Veltioxetine ester pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a vothioxetine ester pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical composition disclosed by the invention has the characteristic of high drug loading capacity, and the drug loading capacity is as high as 100 mg / mL to 400 mg / mL. The pharmaceutical composition disclosed by the invention has the characteristic of high stability, can be prepared by various methods, and is easy to realize industrial production. After intramuscular injection, about 50-1300mg of a drug reservoir can be formed at an injection site, slow and continuous release can be realized in the drug reservoir, the fluctuation of blood concentration is small, continuous and effective drug release as long as 2-24 weeks can be realized, frequent administration is reduced, and the pharmaceutical composition is used for treating adult depression and increasing the compliance of drug use.

Description

1. Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a valifroxitine ester pharmaceutical composition, a preparation method thereof, and uses thereof. 2. Background Art

[0002] Valifroxitine is an antidepressant with a completely new multi-modal mechanism of action, having good safety and tolerance. The currently marketed preparation is valifroxitine hydrobromide tablets, and its antidepressant mechanism of action is not fully clear. According to the pharmacodynamic characteristics and preclinical studies, it is considered that the mechanism of action of valifroxitine hydrobromide is mainly related to its multi-channel activity, that is, selectively blocking serotonin reuptake (inhibiting serotonin transporter [SERT]) and directly regulating the activity of serotonin receptors. In vitro studies have shown that valifroxitine 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 main non-fatal health impairment diseases globally, with the proportion of total disability-adjusted life years lost being 7.5%. There are more than 300 million people suffering from depression worldwide. Depression may directly lead to suicidal behavior. Depression is a multi-dimensional disorder including emotional, physical, and cognitive symptoms. Patients usually show symptoms such as low mood, easy fatigue, difficulty concentrating, and suicidal thoughts in severe cases. Valifroxitine hydrobromide is a typical antidepressant with a completely new multi-modal mechanism of action. This drug combines two different mechanisms of action, namely transporter inhibition and multiple 5-HT receptor regulation, and has a therapeutic effect on a wider clinical symptom spectrum of depression. It can be used for both acute treatment and prevention of recurrence, and has good safety and tolerance.

[0004] Depression patients usually have the characteristics of repeated illness and a high recurrence rate. Preventing the recurrence of the disease is a very important link in the treatment of depression, and effectively improving the drug treatment compliance of depression patients is crucial for preventing the recurrence of the disease. This requires higher efficacy of antidepressant drugs, fewer doses, administration times, and adverse reactions, so as to improve the compliance of antidepressant drugs. Valifroxitine hydrobromide tablets are administered once a day, and the treatment compliance of patients is poor. Therefore, compared with tablets, developing a long-acting injection for treating depression has great clinical application value for maintaining long-term treatment effects and alleviating symptoms. A long-acting preparation can maintain the drug effect for several weeks after a single injection and maintain a stable blood drug level, which can improve the treatment efficacy, reduce adverse reactions. When applied clinically, the treatment compliance of patients will be greatly improved, and the work intensity of patients' families and nursing management will be significantly reduced, further obtaining better social and economic benefits.

[0005] CN109922806B discloses a long-acting aqueous suspension injection of vilazodone hydrobromide, and CN115052601B discloses a long-acting aqueous suspension injection of vilazodone. The long-acting injections in both patents have a certain sustained-release effect. However, due to the relatively high water solubility of vilazodone hydrobromide and vilazodone, the initial burst release in vivo is relatively severe, resulting in too high blood drug concentration and adverse reactions. At the same time, the dosing cycle is relatively short.

[0006] Therefore, in the present invention, vilazodone is esterified to further reduce its solubility, reduce the initial burst release of the drug in vivo, extend the release cycle, and at the same time, the drug release is more gentle, reducing the difference between peak and trough concentrations and better exerting the drug effect. 3. Summary of the Invention

[0007] The object of the present invention is to solve the problems existing in the prior art, and provides a vilazodone ester pharmaceutical composition with high drug loading, stable quality and long-acting effect, its preparation method and use, to solve the problem of medication compliance of vilazodone and make the medication safer.

[0008] The present invention provides a vilazodone ester compound, specifically phenyl vilazodone formate, with the chemical name of phenyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate, having the structure of Formula I.

[0009]

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

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

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

[0013] The stabilizer described in the present invention can be one or more of a suspending agent, a wetting agent, a flocculant, a pH regulator, and a filler.

[0014] The suspending agent accounts for 0.1-35%, preferably 5-20% by solid content. The suspending agent is selected from one or more of carboxymethyl cellulose or sodium carboxymethyl cellulose, polyethylene glycol, hypromellose, povidone, polyvinyl alcohol, methyl cellulose, gelatin, sodium hyaluronate, or sodium alginate, preferably sodium carboxymethyl cellulose, polyethylene glycol, povidone, gelatin, sodium hyaluronate, and more preferably sodium carboxymethyl cellulose, polyethylene glycol, povidone. Among them, the model of polyethylene glycol can be polyethylene glycol 400, polyethylene glycol 2000, polyethylene glycol 3350, polyethylene glycol 4000, or a similar molecular weight model, preferably polyethylene glycol 3350, polyethylene glycol 4000; the model of povidone can be povidone K12, povidone K15, povidone K17, povidone K30, or a similar molecular weight model, preferably povidone K17, povidone K30.

[0015] The wetting agent accounts for 0-4%, preferably 1-4% by solid content. The wetting agent 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, preferably polysorbate, sodium deoxycholate, polyoxyethylene castor oil, sorbitan fatty acid ester, polyoxyethylene (15) hydroxystearate, poloxamer, and more preferably polysorbate, polyoxyethylene castor oil, polyoxyethylene (15) hydroxystearate. Among them, the model of polysorbate can be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, preferably polysorbate 20 or polysorbate 80; the model of polyoxyethylene castor oil can be polyoxyethylene (35) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (54) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, preferably polyoxyethylene (35) hydrogenated castor oil; the model of sorbitan fatty acid ester can be span 20, span 40, span 60, span 80, preferably span 20 (sorbitan laurate).

[0016] The flocculant accounts for 0-10%, preferably 0.5-2% by solid content. The flocculant is selected from one or more of citric acid or its salts, tartaric acid or its salts, preferably citric acid or its salts. Among them, citric acid or its salts can be anhydrous citric acid, citric acid hydrate, anhydrous sodium citrate, sodium citrate hydrate, preferably citric acid monohydrate or sodium citrate dihydrate.

[0017] The pH regulator described above accounts for 0.01-10%, preferably 0.1-6% by solid content, and the pH regulator is selected from one or more of sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, phosphoric acid, and disodium hydrogen phosphate. Among them, sodium dihydrogen phosphate and disodium hydrogen phosphate can be anhydrous or hydrates, preferably sodium dihydrogen phosphate monohydrate and anhydrous disodium hydrogen phosphate.

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

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

[0020] After the aqueous suspension or solid mass of the vilazodone ester pharmaceutical composition of the present invention is resuspended with a solvent, the system contains supersaturated vilazodone formate and insoluble vilazodone formate. The proportion of insoluble vilazodone formate in the total amount of vilazodone formate exceeds 95%. The vilazodone formate in the system will settle and will be evenly dispersed after shaking. The pH value of the system is between 3 and 9.5, preferably 6-8. After the aqueous suspension or solid mass of the composition is resuspended with a solvent, the concentration of vilazodone formate (calculated as C 8 H 22 N 2 S) is 100 mg / mL to 400 mg / mL, preferably 200 mg / mL to 260 mg / mL. The solvent is water for injection or normal saline or glucose injection or water for injection containing part of the stabilizer or water for injection containing all the stabilizers.

[0021] The present invention further provides a preparation method of the above vilazodone formate pharmaceutical composition.

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

[0023] Method I: Air jet milling method:

[0024] (1) Subject the vilazodone formate raw material drug to air jet milling to obtain a drug powder with a corresponding particle size distribution;

[0025] (2) Dissolve the prescription excipients in water for injection, add the prepared phthalate of vosixetine drug powder obtained by the above-mentioned pulverization, and disperse evenly to obtain a drug suspension.

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

[0027] (1) Dissolve the prescription excipients in water for injection, add the phthalate of vosixetine drug powder, and disperse evenly;

[0028] (2) Shear the drug solution obtained in step (1) with a shearing machine, monitor the particle size distribution of the drug, and obtain the drug suspension after reaching the target particle size.

[0029] Method III: Media grinding method:

[0030] (1) Dissolve the prescription excipients in water for injection, add the phthalate of vosixetine drug powder, and disperse evenly;

[0031] (2) Grind the drug solution obtained in step (1) with a grinding machine or a sand mill, monitor the particle size distribution of the drug, and obtain the drug suspension after reaching the target particle size.

[0032] Method IV: High-pressure homogenization method:

[0033] (1) Dissolve the prescription excipients in water for injection, add the phthalate of vosixetine drug powder, and disperse evenly;

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

[0035] The present invention discloses a preparation method of a pharmaceutical composition in the form of a solid mass of phthalate of vosixetine, that is, after preparing a pharmaceutical composition in liquid form by any of the above methods, select a suitable container for filling, and freeze-dry to obtain a pharmaceutical composition in the form of a mass.

[0036] The packaging container of the phthalate of vosixetine pharmaceutical composition of the present invention can be one or more of vials, pre-filled syringes, pen injectors, and ampoules.

[0037] The present invention further provides a method of using the above phthalate of vosixetine pharmaceutical composition. Shake the pharmaceutical composition in liquid form or the solid mass pharmaceutical composition re-suspended with a solvent evenly, and inject it into the muscle or subcutaneous tissue, wherein the administration volume is 0.25 mL to 5 mL, and the amount of drug is formed at the injection site (calculated by C 8 H 22 N 2The drug depot has a drug amount of 50 mg to 1300 mg. Among them, the preferred administration volume for 2 weeks is 0.25 mL to 1 mL, and the drug amount is 50 mg to 250 mg; the preferred administration volume for 4 weeks is 0.5 mL to 2 mL, and the drug amount is 100 mg to 450 mg; the preferred administration volume for 8 weeks is 1 mL to 4 mL, and the drug amount is 200 mg to 900 mg; the preferred administration volume for 12 weeks is 1.25 mL to 5 mL, and the drug amount is 300 mg to 1300 mg.

[0038] After the administration of the vilazodone ester pharmaceutical composition of the present invention, phenyl vilazodone formate is slowly and continuously released from the drug depot. After entering the blood, the active ingredient vilazodone is metabolized, and the therapeutic concentration can be maintained for 2 to 24 weeks, preferably 2 to 12 weeks. Among them, the dosage of phenyl vilazodone formate for a 2-week administration cycle (calculated by C 8 H 22 N 2 S) is between 50 and 250 mg, and Dv(50) is between 0.5 and 5 μm; the dosage of phenyl vilazodone formate for a 4-week administration cycle (calculated by C 8 H 22 N 2 S) is between 100 mg and 450 mg, and Dv(50) is between 1 and 10 μm; the dosage of phenyl vilazodone formate for an 8-week administration cycle (calculated by C 8 H 22 N 2 S) is between 200 mg and 900 mg, and Dv(50) is between 1.5 and 15 μm; the dosage of phenyl vilazodone formate for a 12-week administration cycle (calculated by C 8 H 22 N 2 S) is between 300 mg and 1300 mg, and Dv(50) is between 2 and 35 μm.

[0039] The phenyl vilazodone formate pharmaceutical composition provided by the present invention has sufficient stability and can remain stable at room temperature for at least 12 months.

[0040] The present invention also provides the application of the above-mentioned phenyl vilazodone formate pharmaceutical composition for the treatment of adult depression and improving the compliance of patients with medication.

[0041] The present invention provides a method for preparing phenyl valproate formate, a compound, comprising the following steps: Dissolve valproate in an N,N-dimethylformamide solvent, add triethylamine, displace with nitrogen three times, cool the reaction system to -5°C, control the temperature at -5 to 5°C and dropwise add phenyl chloroformate. After addition, stir the reaction at room temperature for 2 to 3 hours. Then cool the reaction solution to below 10°C, dropwise add water, and a large amount of solid will precipitate. Stir at room temperature for 1 to 2 hours and then filter, and wash the filter cake with water. Take the filter cake, disperse it with absolute ethanol, heat under reflux to dissolve, then cool to room temperature to crystallize, filter the solid and dry it to obtain phenyl valproate formate.

[0042] The present invention provides polymorph I of phenyl valproate formate, a compound, whose 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°, 24.7° ± 0.2°, 26.7° ± 0.2°; Further, it has 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 polymorph I described in the present invention is between 95 and 105°C. After being treated at 60°C for 10 days and under high humidity for 10 days, the XRD, DSC, and related substances of polymorph I have no changes, indicating good stability.

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

[0045] (1) The phenyl valproate formate pharmaceutical composition of the present invention has the characteristics of high concentration, no organic solvents, low irritation, and safety, and can achieve efficient drug delivery for large-dose treatment of patients with the smallest administration volume, improving the treatment effect.

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

[0047] (3) The pharmaceutical composition of the present invention is a long-acting suspension preparation and 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 Drawings

[0049] Figure 11H-NMR spectrum of phenyl valproate in Example 1.

[0050] Figure 2 XRD spectrum of Form I of phenyl valproate in Example 1.

[0051] Figure 3 DSC spectrum of Form I of phenyl valproate in Example 1.

[0052] Figure 4 Related substances spectrum of Form I of phenyl valproate in Example 1.

[0053] Figure 5 Particle size determination spectrum of the phenyl valproate pharmaceutical composition in Example 10.

[0054] Figure 6 Liquid chromatography spectrum for the determination of the content of the phenyl valproate pharmaceutical composition in Example 11.

[0055] Figure 7 Plasma concentration-time curve of the phenyl valproate pharmaceutical composition in animals in Example 12. 5. Specific Embodiments

[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 a limitation of the present invention.

[0057] Example 1 Preparation of phenyl (4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate (Compound 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate)

[0058] Dissolve 200 g (0.67 mol, 1 eq) of the compound of formula III in 1 L of N,N-dimethylformamide solvent, add 136 g (1.34 mol, 2 eq) of triethylamine, displace with nitrogen three times, cool the reaction system to -5 °C, and add phenyl chloroformate dropwise at a controlled temperature of -5 to 5 °C. After adding, stir the reaction at room temperature for 2 - 3 h. Then cool the reaction solution to below 10 °C, add 2.5 L of water dropwise, and a large amount of solid will precipitate. Stir at room temperature for 1 - 2 h and then filter. Wash the filter cake with 500 ml of water. Take the filter cake and disperse it in 2.5 L of absolute ethanol, heat to reflux for dissolution and then cool to room temperature for crystallization. Filter and dry the solid to obtain 225 g of the compound of formula I, with a yield of 80.2%.

[0059]

[0060] The structure of the sample was detected by nuclear magnetic resonance hydrogen spectrum, and the hydrogen spectrum was consistent with that of the compound of formula I, indicating that the obtained sample was the compound of formula I. The test results are as Figure 1As shown, 1H-NMR (400 Hz, D6-DMSO): δ 2.26 (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 measurement pattern of this sample is shown in Figure 2 , as 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°, 30.6° ± 0.2°.

[0062] The DSC measurement pattern of Crystal Form I is shown in Figure 3 , and its melting point is between 95 - 105 °C.

[0063] Stability of Crystal Form I: After being treated at 60 °C for 10 days and under high humidity for 10 days, there were no changes in the XRD, DSC, and related substances of Crystal Form I. See Figures 2-4 .

[0064] Example 2 Solubility determination of phenyl (4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate

[0065] To determine the equilibrium solubility of phenyl valproate in different media, different types of media were first prepared, including water, phosphate buffer (pH 6.4, pH 6.8, pH 7.4), 1% Tween 20 aqueous solution, 1% Tween 80 aqueous solution, 1% SDS aqueous solution. The drug was added, and it was shaken at a constant temperature of 37 °C for 24 hours. Then, the supernatant was taken, and the content of phenyl valproate was determined by HPLC. The measurement results are shown in Table 1 below. The results indicate that the solubility of phenyl valproate in aqueous solution is very low, meeting the requirements for making long-acting preparations.

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

[0067] Water pH 6.4 pH 6.8 pH 7.4 1% Tween 20 1% Tween 80 1% SDS 0 mg / ml 0 mg / ml 0 mg / ml 0 mg / ml 0.026 mg / ml 0.029 mg / ml 0.118 mg / ml

[0068] Example 3 Prescription screening of the pharmaceutical composition of phenyl (4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate

[0069] Prepare the phenyl valproate pharmaceutical composition according to the prescription in Table 2 and place it at 40 °C for 5, 10, and 30 days to obtain the stability results of the properties of each prescription, as shown in Table 3, and the particle size change results of each prescription, as shown in Table 4.

[0070] Table 2 Prescription Design Table

[0071]

[0072]

[0073] Table 3 Prescription Stability Results

[0074]

[0075] Table 4 Prescription Particle Size Distribution

[0076]

[0077] The results show that from the perspective of the stability of the prescription properties, there are large particles on the bottle wall of Prescription 1, and resuspension cannot be achieved, and the stability does not meet the requirements. Through the particle size distribution test, it can be seen that the particle size of Prescriptions 2-3 becomes larger after standing, and the stability does not meet the requirements. Prescriptions 4-5 can achieve good effects and stability. Through comprehensive analysis and comparison of Prescriptions 1-5, it is obtained that the key to the prescription lies in the selection and dosage of each excipient. Among them, in the wetting agent, the one containing only lecithin does not meet the expectations, and the solid content ratio (calculated based on the active ingredient as phenyl valproate) of more than 4% does not meet the expectations. The D50 of Prescription 1 does not meet the particle size requirements of the composition.

[0078] Next, continue to explore feasible prescription conditions and prescription preparation methods.

[0079] Example 4 Preparation of the pharmaceutical composition of phenyl (4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate by air jet milling

[0080] Specific implementation method: Take phenyl valproate powder with an average particle size distribution D50 of about 120 μm, and crush the drug with a gas flow at a pressure of 0.6 Mpa. Monitor the particle size distribution during the process, stop crushing after reaching the target particle size distribution, and collect the drug powder.

[0081] Prepare 1500 ml of the sample according to the following Prescription 5: Take the drug powder obtained by gas flow crushing, add it to the excipient solution under stirring conditions, adjust the pH to 7.0 ± 0.5, disperse evenly to obtain a drug suspension, and fill the drug suspension into 3 ml or 10 ml ampoules to obtain a liquid-form drug composition.

[0082] Table 5 Prescription of Phenyl Valproate Composition

[0083]

[0084] Example 5 Preparation of the pharmaceutical composition of phenyl (4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate by high shear method

[0085] Prepare 1000 ml of the sample according to the formulation in Table 6 below: Take the phenyl (R)-3-(2-fluoro-4-(methylsulfonyl)phenyl)-3-hydroxypropionate powder with an average particle size distribution D50 of about 130 μm, add it to the excipient solution under stirring conditions, adjust the pH to 7.0 ± 0.5, make it uniformly dispersed, supplement the volume to the labeled amount, shear, monitor the particle size distribution during the process, stop shearing after reaching the target particle size distribution to obtain a drug suspension, fill the drug suspension into 3-ml or 10-ml vials to obtain the drug composition in liquid form, and set aside for use.

[0086] Table 6 Formulation of phenyl (R)-3-(2-fluoro-4-(methylsulfonyl)phenyl)-3-hydroxypropionate composition

[0087]

[0088]

[0089] Example 6 Preparation of the pharmaceutical composition of phenyl (4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate by media milling

[0090] Prepare 500 ml of the sample according to the formulation in Table 7 below: Take the phenyl (R)-3-(2-fluoro-4-(methylsulfonyl)phenyl)-3-hydroxypropionate powder with an average particle size distribution D50 of about 75 μm, add it to the aqueous solution containing all wetting agents at 50% volume under stirring conditions, make it uniformly dispersed and grind, monitor the particle size distribution during the process, stop grinding after reaching the target particle size distribution to obtain a drug suspension, mix the drug suspension evenly with the remaining excipient solution, adjust the pH to 7.0 ± 0.5, and then fill the drug suspension into 2.25-ml or 5-ml or 7-ml prefilled syringes to obtain the drug composition in liquid form.

[0091] Table 7 Formulation of phenyl (R)-3-(2-fluoro-4-(methylsulfonyl)phenyl)-3-hydroxypropionate composition

[0092]

[0093]

[0094] Example 7 Preparation of the pharmaceutical composition of phenyl (4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazin-1-yl)formate by high pressure homogenization

[0095] Prepare 2000 ml of the sample according to the formulation in Table 8 below: Take the phenyl (R)-3-(2-fluoro-4-(methylsulfonyl)phenyl)-3-hydroxypropionate powder with an average particle size distribution D50 of about 50 μm, add it to the excipient solution under stirring conditions, adjust the pH to 7.0 ± 0.5, make it uniformly dispersed, and homogenize it with a microfluidizer high-pressure homogenizer. Monitor the particle size distribution during the process, stop homogenizing after reaching the target particle size distribution to obtain a drug suspension, and fill the drug suspension into 2.25-ml or 5-ml or 7-ml prefilled syringes to obtain the drug composition in liquid form.

[0096] Table 8 Formulation of phenyl (R)-3-(2-fluoro-4-(methylsulfonyl)phenyl)-3-hydroxypropionate composition

[0097]

[0098]

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

[0100] Take samples of part of Formulation 2, Formulation 3, Formulation 8, Formulation 12, Formulation 18, and Formulation 20, fill them into vials or dual-chamber syringes, and lyophilize the filled drug solutions. After pre-freezing at -40 °C for 3 h, primary drying for 30 h, and secondary drying for 20 h, a drug composition in the form of a solid mass is obtained.

[0101] Example 9 Method of use of the pharmaceutical composition in solid mass form

[0102] The industrial production of Formulations 1 to 20 using a sterile production process can obtain sterile products that can be injected. Take the bulk drug compositions prepared from Formulations 8 and 12 respectively, add 1 mL of water for injection, shake well, select the injection volume (0.25 mL to 5 mL) according to the oral tolerance, and inject intramuscularly or subcutaneously to form a drug depot with a drug amount of 50 mg to 1300 mg at the injection site. After injection, it can be slowly released to treat depression.

[0103] Example 10 Particle size determination

[0104] The particle size distribution of the phenyl ester of vilazodone formate in Formulations 1 to 20 was determined by the wet method using a New Patek laser particle size analyzer. The results are shown in Table 9 below. Figure 5 。

[0105] Table 9 Particle Size Distribution of Phenyl Ester of Vilazodone Formate

[0106]

[0107]

[0108] Example 11 Stability of the composition

[0109] The stability of the drug composition in Example 6 (Formulation 12) was investigated, including stress tests (high temperature, high humidity, light), accelerated stability test (6 months), and long-term stability test (12 months). The drug could remain stable, the related substances were qualified, and the quality fluctuation was small, as shown in Table 10 below. Figure 6 。

[0110] Table 10 Stability Test

[0111]

[0112] Example 12 Pharmacokinetics in animals

[0113] Using rats as model animals, intramuscular injection (40 mg / kg) was performed to investigate the in vivo pharmacokinetics of the prodrug of vilazodone hydrochloride and the drug composition of the prodrug of vilazodone hydrochloride. 200 μL of whole blood 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 was used for anticoagulation. After blood collection, centrifugation was performed (4 °C, 3000 r·min-1, 5 min), and the supernatant was taken and placed in an EP tube, labeled, and the blood drug concentration was detected by liquid chromatography-mass spectrometry. The blood drug concentration is shown in Table 11. Figure 7 , the drug release is slow, which can meet the requirement of once-a-three-month administration. It can be seen from the drug-time curve that the in vivo release of the prodrug of vilazodone hydrochloride drug composition is relatively gentle, and the blood drug concentration C max / C min is less than 5 times, which can reduce the drug fluctuation in vivo.

[0114] Table 11 Blood drug concentration of pharmacokinetics in animals

[0115]

[0116]

Claims

1. A vortioxetine ester pharmaceutical composition, characterized in that: The composition comprises a therapeutically effective amount of a compound vortioxetine ester or a hydrate thereof, wherein the drug particle size of the compound has a Dv(50) of 0.1 μm to 42 μm, and the vortioxetine ester is vortioxetine formate phenyl ester.

2. The vortioxetine ester pharmaceutical composition according to claim 1, characterized in that The particle size includes one or more particle size ranges of Dv(10) from 0.01 μm to 19 μm, Dv(50) from 0.5 μm to 35 μm, and Dv(90) from 1 μm to 98 μm.

3. The vortioxetine ester pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition further comprises a stabilizer, wherein, calculated on a solid basis, vortioxetine phenyl formate accounts for 50-95% and the stabilizer accounts for 5-50%.

4. The vortioxetine ester pharmaceutical composition according to claim 3, characterized in that: The stabilizer can be one or more of a suspending agent, a wetting agent, a flocculant, a pH regulator, and a filler.

5. The vortioxetine ester pharmaceutical composition according to claim 4, characterized in that: Calculated on the basis of solids, the suspending agent accounts for 0.1 to 35%, and the suspending agent is selected from one or more of carboxymethyl cellulose or sodium carboxymethyl cellulose, polyethylene glycol, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol, methyl cellulose, gelatin, sodium hyaluronate or sodium alginate.

6. The vortioxetine ester pharmaceutical composition according to claim 4, characterized in that: Calculated on the basis of solids, the wetting agent accounts for 0 to 4%, and the wetting agent is selected from one or more of polysorbate, sodium lauryl sulfate, sodium deoxycholate, polyoxyethylene castor oil, sorbitan fatty acid ester, polyoxyethylene (15) hydroxystearate, poloxamer, carbomer, vitamin E polyethylene glycol succinate or glycine.

7. The vortioxetine ester pharmaceutical composition according to claim 4, characterized in that: Calculated on the basis of solid matter, the flocculant accounts for 0-10%, and the flocculant is selected from one or more of citric acid or its salt, tartaric acid or its salt.

8. The vortioxetine ester pharmaceutical composition according to claim 4, characterized in that: Calculated on the basis of solids, the pH adjuster accounts for 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.

9. The vortioxetine ester pharmaceutical composition according to claim 4, characterized in that: Calculated on the basis of solids, the filler accounts for 0 to 30%, and the filler is selected from one or more of mannitol, sucrose, glucose, sorbitol, lactose, and sodium chloride.

10. The vortioxetine ester pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition can be in the form of an aqueous suspension or a solid block, and can be used after being diluted with a solvent. After being resuspended in the solvent, the concentration of vortioxetine phenyl formate is 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 part of the stabilizer, and water for injection containing all the stabilizers.

11. Use of the vortioxetine ester pharmaceutical composition according to claims 1-10 in treating depression in adults.

12. The vortioxetine ester pharmaceutical composition according to claims 1-10, characterized in that: The crystalline XRD spectrum of vortioxetine phenyl 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°.

13. The pharmaceutical composition of vortioxetine ester according to claims 1-10, characterized in that: The preparation of vortioxetine phenyl formate comprises the following steps: Vortioxetine reacts with phenyl chloroformate under alkaline conditions to undergo an amine esterification reaction to precipitate a solid;

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