A vortioxetine ester pharmaceutical composition, a preparation method and use thereof

Abstract

The present application relates to the technical field of medicine, in particular to a fluvoxamine ester pharmaceutical composition, a preparation method and application thereof.The pharmaceutical composition has the characteristics of high drug loading, and has a drug loading of up to 100mg / mL-400mg / mL.The pharmaceutical composition has the characteristics of high stability, can be prepared by various methods, and is easy to realize industrial production.After intramuscular injection, a drug depot of about 50mg-1300mg can be formed at the injection site, the drug is slowly and continuously released in the drug depot, the blood drug concentration fluctuation is small, and sustained effective drug release of up to 2 weeks-24 weeks can be obtained, frequent drug administration is reduced, and the pharmaceutical composition is used for treating adult depression and increasing drug use compliance.

Description

1. Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a vortioxetine ester pharmaceutical composition, its preparation method, and its uses. 2. Background Technology

[0002] Vortioxetine is a novel antidepressant with a multimodal mechanism of action, exhibiting good safety and tolerability. Currently marketed as vortioxetine hydrobromide tablets, its antidepressant mechanism of action is not fully understood. Based on pharmacodynamic characteristics and preclinical studies, it is believed that the mechanism of action of vortioxetine hydrobromide is mainly related to its multi-channel activity, namely, selectively blocking serotonin reuptake (inhibiting the serotonin transporter [SERT]) and directly regulating serotonin receptor activity. In vitro studies have shown that vortioxetine is a partial agonist of the 5-HT1B receptor, an antagonist of the 5-HT3, 5-HT7, and 5-HT1D receptors, an agonist of the 5-HT1A receptor, and an inhibitor of the 5-HT transporter (SERT).

[0003] Depression is listed as one of the leading non-fatal health impairments worldwide, accounting for 7.5% of all disability-related lost healthy life years, affecting over 300 million people globally. Depression can directly lead to suicidal behavior. Depression is a multidimensional disorder encompassing mood, physical, and cognitive symptoms; patients typically experience depressed mood, fatigue, difficulty concentrating, and, in severe cases, suicidal thoughts. Vortioxetine hydrobromide is a novel antidepressant with a multimodal mechanism of action. This drug combines transporter inhibition and regulation of multiple 5-HT receptors, offering therapeutic benefits across a broader spectrum of clinical symptoms of depression. It can be used for both acute treatment and relapse prevention, exhibiting good safety and tolerability.

[0004] Depression is characterized by recurrent episodes and a high relapse rate. Preventing relapse is a crucial aspect of depression treatment, and effectively improving medication adherence is essential for this. This necessitates antidepressants with higher efficacy, lower dosage, fewer frequency of administration, and fewer adverse reactions to improve adherence. Vortioxetine hydrobromide tablets, administered once daily, have poor patient adherence. Therefore, compared to tablets, developing long-acting injectable antidepressants has significant clinical value in maintaining long-term therapeutic effects and alleviating symptoms. A single injection of a long-acting formulation can maintain efficacy for several weeks and maintain stable blood drug levels, improving treatment efficacy and reducing adverse reactions. Clinical application of such formulations would greatly improve patient adherence, significantly reduce the workload for patients' families and caregivers, and ultimately achieve greater social and economic benefits.

[0005] CN109922806B discloses a long-acting aqueous suspension injection of vortioxetine hydrobromide, and CN115052601B discloses a long-acting aqueous suspension injection of vortioxetine hydrobromide. Both patents disclose long-acting injections with a certain sustained-release effect. However, due to the high water solubility of vortioxetine hydrobromide and vortioxetine, the sudden release in vivo is severe, resulting in excessively high blood drug concentrations and adverse reactions. At the same time, the dosing cycle is relatively short.

[0006] Therefore, this invention esterifies vortioxetine to further reduce solubility, decrease the burst release of the drug in vivo, prolong the release cycle, and at the same time, make the drug release more gradual, reduce the difference between peak and trough concentrations, and better exert the drug efficacy. 3. Summary of the Invention

[0007] The purpose of this invention is to solve the problems existing in the prior art and to provide a vortioxetine ester drug composition with high drug loading, stable quality, and long-lasting effect, as well as its preparation method and uses, thereby solving the problem of medication adherence of vortioxetine and making the use of the drug safer.

[0008] This invention provides a vortioxetine ester compound, specifically vortioxetine phenyl carboxylate, chemically named 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate phenyl ester, having the structure of Formula I.

[0009]

[0010] The present invention provides a vortioxetine ester pharmaceutical composition comprising a therapeutically effective amount of the compound vortioxetine ester or its hydrate, wherein the vortioxetine ester is vortioxetine phenyl formate, namely 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylic acid phenyl ester.

[0011] The particle size of the compound drug of the present invention, as determined by a laser particle size analyzer, has one or more of the following particle size ranges: about 0.01 μm to about 19 μm (10), preferably 0.5 μm to 10 μm; about 0.1 μm to about 42 μm (50), preferably 0.5 μm to 35 μm, more preferably 0.5 μm to 20 μm; about 1 μm to about 98 μm (90), preferably 3 μm to 50 μm.

[0012] The vortioxetine ester pharmaceutical composition of the present invention can be an aqueous suspension or a solid mass, comprising vortioxetine phenyl formate and a certain proportion of stabilizer. The stabilizer's function is to prevent the rapid aggregation of vortioxetine phenyl formate drug particles and maintain the stability of the formulation system. Based on solids (active ingredient calculated as vortioxetine phenyl formate), the proportion of vortioxetine phenyl formate is between 50% and 95%, preferably 70% to 90%, more preferably 75% to 85%; the proportion of stabilizer is between 5% and 50%, preferably 10% to 30%, more preferably 15% to 25%.

[0013] The stabilizer described in this invention may be one or more of a suspending agent, wetting agent, flocculant, pH adjuster, and filler.

[0014] The suspending agent, calculated by solids content, comprises 0.1% to 35%, preferably 5% to 20%. The suspending agent is selected from one or more of carboxymethyl cellulose or sodium carboxymethyl cellulose, polyethylene glycol, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, methylcellulose, gelatin, sodium hyaluronate, or sodium alginate, preferably sodium carboxymethyl cellulose, polyethylene glycol, povidone, gelatin, or sodium hyaluronate, and more preferably sodium carboxymethyl cellulose, polyethylene glycol, or povidone. The polyethylene glycol can be polyethylene glycol 400, polyethylene glycol 2000, polyethylene glycol 3350, polyethylene glycol 4000, or a similar molecular weight designation, preferably polyethylene glycol 3350 or polyethylene glycol 4000; the povidone can be povidone K12, povidone K15, povidone K17, povidone K30, or a similar molecular weight designation, preferably povidone K17 or povidone K30.

[0015] The wetting agent, calculated by solids, accounts for 0-4%, preferably 1-4%, and is selected from one or more of polysorbate, sodium dodecyl sulfate, sodium deoxycholate, polyoxyethylene castor oil, sorbitan fatty acid ester, polyoxyethylene (15) hydroxystearate, poloxamer, carbomer, vitamin E polyethylene glycol succinate, or glycine. Polysorbate, sodium deoxycholate, polyoxyethylene castor oil, sorbitan fatty acid ester, polyoxyethylene (15) hydroxystearate, and poloxamer are preferred, and polysorbate, polyoxyethylene castor oil, and polyoxyethylene (15) hydroxystearate are even more preferred. Among them, the polysorbate can be polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80, with polysorbate 20 or polysorbate 80 being preferred; the polyoxyethylene castor oil can be polyoxyethylene (35) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (54) hydrogenated castor oil, or polyoxyethylene (60) hydrogenated castor oil, with polyoxyethylene (35) hydrogenated castor oil being preferred; the dehydrated sorbitan fatty acid ester can be Span 20, Span 40, Span 60, or Span 80, with Span 20 (laurate sorbitan) being preferred.

[0016] The flocculant, calculated by solids content, comprises 0-10%, preferably 0.5-2%, and is selected from one or more of citric acid or its salts, tartaric acid or its salts, preferably citric acid or its salts. The citric acid or its salt can be anhydrous citric acid, citric acid hydrate, anhydrous sodium citrate, or sodium citrate hydrate, preferably citric acid monohydrate or sodium citrate dihydrate.

[0017] The pH adjuster, calculated by solids content, comprises 0.01–10%, preferably 0.1–6%, and is selected from one or more of sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, phosphoric acid, and disodium hydrogen phosphate. Sodium dihydrogen phosphate and disodium hydrogen phosphate can be anhydrous or hydrated, preferably sodium dihydrogen phosphate monohydrate and anhydrous disodium hydrogen phosphate.

[0018] The filler, calculated by solids, accounts for 0-30%, preferably 0-10%, and is selected from one or more of mannitol, sucrose, glucose, sorbitol, lactose, and sodium chloride, preferably mannitol, glucose, and sodium chloride.

[0019] In the vortioxetine ester pharmaceutical composition of the present invention, the vortioxetine phenyl formate solid can be used in combination with a solvent. The combination can be vortioxetine phenyl formate plus an aqueous solution containing a stabilizer, or a mixture of vortioxetine phenyl formate and a certain proportion of stabilizer plus an aqueous solution containing the remaining stabilizer, or a mixture of vortioxetine phenyl formate and all stabilizers plus water.

[0020] The aqueous suspension or solid mass of the vortioxetine ester pharmaceutical composition of the present invention, after resuspending with a solvent, contains supersaturated vortioxetine phenyl formate and insoluble vortioxetine phenyl formate, with the insoluble vortioxetine phenyl formate accounting for more than 95% of the total vortioxetine phenyl formate. The vortioxetine phenyl formate in the system will precipitate and disperse evenly after shaking. The pH value of the system is between 3 and 9.5, preferably 6 to 8. After resuspending with a solvent, the aqueous suspension or solid mass of the composition contains vortioxetine phenyl formate (according to C8H... 22 The concentration of N2S (calculated as N2S) is 100 mg / mL to 400 mg / mL, preferably 200 mg / mL to 260 mg / mL, and the solvent is water for injection, physiological saline, glucose injection, or water for injection containing some stabilizers or water for injection containing all stabilizers.

[0021] The present invention further provides a method for preparing the above-mentioned phenyl thioxetine formate pharmaceutical composition.

[0022] This invention discloses a method for preparing a pharmaceutical composition in the form of vortioxetine phenyl formate suspension. The preparation method includes air jet milling, high-speed shear milling, media milling, and high-pressure homogenization, and can be achieved through the following steps:

[0023] Method I: Airflow pulverization:

[0024] (1) The phenyl fotioxetine formate raw material was subjected to air jet milling to obtain drug powder with the corresponding particle size distribution;

[0025] (2) Dissolve the prescription excipients in water for injection, add the pulverized phenyl thioxetine formate powder obtained above, disperse evenly, and obtain a drug suspension.

[0026] Method II: High-speed shearing method:

[0027] (1) Dissolve the prescription excipients in water for injection, add vortioxetine phenyl ester drug powder, and disperse evenly;

[0028] (2) The drug solution obtained in step (1) is sheared using a shearing machine, and the drug particle size distribution is monitored. Once the target particle size is reached, the drug suspension is obtained.

[0029] Method III: Media grinding method

[0030] (1) Dissolve the prescription excipients in water for injection, add vortioxetine phenyl ester drug powder, and disperse evenly;

[0031] (2) Grind the drug solution obtained in step (1) using a grinder or sand mill, monitor the drug particle size distribution, and obtain the drug suspension after the target particle size is reached.

[0032] Method IV: High-pressure homogenization method

[0033] (1) Dissolve the prescription excipients in water for injection, add vortioxetine phenyl ester drug powder, and disperse evenly;

[0034] (2) Grind the drug solution obtained in step (1) using a microfluidic jet or high-pressure homogenizer, monitor the drug particle size distribution, and obtain a drug suspension after reaching the target particle size.

[0035] This invention discloses a method for preparing a pharmaceutical composition in the form of phenyl vortioxetine formate solid block, namely, after preparing a liquid pharmaceutical composition using any of the above methods, filling it into a suitable container, and freeze-drying it to obtain a pharmaceutical composition in the form of block.

[0036] The packaging container for the vortioxetine ester pharmaceutical composition of the present invention can be one or more of a vial, a pre-filled syringe, a pen syringe, or an ampoule.

[0037] This invention further provides a method of using the above-mentioned vortioxetine phenyl ester pharmaceutical composition. The liquid pharmaceutical composition or the block pharmaceutical composition resuspended in a solvent and shaken thoroughly is injected into the muscle or subcutaneous tissue, wherein the administration volume is 0.25 mL to 5 mL, forming a drug concentration (according to C8H) at the injection site. 22The drug reservoir (calculated as N2S) ranges from 50 mg to 1300 mg. The preferred dosing volume for 2 weeks is 0.25 mL to 1 mL, with a drug dose of 50 mg to 250 mg; for 4 weeks, the preferred dosing volume is 0.5 mL to 2 mL, with a drug dose of 100 mg to 450 mg; for 8 weeks, the preferred dosing volume is 1 mL to 4 mL, with a drug dose of 200 mg to 900 mg; and for 12 weeks, the preferred dosing volume is 1.25 mL to 5 mL, with a drug dose of 300 mg to 1300 mg.

[0038] After administration of the vortioxetine ester pharmaceutical composition of the present invention, vortioxetine phenyl formate is slowly and continuously released from the drug reservoir, enters the bloodstream, and is metabolized into the active ingredient vortioxetine, maintaining a therapeutic concentration for 2 to 24 weeks, preferably 2 to 12 weeks. The dosage of vortioxetine phenyl formate administered over a 2-week dosing cycle (according to C8H...) 22 N2S (calculated) is 50-250 mg, Dv(50) is between 0.5-5 μm; the dosage of vortioxetine phenyl ester in a 4-week drug cycle (based on C8H) is 50-250 mg. 22 N2S content ranges from 100 mg to 450 mg, and Dv(50) ranges from 1 to 10 μm; the dosage of vortioxetine phenyl ester administered over an 8-week treatment cycle (based on C8H) is... 22 The dosage of vortioxetine phenyl ester (calculated as N2S) ranged from 200 mg to 900 mg, and the Dv(50) ranged from 1.5 to 15 μm. The dosage of vortioxetine phenyl ester in a 12-week treatment cycle (based on C8H) was 200 mg to 900 mg. 22 The N2S content ranges from 300 mg to 1300 mg, and the Dv(50) content ranges from 2 to 35 μm.

[0039] The vortioxetine phenyl ester pharmaceutical composition provided by the present invention has sufficient stability to remain stable at room temperature for at least 12 months.

[0040] The present invention also provides the application of the above-mentioned vortioxetine phenyl ester pharmaceutical composition for the treatment of adult depression and to improve patient medication adherence.

[0041] This invention provides a method for preparing phenyl vortioxetine formate, comprising the following steps: dissolving vortioxetine in N,N-dimethylformamide solvent, adding triethylamine, purging with nitrogen three times, cooling the reaction system to -5°C, and adding phenyl chloroformate dropwise while maintaining the temperature between -5 and 5°C. After the addition is complete, stirring the reaction mixture at room temperature for 2-3 hours. Then, cooling the reaction solution to below 10°C, adding water dropwise, a large amount of solid precipitates out. After stirring at room temperature for 1-2 hours, filtering is performed, and the filter cake is washed with water. The filter cake is dispersed in anhydrous ethanol, dissolved by reflux, and then cooled to room temperature to crystallize. The solid is filtered and dried to obtain phenyl vortioxetine formate.

[0042] This invention provides a crystalline form I of the compound phenyl fotioxetine formate, whose XRD pattern exhibits characteristic peaks at the following 2θ angles: 7.6°±0.2°, 11.8°±0.2°, 13.4°±0.2°, 15.2°±0.2°, 17.9°±0.2°, 24.7°±0.2°, and 26.7°±0.2°; further, it exhibits the following characteristic peaks: 7.6°± 0.2°, 11.8°±0.2°, 13.4°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 17.9°±0.2°, 18.9°±0.2°, 20.9°±0.2°, 22.8°±0.2°, 24.1°±0.2°, 24.7°±0.2°, 26.7°±0.2°, 30.6°±0.2°.

[0043] The melting point of crystal form I described in this invention is between 95 and 105°C. After being treated at 60°C for 10 days and then at high humidity for 10 days, crystal form I showed no changes in XRD, DSC, or related substances, indicating good stability.

[0044] The beneficial technical effects of this invention are as follows:

[0045] (1) The vortioxetine phenyl ester pharmaceutical composition of the present invention has the characteristics of high concentration, no organic solvent, low irritation and safety, and can achieve efficient drug delivery for patients with large doses with the smallest administration volume, thereby improving the therapeutic effect.

[0046] (2) The pharmaceutical composition of the present invention is administered by injection, which improves bioavailability and can achieve a sustained-release effect for up to 2 weeks to 24 weeks, effectively improving patients' medication compliance.

[0047] (3) The pharmaceutical composition of the present invention is a long-acting suspension that can remain stable for a long time.

[0048] (4) The preparation process of the pharmaceutical composition of the present invention is simple and easy to realize industrial production. 4. Description of the attached drawings

[0049] Figure 1 The image shows the 1H-NMR spectrum of phenyl thioxetine formate from Example 1.

[0050] Figure 2 The image shows the XRD pattern of phenyl thioxetine form I in Example 1.

[0051] Figure 3 This is the DSC spectrum of phenyl thioxetine formate crystal form I in Example 1.

[0052] Figure 4 The relevant material spectrum is shown for phenyl thioxetine form I in Example 1.

[0053] Figure 5 The particle size distribution spectrum of the phenyl fotioxetine formate pharmaceutical composition in Example 10 is shown.

[0054] Figure 6 This is the liquid chromatography chromatogram for determining the content of the phenyl fosetyl-methyl ester pharmaceutical composition in Example 11.

[0055] Figure 7 The in vivo drug-time curves of the vortioxetine phenyl ester drug composition in Example 12 are shown. 5. Detailed Implementation Methods

[0056] The specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0057] Example 1: Voltioxitine phenyl formate (compound 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1- Preparation of phenyl formate

[0058] 200 g (0.67 mol, 1 eq) of compound III was dissolved in 1 L of N,N-dimethylformamide solvent. 136 g (1.34 mol, 2 eq) of triethylamine was added, and the mixture was purged with nitrogen three times. The reaction system was cooled to -5 °C, and 125 g (0.80, 1.2 eq) of phenyl chloroformate was added dropwise while maintaining the temperature between -5 and 5 °C. After the addition was complete, the mixture was stirred at room temperature for 2–3 h. The reaction solution was then cooled to below 10 °C, and 2.5 L of water was added dropwise. A large amount of solid precipitated. The mixture was stirred at room temperature for 1–2 h, then filtered. The filter cake was washed with 500 ml of water. The filter cake was dispersed in 2.5 L of anhydrous ethanol, heated under reflux to dissolve, and then cooled to room temperature to crystallize. The solid was filtered and dried to obtain 225 g of compound I, with a yield of 80.2%.

[0059]

[0060] The structure of the sample was determined by proton nuclear magnetic resonance (NMR) spectroscopy. The NMR spectrum was consistent with that of compound I, indicating that the sample was compound I. The detection results are as follows: Figure 1 As shown, 1H-NMR (400Hz, D6-DMSO): δ2.26 (3H, s), 2.33 (3H, s), 3.05 (4H, m), 3.60~3.76 (4H, m), 6.41~6.42 (1H, dd), 6.93~6.96 (1H, m), 7.10~7.20 (5H, m), 7.22~7.25 (2H, overlap), 7.36~7.39 (1H, dd), 7.40~7.42 (2H, overlap).

[0061] The XRD pattern of this sample is shown below. Figure 2As crystal form I, its XRD pattern has characteristic peaks at the following 2θ angles: 7.6°±0.2°, 11.8°±0.2°, 13.4°±0.2°, 15.2°±0.2°, 17.9°±0.2°, 20.9°±0.2°, 22.8°±0.2°, 24.7°±0.2°, 26.7°±0.2°, and 30.6°±0.2°.

[0062] The DSC chromatogram of crystal form I is shown below. Figure 3 Its melting point is between 95 and 105°C.

[0063] Stability of Crystal Form I: After treatment at 60℃ for 10 days and high humidity for 10 days, the XRD, DSC, and related substances of Crystal Form I showed no changes. See details below. Figures 2-4 .

[0064] Example 2: Determination of the solubility of phenyl thioxetine formate

[0065] To determine the equilibrium solubility of phenyl vortioxetine formate in different media, different media were prepared, including water, phosphate buffer (pH 6.4, pH 6.8, pH 7.4), 1% Tween 20 aqueous solution, 1% Tween 80 aqueous solution, and 1% SDS aqueous solution. The drug was added, and the mixture was kept at 37°C with shaking for 24 hours. The supernatant was then collected, and the phenyl vortioxetine formate content was determined by HPLC. The results are shown in Table 1 below. The results indicate that the solubility of phenyl vortioxetine formate in aqueous solution is very low, which meets the requirements for long-acting formulations.

[0066] Table 1. Equilibrium solubility of phenyl thioxetine in different media

[0067] 0mg / ml 0mg / ml 0mg / ml 0mg / ml 0.026mg / ml 0.029mg / ml 0.118mg / ml

[0068] Example 3: Screening of formulations for phenyl thioxetine formate drug compositions

[0069] The phenyl tebufenozide drug composition was prepared according to the prescription in Table 2. It was placed at 40°C for 5, 10 and 30 days. The results of the morphological stability of each prescription are shown in Table 3, and the results of the particle size change of each prescription are shown in Table 4.

[0070] Table 2 Prescription Design Table

[0071]

[0072]

[0073] Table 3. Results of prescription stability

[0074]

[0075] Table 4. Formulation Particle Size Distribution

[0076]

[0077] The results showed that, based on the stability of the formulations, Formulation 1 had large particles on the bottle wall, making resuspension impossible and failing to meet stability requirements. Particle size distribution testing revealed that Formulations 2-3 exhibited increased particle size after standing, also failing to meet stability requirements, while Formulations 4-5 achieved good results and stability. A comprehensive analysis comparing Formulations 1-5 indicated that the key to successful formulation lies in the selection and dosage of excipients. Specifically, the wetting agent containing only lecithin did not meet expectations, and the solids content (calculated as phenyl fosetyl-methyl ether, active ingredient) exceeding 4% was also below expectations. The D50 of Formulation 1 did not meet the particle size requirements of the composition.

[0078] The following will continue to explore feasible prescription conditions and prescription preparation methods.

[0079] Example 4: Preparation of phenyl vortioxetine formate pharmaceutical composition by air jet milling

[0080] Specific implementation method: Take phenyl fotioxetine formate powder with an average particle size distribution D50 of about 120 μm, pulverize the drug with a pressure airflow of 0.6 MPa, monitor the particle size distribution during the process, stop pulverizing after the target particle size distribution is reached, and collect the drug powder.

[0081] Prepare a 1500ml sample according to the prescription in Table 5: Take the drug powder obtained by air jet milling, add it to the excipient solution under stirring, adjust the pH to 7.0±0.5, disperse evenly to obtain a drug suspension, fill the drug suspension into 3ml or 10ml ampoules to obtain a liquid form of drug composition.

[0082] Table 5. Formulation of phenyl thioxetine formate composition.

[0083]

[0084] Example 5: Preparation of phenyl vortioxetine formate pharmaceutical composition by high-shear method

[0085] Prepare 1000ml samples according to the prescription in Table 6: Take phenyl fotiam formate powder with an average particle size distribution D50 of about 130μm, add it to the excipient solution under stirring, adjust the pH to 7.0±0.5, disperse evenly, and add volume to the labeled amount. Shear the sample, monitor the particle size distribution during the process, and stop shearing after the target particle size distribution is reached to obtain a drug suspension. Fill the drug suspension into 3ml or 10ml vials to obtain the drug composition in liquid form for later use.

[0086] Table 6. Formula for Voltacritin Benzoate Composition

[0087]

[0088]

[0089] Example 6: Preparation of phenyl thioxetine formate pharmaceutical composition by media milling method

[0090] Prepare a 500ml sample according to the formulation in Table 7: Take phenyl fotiam formate powder with an average particle size distribution D50 of about 75μm, add it to 50% of the volume of an aqueous solution containing all the wetting agent under stirring, disperse it evenly and grind it, monitor the particle size distribution during the process, stop grinding after the target particle size distribution is reached, and mix the drug suspension with the remaining excipient solution evenly, adjust the pH to 7.0±0.5, and then fill the drug suspension into 2.25ml, 5ml or 7ml pre-filled syringes to obtain the drug composition in liquid form.

[0091] Table 7 Formulas for Voltioxitine Formate Compositions

[0092]

[0093]

[0094] Example 7: Preparation of phenyl thioxetine formate pharmaceutical composition by high-pressure homogenization

[0095] Prepare 2000ml samples according to the formulation in Table 8: Take phenyl fotiam formate powder with an average particle size distribution D50 of about 50μm, add it to the excipient solution under stirring, adjust the pH to 7.0±0.5, disperse evenly, and homogenize using a microfluidic high-pressure homogenizer. Monitor the particle size distribution during the process. Stop homogenization after the target particle size distribution is reached to obtain a drug suspension. Fill the drug suspension into 2.25ml, 5ml, or 7ml pre-filled syringes to obtain the drug composition in liquid form.

[0096] Table 8 Formula for Voltiroxetine Formate Composition

[0097]

[0098]

[0099] Example 8: Preparation of the composition in solid block form

[0100] Samples of formulations 2, 3, 8, 12, 18, and 20 were taken and filled into vials or double-lumen syringes. The drug solutions were then lyophilized, pre-frozen at -40°C for 3 hours, dried once for 30 hours, and dried a second time for 20 hours to obtain a drug composition in the form of solid blocks.

[0101] Example 9: Method of using the pharmaceutical composition in solid block form

[0102] Preparations 1-20 can be manufactured using aseptic processes to obtain injectable sterile products. Take the block-shaped drug composition prepared by preparations 8 and 12, add 1 mL of water for injection, shake thoroughly, and select the injection volume (0.25 mL to 5 mL) according to the oral tolerance. Intramuscular or subcutaneous injection is then administered to form a drug reservoir of 50 mg to 1300 mg at the injection site, which is slowly released after injection to treat depression.

[0103] Example 10 Particle size determination

[0104] The particle size distribution of vortioxetine phenyl formate formulations 1–20 was determined using a wet method with a Neopatek laser particle size analyzer. The results are shown in Table 9 below. Figure 5 .

[0105] Table 9. Particle size distribution of phenyl thioxetine formate.

[0106]

[0107]

[0108] Stability of the composition in Example 11

[0109] The stability of the pharmaceutical composition (formulation 12) from Example 6 was investigated, including experiments on influencing factors (high temperature, high humidity, and light exposure), accelerated stability testing (6 months), and long-term stability testing (12 months). The drug remained stable, related substances were within acceptable limits, and quality fluctuations were minimal, as shown in Table 10 below. Figure 6 .

[0110] Table 10 Stability Tests

[0111]

[0112] Example 12 Pharmacokinetics in Animals

[0113] Using rats as animal models, the pharmacokinetics of the drug combinations of formulations 11 and 12, vortioxetine phenylformate, were investigated by intramuscular injection (40 mg / kg). Whole blood (200 μL) was collected at 1 h, 3 h, 6 h, 10 h, 24 h (D1), D2, D3, D5, D7, D10, D14, D17, D21, D24, D28, D31, D35, D38, D42, D49, D52, D56, D59, D63, D66, D70, D73, D77, D80, and D84 after administration. EDTA-K2 anticoagulation was used. After collection, the blood was centrifuged (4℃, 3000 r·min⁻¹, 5 min), and the supernatant was collected in EP tubes, labeled, and analyzed by liquid chromatography-mass spectrometry (LC-MS). Blood drug concentrations are shown in Table 11 below. Figure 7The drug release is relatively slow, allowing for dosing once every 3 months. As can be seen from the pharmacokinetic curve, the in vivo release of the vortioxetine phenylformate drug combination is relatively gradual, and the blood drug concentration C during the treatment period is [not specified]. max / C min A dose less than 5 times the normal dose can reduce fluctuations in drug levels within the body.

[0114] Table 11 Pharmacokinetics and Blood Drug Concentrations in Animals

[0115]

[0116]

Claims

1. A vortioxetine ester pharmaceutical composition, characterized in that, The composition contains a therapeutically effective amount of the compound vortioxetine ester, wherein the compound drug particle size has a Dv (10) of 0.5 μm to 10 μm, a Dv (50) of 0.5 μm to 20 μm, and a Dv (90) of 3 μm to 50 μm, and the vortioxetine ester is phenyl vortioxetine formate, the structure of which is shown in Formula I: ； The pharmaceutical composition further comprises a stabilizer, which includes a suspending agent and a wetting agent; The suspending agent has a w / w ratio of 0.1-35%, and the suspending agent is selected from one or more of carboxymethyl cellulose or sodium carboxymethyl cellulose, polyethylene glycol, hydroxypropyl methylcellulose, and povidone. The wetting agent has a solid content of 0-4% w / w and is selected from one or more of polysorbate, sodium deoxycholate, polyoxyethylene castor oil, dehydrated sorbitan fatty acid ester, polyoxyethylene (15) hydroxystearate, and vitamin E polyethylene glycol succinate.

2. The vortioxetine ester pharmaceutical composition according to claim 1, characterized in that, The stabilizer may further include flocculants, pH adjusters, and fillers.

3. The vortioxetine ester pharmaceutical composition according to claim 2, characterized in that, The flocculant content (w / w) is 0-10% based on solids, and the flocculant is selected from one or more of citric acid or its salts, tartaric acid or its salts.

4. The vortioxetine ester pharmaceutical composition according to claim 2, characterized in that, The pH adjuster, calculated by solids content, has a w / w ratio of 0.01-10%, and the pH adjuster is selected from one or more of sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, phosphoric acid, and disodium hydrogen phosphate.

5. The vortioxetine ester pharmaceutical composition according to claim 2, characterized in that, The filler content (w / w) is 0-30% based on solids, and the filler is selected from one or more of mannitol, sucrose, glucose, sorbitol, lactose, and sodium chloride.

6. The vortioxetine ester pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition may be in the form of an aqueous suspension or a solid mass, and may be used after dilution with a solvent. After resuspension with a solvent, vortioxetine phenyl formate has a concentration of 100 mg / mL to 400 mg / mL, and the pH value of the vortioxetine phenyl formate system is 3 to 9.

5. The solvent is selected from one or more of water for injection, physiological saline, glucose injection, water for injection containing some stabilizers, and water for injection containing all stabilizers.

7. Use of the vortioxetine ester pharmaceutical composition according to any one of claims 1-6 in the preparation of a medicament for treating adult depression.

8. The vortioxetine ester pharmaceutical composition according to any one of claims 1-6, characterized in that, The XRD pattern of the phenyl thioxetine formate has characteristic peaks at the following 2θ angle positions: 7.6°±0.2°, 11.8°±0.2°, 13.4°±0.2°, 15.2°±0.2°, 17.9°±0.2°, 24.7°±0.2°, and 26.7°±0.2°.

9. The pharmaceutical composition of vortioxetine ester according to any one of claims 1-6, characterized in that, The preparation of the phenyl vortioxetine formate includes the following steps: Vortioxetine reacts with phenyl chloroformate under alkaline conditions to undergo an amino esterification reaction, precipitating a solid. 。

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