more diluents; and one or more pH buffer salts.

[0011] The suspending agent dosage range of this patent is 0.1-20%, preferably 0.5-5%. It includes cellulose polymers, including hydroxypropyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium salt, polyvinyl pyrrolidone, and combinations thereof, with sodium carboxymethyl cellulose being preferred. Carrier materials are not limited to cellulose polymers and also include other polymers: surfactants (nonionic and ionic), such as fatty acid glycerides, fatty acid sorbitan, polysorbates, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene-polyoxypropylene polymers, lecithin, and gelatin. Furthermore, natural products, polymers, and polysaccharides are also included.

[0012] The diluent dosage range of this patent is 5-50%, preferably 15-20%, and its types include lyxose, arabinose, xylose, ribose, glucose, galactose, lactose, sucrose, maltose, mannitol, trehalose, xylitol, sorbitol and their combinations, among which mannitol is preferred.

[0013] The amount of the buffer described in this patent ranges from 0.01 to 2.0%, preferably from 0.05 to 0.5%. The types include sodium phosphate buffer salt system, potassium phosphate buffer salt system and Tris buffer system, among which sodium phosphate buffer system is preferred.

[0014] The average particle size of relugolix crystals in the sustained-release suspension obtained by mixing this patented formulation with water ranges from 1 to 20 μm. Increasing particle size increases the sustained-release period of the drug in vivo, but also increases the time it takes to initially reach an effective therapeutic dose. Smaller particle sizes result in poor sustained-release effects in vivo and are prone to burst release, so a particle size of 2 to 5 μm is preferred.

[0015] The sterile lyophilized powder is combined with water for injection to form a suspension, which is then injected, preferably intramuscularly, to provide sustained drug release for at least two weeks, preferably four to six weeks. Therefore, the present invention allows for the in vivo drug release rate and duration of the sustained-release period to be adjusted based on the particle size and distribution of relugolix.

[0016] The sterile freeze-dried powder preparation process of the present invention includes: preparing a carrier solution and filtering it through 0.22 μm to obtain a sterile liquid; mixing relugolix and the carrier solution at a low stirring speed; initially homogenizing the suspension; further homogenizing by high-pressure homogenization; quantitative filling; and freeze-drying to obtain a powder. The crystalline composition prepared by the above process has an average particle size of 1 to 20 μm, preferably 2 to 5 μm. Example

[0017] [Example 1]

[0018] Prescription composition: relugolix 85%, mannitol 10%, sodium carboxymethyl cellulose 4.5%, sodium dihydrogen phosphate 0.5%, and 2M sodium hydroxide to adjust pH 6.5-7.5.

[0019] Process: Dissolve mannitol, sodium carboxymethyl cellulose and sodium dihydrogen phosphate in purified water, adjust the pH to 7, filter and sterilize, add sterile raw material drug relugolix, stir to completely wet, and then high-speed shear to D 10 :≤10μm,D 50 :≤100μm,D 90 :≤150μm, suspend the primary crystal solution and perform microfluidization homogenization, pressure ≤20000psi, and obtain D 10 :≤1μm,D 50 :≤5μm,D 90 : ≤20μm nanocrystal solution, after filtering, quantitative filling is carried out according to the content, the nanocrystal solution is freeze-dried to obtain solid powder sample 1, the freeze-dried powder is added to sterile water for injection, shaken for 30s to completely disperse and moisten it, and then injected intramuscularly according to the patient's needs.

[0020] [Example 2]

[0021] Prescription composition: relugolix 75%, mannitol 19.5%, sodium carboxymethyl cellulose 5%, sodium dihydrogen phosphate 0.5%, 2M sodium hydroxide to adjust pH 7.0.

[0022] Process: Dissolve mannitol, sodium carboxymethyl cellulose and sodium dihydrogen phosphate in purified water, adjust the pH to 7, filter and sterilize, add sterile raw material drug relugolix, stir to completely wet, and then high-speed shear to D 10 :≤10μm,D 50 :≤100μm,D 90:≤150μm, suspend the primary crystal solution and perform microfluidization homogenization, pressure ≤20000psi, and obtain D 10 :≤1μm,D 50 :≤5μm,D 90 : ≤20μm nanocrystal solution, after filtering, quantitative filling is carried out according to the content, the nanocrystal solution is freeze-dried to obtain solid powder sample 2, the freeze-dried powder is added to sterile water for injection, shaken for 30s to completely disperse and moisten it, and then injected intramuscularly according to the patient's needs.

[0023] [Example 3]

[0024] Prescription composition: relugolix 75%, mannitol 19.5%, sodium carboxymethyl cellulose 5%, sodium dihydrogen phosphate 0.5%, 2M sodium hydroxide to adjust pH 7.0.

[0025] Process: Dissolve mannitol, sodium carboxymethyl cellulose and sodium dihydrogen phosphate in purified water, adjust the pH to 7, filter and sterilize, add sterile raw material drug relugolix, stir to completely wet, and then high-speed shear to D 10 :≤10μm,D 50 :≤100μm,D 90 :≤150μm, suspend the primary crystal solution and perform high pressure homogenization, the initial pressure is ≤85MPa, and obtain D 10 :≤1μm,D 50 :≤5μm,D 90 : ≤20μm nanocrystal solution, after filtering, quantitative filling is carried out according to the content, the nanocrystal solution is freeze-dried to obtain solid powder sample 3, the freeze-dried powder is added to sterile water for injection, shaken for 30s to completely disperse and moisten it, and then injected intramuscularly according to the patient's needs.

[0026] [Example 4]

[0027] Prescription composition: relugolix 75%, mannitol 19.5%, sodium carboxymethyl cellulose 5%, sodium dihydrogen phosphate 0.5%, 2M sodium hydroxide to adjust pH 7.0.

[0028] Process: Dissolve mannitol, sodium carboxymethyl cellulose and sodium dihydrogen phosphate in purified water, adjust the pH to 7, filter and sterilize, add sterile raw material drug relugolix, stir to completely wet, and then high-speed shear to D 10 :≤10μm,D 50 :≤100μm,D 90 :≤150μm, suspend the primary crystal solution and perform ball milling to homogenize, and obtain D 10 :≤1μm,D 50 :≤5μm,D 90: ≤20μm nanocrystal solution, after filtering, quantitative filling is carried out according to the content, the nanocrystal solution is freeze-dried to obtain solid powder sample 4, the freeze-dried powder is added to sterile water for injection, shaken for 30s to completely disperse and moisten it, and then injected intramuscularly according to the patient's needs.

[0029] [Example 5]

[0030] Prescription composition: relugolix 70%, mannitol 25%, sodium carboxymethyl cellulose 4.7%, sodium dihydrogen phosphate 0.3%, 2M sodium hydroxide to adjust pH 7.0.

[0031] Process: Dissolve mannitol, sodium carboxymethyl cellulose and sodium dihydrogen phosphate in purified water, adjust the pH to 7, filter and sterilize, add sterile raw material drug relugolix, stir to completely wet, and then high-speed shear to D 10 :≤10μm,D 50 :≤100μm,D 90 :≤150μm, suspend the primary crystal solution and perform microfluidization homogenization to obtain D 10 :≤1μm,D 50 :≤5μm,D 90 : ≤20μm nanocrystal solution, after filtering, quantitative filling is carried out according to the content, the nanocrystal solution is freeze-dried to obtain solid powder sample 5, the freeze-dried powder is added to sterile water for injection, shaken for 30s to completely disperse and moisten it, and then injected intramuscularly according to the patient's needs.

[0032] Freezing: Freeze at -40℃ for at least 6 hours; Primary drying: Warm the sample to -5℃ within 2~3 hours, reduce the pressure in the chamber to 30 Pa, and maintain it for at least 30 hours; Desorption drying: Warm the sample to 15℃ within 3~4 hours, maintain the vacuum pressure at 30 Pa, and maintain it for at least 10 hours.

Claims

1. The sterile relugolix suspension injection should maintain stable release for at least one week after injection and its composition should include: Relugolix crystals, with an average particle size range of 0.5-50 μm; Its stabilizers and related carriers; water for injection and its buffered salt solvent. The above-mentioned sterile injection preparation should include the following amount of relugolix: in the sterile preparation (solid), it is in the range of 1% to 90% by weight.

2. The sterile preparation according to claim 1 should contain one or more diluents.

3. The sterile preparation according to claim 1 should contain one or more suspending agents.

4. The sterile preparation according to claim 1 should contain one or more lyoprotectants.

5. The sterile preparation of claim 1 should contain one or more pH buffering agents.

6. The preparation process of the sterile preparation according to claim 1 is a wet ball milling process, a high-pressure homogenization process, a microfluidization homogenization process, a high-speed shearing process and a combination thereof.

7. The administration route of the sterile preparation according to claim 1 is intramuscular and subcutaneous injection.

8. The sterile preparation according to claim 1 is used to treat prostate cancer, uterine fibroids, endometriosis and other indications.

9. The preparation of claim 1 is a yellow suspension preparation, wherein the average particle size of relugolix is ​​1 to 20 μm. The weight ratio of relugolix as the active ingredient in the preparation is in the range of 20 to 90%; the weight ratio of the diluent in the preparation is in the range of 5 to 50%; the weight ratio of the suspending agent in the preparation is in the range of 0.1 to 20%; and the weight ratio of the buffer in the preparation is in the range of 0.01 to 2.0% to adjust the pH of the suspension to 6.0 to 8.

0.

10. The diluent of claim 9 comprising glucose, sucrose, mannitol, lactose, xylitol, sorbitol, maltose, and combinations thereof.

11. The suspending agent of claim 9 comprises hydroxypropyl cellulose, hydroxypropylethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium salt, polyvinyl pyrrolidone and a combination thereof.

12. The buffer according to claim 9 comprises a sodium phosphate buffer salt system, a potassium phosphate buffer salt system and a citrate buffer salt system.

13. The preparation according to claim 1, wherein after injection, the preparation can slowly release relugolix within 1 to 8 weeks, and the preparation comprises: Rui Lugoli; Mannitol; Sodium carboxymethyl cellulose; Sodium dihydrogen phosphate, and adjust the suspension pH to 7 with sodium hydroxide solution; Water for injection.

14. According to claim 9, the particle size of relugolix is ​​further required to be in the range of 1 to 10 μm. The weight ratio of relugolix as the active ingredient in the formulation is in the range of 50 to 85%; the weight ratio of the diluent in the formulation is in the range of 10 to 30%; the weight ratio of the suspending agent in the formulation is in the range of 0.5 to 10%; and the weight ratio of the buffer in the formulation is in the range of 0.02 to 1.0% to adjust the pH of the suspension to 6.0 to 8.

0.

15. According to claim 14, the particle size of relugolix is ​​further required to be in the range of 2-5 μm. The weight ratio of relugolix as the active ingredient in the formulation is in the range of 65-80%; the weight ratio of the diluent in the formulation is in the range of 15-20%; the weight ratio of the suspending agent in the formulation is in the range of 0.5-5%; and the weight ratio of the buffer in the formulation is in the range of 0.05-0.5% to adjust the pH of the suspension to 6.0-8.

0.

16. The preparation according to claims 9 to 15, wherein the solution of relugolix and its excipients is thoroughly mixed and subjected to high-speed shearing to prepare an initial suspension, which is then subjected to high-pressure homogenization to prepare a secondary suspension solution with a more uniform particle size distribution. The secondary suspension solution is quantitatively filled and freeze-dried to obtain a lyophilized powder. The lyophilized powder is added to 1.5 ml of water for injection and shaken until completely moistened before injection.

17. The freeze-drying of claim 16 is performed by freezing the secondary suspension at -40°C, then performing sublimation drying at 0°C to remove most of the water in the solution, and then performing secondary desorption drying to remove the remaining free water, thereby finally obtaining an anhydrous freeze-dried powder preparation.

18. The freeze-drying method of claim 17, wherein the process is divided into three steps: freezing the suspension solution to a completely solid state at -40°C; removing part of the water from the solution by sublimation below 0°C under vacuum to achieve primary drying of the sample; further removing residual water by primary drying the sample above 0°C under vacuum to ultimately obtain an anhydrous freeze-dried preparation.

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