A pharmaceutical composition comprising a vortioxetine prodrug or a salt thereof

Abstract

The present application relates to a kind of pharmaceutical composition comprising vortioxetine prodrug or its salt;Particularly related to a kind of solid dispersion comprising vortioxetine prodrug compound A or its pharmaceutically acceptable salt, and its preparation method and application.The solid dispersion comprises the compound shown in formula A, surfactant and water-soluble carrier material;The solid dispersion has improved solubility and dissolution rate, can significantly improve the brain blood ratio compared with the compound shown in formula A, improve the bioavailability of active ingredient, and has good stability,

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing a vortioxetine prodrug or a pharmaceutically acceptable salt thereof, and especially to a solid dispersion containing a vortioxetine prodrug or a pharmaceutically acceptable salt thereof. BACKGROUND

[0002] Vortioxetine is a new drug for treating depression, developed by Lundbeck of Denmark and Takeda of Japan, and is a potent serotonin reuptake inhibitor (SSRIs). It has a high affinity for the serotonin transporter (SERT) in the human body (Ki = 1.6 nM), and has little affinity for norepinephrine transporter (Ki = 113 nM) and dopamine transporter (Ki = 1000 nM). In addition, vortioxetine is also a 5-HT1A receptor agonist, a 5-HT1B receptor partial agonist, a 5-HT1D, 5-HT3 and 5-HT7 receptor antagonist. It was approved for marketing by FDA on September 30, 2013, and is commercially available as Brintellix, used for the treatment of major depressive disorder (MDD).

[0003] The common adverse reactions of vortioxetine are gastrointestinal side effects, such as nausea, constipation and vomiting, which are the main side effects of SSRIs. The incidence of adverse reactions in the 5mg vortioxetine group was higher than that in the placebo group, with higher incidence of nausea (19.4 vs 9.4%) and diarrhea (11.4 vs 7.0%), and the incidence of gastrointestinal side effects also increased with further increase of the dose of administration ([J]. Pharmacology & therapeutics, 2015, 145: 43-57).

[0004] WO2021115372A1 discloses that by connecting vortioxetine with different lipid-soluble side chains to prepare vortioxetine prodrugs, the brain-blood ratio of vortioxetine can be significantly improved, the peripheral exposure is reduced, and the effect of improving the gastrointestinal side effects of vortioxetine is potential, and the brain-targeted drug delivery effect is significant. At the same time, the provided prodrug compound has good pharmacokinetic properties.

[0005] Although the introduction of the liposoluble side chain makes it a liposoluble prodrug, improves the membrane penetration ability, makes it easier to pass through the BBB into the brain tissue, increases the brain / blood ratio of the drug, and has the effect of central nervous system targeted drug delivery. However, due to the introduction of the liposoluble side chain, the solubility of the drug is significantly reduced, for example, the prodrug compound A of vortioxetine is slightly soluble in methanol and ethanol, and almost insoluble in aqueous medium. The low solubility in aqueous medium will become the main rate-limiting factor for the effect of the drug in the oral administration route,

[0006] SUMMARY

[0007] The inventors found that the compound represented by formula A has low solubility in aqueous medium due to the introduction of the liposoluble side chain, which limits the development of oral preparations. To solve the above technical problems, the inventors found that mixing the compound represented by formula A or a pharmaceutically acceptable salt thereof with a suitable pharmaceutical carrier to prepare a solid dispersion can well solve the above problems.

[0008] The present application uses the technology of solid dispersion to improve the solubility of the prodrug compound of vortioxetine, especially the compound represented by formula A, in aqueous medium, and further improve the bioavailability of oral administration.

[0009]

[0010] On the other hand, the purpose of the present application is to provide a pharmaceutical composition comprising the solid dispersion and a related preparation method.

[0011] Firstly, the present application provides a solid dispersion of a compound represented by formula A or a pharmaceutically acceptable salt thereof, comprising a compound represented by formula A or a pharmaceutically acceptable salt thereof, a surfactant and a water-soluble carrier material; wherein the weight ratio of the compound represented by formula A to the water-soluble carrier material is 1:(0.1-10); the weight ratio of the compound represented by formula A to the surfactant is 1:(0.01-1),

[0012]

[0013] In an embodiment of the present application, the hydrophilic-lipophilic balance (HLB value) of the surfactant is greater than 8, preferably greater than or equal to 10, more preferably greater than or equal to 15, for example 15, 16, or 17, etc.

[0014] In an embodiment of the present application, the surfactant is selected from at least one of polysorbate, triethanolamine oleate, poloxamer, preferably at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, triethanolamine oleate.

[0015] In one embodiment of the present application, the water-soluble carrier material is selected from at least one of water-soluble cellulose derivatives, sugars, organic acids, urea, povidone, copovidone, polyethylene glycol;

[0016] Preferably, the water-soluble cellulose derivatives are selected from at least one of hydroxypropyl methylcellulose (HPMC), or hydroxypropyl cellulose (HPC);

[0017] Preferably, the sugars are selected from at least one of fructose, sucrose, lactose, galactose, mannitol, sorbitol, xylitol;

[0018] Preferably, the organic acids are selected from at least one of citric acid, tartaric acid, fumaric acid, maleic acid or succinic acid.

[0019] In one embodiment of the present application, the surfactant is at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, preferably polysorbate 80; and the water-soluble carrier material is at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, PEG 2000, sorbitol, mannitol, preferably at least one of povidone K30, povidone K90.

[0020] In one preferred embodiment of the present application, the weight ratio of the compound of Formula A to the surfactant is 1:(0.02-0.3), for example 1:0.02, 1:0.04, 1:0.05, 1:0.06, 1:0.1, 1:0.2 or 1:0.3, and any range therebetween, preferably 1:(0.1-0.3), more preferably 1:0.1.

[0021] In one preferred embodiment of the present application, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(0.2-6), for example 1:0.2, 1:1, 1:2, 1:3, 1:4, 1:5, or 1:6, and any range therebetween, preferably 1:(1-6).

[0022] In one preferred embodiment of the present application, the solid dispersion comprises the compound of Formula A or a pharmaceutically acceptable salt thereof, polysorbate 80 and povidone K30; wherein the weight ratio of the compound of Formula A to the polysorbate 80 is 1:(0.01-1), preferably 1:(0.01-0.5), more preferably 1:(0.02-0.3), for example 1:0.1; and the weight ratio of the compound of Formula A to the povidone K30 is 1:(0.1-10), preferably 1:(1-6), more preferably 1:2.

[0023] The present application also provides a method for preparing the solid dispersion, comprising: (1) dissolving the compound of Formula A or a pharmaceutically acceptable salt thereof, a surfactant and a water-soluble carrier material in the same solvent; and (2) spray drying, freeze drying or hot-melt extruding the solution obtained in step (1) to obtain the solid dispersion.

[0024] Preferably, the solvent is at least one of alcohol, phenol, ether, halogenated hydrocarbon, ketone, aldehyde, nitrile, amide, sulfone, sulfoxide, carboxylic acid and water, preferably the solvent is methanol, ethanol or acetone.

[0025] Further preferably, in the above method, the inlet temperature of the spray dryer is 50-65°C, the outlet temperature is 30-50°C, and the atomization pressure is 0.1-0.3 MPa.

[0026] The present application also provides a pharmaceutical composition comprising the solid dispersion of the present application and at least one other pharmaceutically acceptable carrier.

[0027] The amount of the pharmaceutical excipient in the pharmaceutical composition can be adjusted according to the type and specification of the preparation, and in the present application, the preferred pharmaceutical composition is an oral preparation, wherein the weight of the other pharmaceutically acceptable carrier is 0.1-80% of the weight of the solid dispersion, for example, 1-80%, 1-70%, 10-80%, 15-80%, 20-80%, preferably 20-80%.

[0028] Further, in the above pharmaceutical composition, the other pharmaceutically acceptable carrier is at least one of excipient, propellant, solubilizer, co-solvent, emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesion agent, integrating agent, penetration enhancer, pH regulator, buffer, plasticizer, surfactant, defoaming agent, thickening agent, inclusion agent, humectant, absorbent, diluent, flocculating agent and deflocculating agent, antioxidant, adsorbent, filter aid, release retardant.

[0029] In a preferred embodiment of the present application, the pharmaceutical composition, wherein the other pharmaceutically acceptable carrier is at least one of mannitol, microcrystalline cellulose, lactose, starch or dextrin, preferably the other pharmaceutically acceptable carrier is at least one of mannitol or microcrystalline cellulose.

[0030] It is further preferred that the pharmaceutical composition comprises the solid dispersion comprising Compound A or a pharmaceutically acceptable salt thereof according to the present application and mannitol and / or microcrystalline cellulose; more preferably, the weight ratio of the solid dispersion to mannitol in the composition is 1 : 0.1-10, for example more preferably 1 : 1-5; and the weight ratio of the solid dispersion to microcrystalline cellulose is 1 : 0.1-5, preferably 1 : 0.1-1. For example, the pharmaceutical composition wherein the solid dispersion of the compound of Formula A or a pharmaceutically acceptable salt thereof provides the compound of Formula A in an amount of 0.01 mg-1000 mg, preferably 0.1 mg-500 mg, or 10 mg-200 mg per unit formulation.

[0031] The present application also provides a method for preparing the pharmaceutical composition according to the present application, which comprises mixing the solid dispersion according to the present application with other pharmaceutically acceptable carriers to prepare a pharmaceutically acceptable pharmaceutical dosage form, preferably an oral dosage form, more preferably a tablet, a capsule, a pill, a granule, a dry suspension, a powder, or a liquid for oral administration.

[0032] The present application also provides the use of the pharmaceutical composition according to the present application and the solid dispersion according to the present application in the preparation of a medicament for the treatment of a neuropsychiatric disorder, wherein the neuropsychiatric disorder is selected from any one or more of schizophrenia, depression, anxiety, sleep disorder, cognitive disorder, neurodegenerative disease, bipolar disorder, post-traumatic stress syndrome, addictive disease, withdrawal syndrome, or attention deficit disorder, preferably any one or more of depression, cognitive disorder, anxiety, schizophrenia, sleep disorder, neurodegenerative disease, or bipolar disorder, more preferably depression.

[0033] Further, the depression is selected from mild depression, moderate depression, severe depression, depression accompanied by other mental disorders, and recurrent depression; and the mental disorder is selected from one or more of sleep disorder, cognitive disorder, anxiety, obsessive-compulsive disorder, affective disorder, or personality disorder, preferably the mental disorder is selected from cognitive disorder, anxiety, or sleep disorder. DETAILED DESCRIPTION

[0034] The present application is intended to embrace all alternatives, modifications and equivalents thereof which are included within the scope of the present application as defined by the claims. One skilled in the art will recognize many methods and materials as being suitable for use in practicing the present application. The present application is in no way limited to the methods and materials described herein.

[0035] It should be further understood that certain features of the application, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the application, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications referred to in this application are incorporated herein by reference in their entirety.

[0037] Definitions of Terms

[0038] The terms "comprising" or "including" or "having" are open-ended terms that are intended to encompass both the express elements listed and any additional elements that are not expressly listed.

[0039] In the context of the present application, all numbers disclosed herein are approximate unless otherwise indicated. Each numerical value should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques to the end value. Numerical values disclosed herein are approximations that can vary depending on the desired properties sought to be obtained by those of ordinary skill in the art utilizing the teachings disclosed herein.

[0040] The "pharmaceutically acceptable carrier" of the present application refers to a pharmaceutical adjuvant or excipient that can be used for dilution, filling, adhesion, disintegration, lubrication, coloring, flavoring, wetting, etc. in addition to the main pharmaceutical ingredient in the pharmaceutical preparation (or composition), and the pharmaceutically acceptable carrier can form a dispersion system or a solid dispersion of a solid dispersion of the compound of Formula A or a pharmaceutically acceptable salt thereof together with the surfactant described in the solid dispersion and the water-soluble carrier material.

[0041] The "pharmaceutical composition" of the present application refers to a semi-finished product, preparation, preparation composition, etc. containing a pharmaceutical active ingredient and a pharmaceutical adjuvant ingredient.

[0042] AUC refers to the area under the blood concentration-time curve, and Cmax refers to the peak blood concentration.

[0043] h refers to hour, g refers to gram, μl refers to microliter, min refers to minute, ℃ refers to Celsius, mg refers to milligram, mL refers to milliliter, and rpm refers to revolutions per minute.

[0044] Generally, the term "solid dispersion" refers to a system in the solid state which comprises at least two components, one of which is dispersed throughout the other or others. As used herein, the term "solid dispersion" refers to a stable solid dispersion comprising an amorphous drug substance and one or more polymers or carriers. Further, as used herein, the term "solid dispersion" also refers to a stable solid dispersion comprising an amorphous drug substance and one or more surfactants and one or more water-soluble carrier materials. By "amorphous drug substance" is meant that the amorphous solid contains a substantial amount of the drug substance in amorphous solid form, i.e., at least about 80% of the drug substance in the dispersion is in amorphous form. More preferably, at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.

[0045] In one embodiment of the present application, there is provided a solid dispersion of a compound of Formula A, comprising a compound of Formula A or a pharmaceutically acceptable salt thereof, a surfactant, and a water-soluble carrier material; wherein the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(0.1-10); and the weight ratio of the compound of Formula A to the surfactant is 1:(0.01-1),

[0046]

[0047] In one embodiment of the present application, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(0.2-8);

[0048] Preferably, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(0.2-6);

[0049] Preferably, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(1-6);

[0050] Preferably, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(1-5);

[0051] Preferably, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(1-4);

[0052] Preferably, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:(2-3);

[0053] Preferably, the weight ratio of the compound of Formula A to the water-soluble carrier material is 1:2.

[0054] Preferably, the weight ratio of the compound of Formula A to the surfactant is 1:(0.01-0.5); and more preferably, the weight ratio of the compound of Formula A to the surfactant is 1:(0.04-0.3).

[0055] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.05-0.1);

[0056] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.05-0.2);

[0057] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.05-0.3);

[0058] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.05-0.4);

[0059] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.06-0.3);

[0060] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.04-0.2);

[0061] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.02-0.3);

[0062] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.02-0.2);

[0063] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.1-0.3);

[0064] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:(0.1-0.2);

[0065] Preferably, the weight ratio of the compound of formula A to the surfactant is 1:0.1;

[0066] Preferably, the hydrophilic-lipophilic balance (HLB) of the surfactant is greater than 8, preferably greater than or equal to 10, more preferably greater than or equal to 15. For the use of two or more surfactants, the HLB of the mixture should meet the requirement, and the calculation method of the theoretical HLB of the mixed surfactant is as follows:

[0067] HLB 混合 =(aX+bY+cZ) / (X+Y+Z)

[0068] wherein a, b, c are the HLB values of surfactants x, y, z respectively; X, Y, Z are the relative molecular masses of surfactants x, y, z.

[0069] In one specific embodiment of the present application, the surfactant is selected from at least one of polysorbate, triethanolamine oleate, poloxamer, preferably at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, triethanolamine oleate.

[0070] The polysorbate 80, also known as Tween 80;

[0071] The poloxamer, also known as Poloxamer, is a new type of high molecular non-ionic surfactant. According to the different molecular weight, there are different types, such as 188, 407, 124, 128, 108, 237, 338, etc. The "poloxamer" in the present application includes all types and mixtures of any different types, preferably using type 188, 407, such as the commonly used 188 type with the trade name Pluronic F68; wherein the water-soluble carrier material is selected from at least one of water-soluble cellulose derivatives, sugars, organic acids, urea, povidone, copovidone, polyethylene glycol;

[0072] Further, the water-soluble cellulose derivative is selected from: hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC);

[0073] The polyethylene glycol is a mixture of ethylene oxide and water condensation, and the molecular formula is HO(CH2CH2O)nH, wherein n represents the average number of oxyethylene groups, and the English abbreviation is PEG. Polyethylene glycol has various molecular weights and physical properties. At room temperature and normal pressure, polyethylene glycol with a molecular weight of 100-700 is a liquid, and polyethylene glycol with a molecular weight of 1000 or more is a solid. Polyethylene glycol has very good hydrophilicity and is a commonly used pharmaceutical excipient in pharmaceutical science. It is safe and non-toxic. The solid dispersion of the present application selectively uses polyethylene glycol which is solid at room temperature and normal pressure, such as PEG1000, PEG1500, PEG2000, PEG3000, PEG4000, PEG5000, PEG6000, PEG7000, PEG8000, PEG9000, PEG10000, PEG15000, PEG20000, etc. and mixtures of any two or more of the above; preferably using PEG2000, PEG4000.

[0074] The sugar is selected from fructose, sucrose, lactose, galactose, mannitol, sorbitol, xylitol; preferably using sorbitol or mannitol.

[0075] The organic acid is selected from citric acid, tartaric acid, fumaric acid, maleic acid and succinic acid.

[0076] The polyvinylpyrrolidone, also known as polyvinylpyrrolidone, English abbreviation PVP, is a homopolymer of 1-vinyl-2-pyrrolidone, according to its molecular weight, there are different types, such as K30, K32, K25, K29, K90, K17, C15, C30 and so on, the "polyvinylpyrrolidone" described in the application includes all types and mixtures of any different types, preferably K30, K25, K90 is used.

[0077] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0078]

[0079]

[0080] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0081] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 PVP K30 4 TW60 0.05

[0082] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0083] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 PVP K30 6 TW40 0.2

[0084] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0085] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 PVP K30 3 TW20 0.3

[0086] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0087] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 PVP K90 0.2 TW80 0.2

[0088] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0089] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 Hydroxypropyl methylcellulose 1 Poloxamer 0.2

[0090] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0091] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 PEG 2000 1 Poloxamer 0.1

[0092] In a preferred embodiment of the application, the solid dispersion of the compound of formula A comprises:

[0093] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 Hydroxypropyl cellulose 1 Triethanolamine oleate 0.02

[0094] In a preferred embodiment of the present application, the solid dispersion of the compound of Formula A comprises:

[0095] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 Hydroxypropyl cellulose 1 Tween 80 0.04

[0096] In a preferred embodiment of the present application, the solid dispersion of the compound of Formula A comprises:

[0097] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 PVP K30 1 Tween 80 0.04

[0098] In a preferred embodiment of the present application, the solid dispersion of the compound of Formula A comprises:

[0099] Ingredients Parts by weight Vortioxetine prodrug Compound A 1 Sorbitol 4 Tween 80 0.06

[0100] In a preferred embodiment of the present application, the solid dispersion of the compound of Formula A comprises:

[0101]

[0102]

[0103] The "vortioxetine prodrug", "Compound A", "compound of Formula A", "vortioxetine prodrug Compound A" mentioned in the present application can be replaced by each other, and all refer to a compound having the following structure:

[0104]

[0105] The compound of Formula A or its pharmaceutically acceptable salt in the solid dispersion of the compound of Formula A and the pharmaceutical composition comprising the solid dispersion of the compound of Formula A according to the present application is in amorphous state, and the X-ray powder diffraction spectrum of the solid dispersion or the pharmaceutical composition does not have the characteristic peaks of the crystal of the compound of Formula A or its pharmaceutically acceptable salt after deducting the background peaks of the pharmaceutical excipients.

[0106] The present application defines the mass ratio range of the compound of formula A or its pharmaceutically acceptable salt and the water-soluble carrier material selected from one or more of water-soluble cellulose derivatives, sugars, organic acids, urea, povidone, copovidone, polyethylene glycol and the surfactant selected from one or more of polysorbate, triethanolamine oleate, poloxamer, which is based on the consideration of the contribution degree of improving the dissolution and solubility of the compound of formula A or its pharmaceutically acceptable salt and the improvement of the in-vivo pharmacokinetic properties and bioavailability of the active ingredient of the solid dispersion and other factors. If the amount of the water-soluble carrier material selected from one or more of water-soluble cellulose derivatives, sugars, organic acids, urea, povidone, copovidone, polyethylene glycol and the surfactant selected from one or more of polysorbate, triethanolamine oleate, poloxamer is too small, the dispersion degree of the compound of formula A or its pharmaceutically acceptable salt in the solid dispersion will not be complete and the improvement of its dissolution and solubility will not be significant, and the pharmaceutical effect will be poor. If the amount of the water-soluble carrier material selected from one or more of water-soluble cellulose derivatives, sugars, organic acids, urea, povidone, copovidone, polyethylene glycol and the surfactant selected from one or more of polysorbate, triethanolamine oleate, poloxamer is too large, the drug content of the compound of formula A or its pharmaceutically acceptable salt in the dispersion is low and the contribution degree of improving its dissolution, solubility, bioavailability, pharmacokinetic properties and the like is also not remarkable, which is not conducive to the subsequent application and cost accounting in the production of the formulation composition.

[0107] In a more preferred embodiment of the present application, the surfactant is at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, and the water-soluble carrier material is at least one of povidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, PEG2000, sorbitol; wherein the weight ratio of the compound of formula A to the surfactant is 1:(0.01-1), preferably 1:(0.1-1), more preferably 1:(0.02-0.3), such as 1:0.1; and the weight ratio of the compound of formula A to the water-soluble carrier material is 1:(0.1-10), preferably 1:(0.2-6), more preferably 1:(1-6), such as 1:(1-5) or 1:2, etc.

[0108] In a more preferred embodiment of the present application, the surfactant is at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, and the water-soluble carrier material is at least one of povidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, PEG2000, sorbitol; wherein the weight ratio of the compound of formula A to the surfactant is 1:(0.01-1), preferably 1:(0.1-1), more preferably 1:(0.02-0.3), such as 1:0.1; and the weight ratio of the compound of formula A to the water-soluble carrier material is 1:(0.1-10), preferably 1:(0.2-6), more preferably 1:(1-6), such as 1:(1-5) or 1:2, etc.

[0109] The solid dispersion of the compound of formula A can be prepared by using the conventional preparation method in the art, such as solvent method, solvent deposition method, spray drying method, fluidized bed method, freeze drying method, etc., preferably spray drying method.

[0110] In a specific embodiment of the present application, the preparation method of the solid dispersion comprises: (1) dissolving the compound of formula A or its pharmaceutically acceptable salt, surfactant and water-soluble carrier material in the same solvent according to the weight ratio; (2) spray drying, freeze drying or hot melt extrusion of the solution obtained in step (1) to prepare the solid dispersion.

[0111] The solvent is at least one of alcohol, phenol, ether, halogenated hydrocarbon, ketone, aldehyde, nitrile, amide, sulfone, sulfoxide, carboxylic acid and water containing 1-6 carbon atoms, preferably the solvent is methanol, ethanol or acetone.

[0112] Further, the inlet temperature of the spray drying is 50-65℃, preferably 55-61℃, the outlet temperature is 30-50℃, preferably 35-45℃, the atomization pressure is 0.1-0.3MPa, preferably 0.1-0.2MPa, the average liquid feed rate is 7-15(ml / min), preferably 8.2-11.3(ml / min), the average drying air flow is 0.4-0.8m 3 / min (220V, 50Hz), preferably 0.5-0.65m 3 / min (220V, 50Hz), and the cooling temperature is -10--5℃, preferably -7--5℃.

[0113] In another aspect of the present application, the use of the above-mentioned vortioxetine prodrug and the solid dispersion of the compound of formula A is provided. The specific schemes are as follows:

[0114] The use of the solid dispersion of the compound of formula A in the preparation of the pharmaceutical preparation of the compound of formula A. The solid dispersion of the compound of formula A can be further prepared into oral preparations, such as tablets (ordinary tablets, dispersible tablets, sustained-release tablets, enteric-coated tablets, effervescent tablets, oral disintegrating tablets, chewable tablets, shaped tablets, etc.), capsules (hard capsules, soft capsules, enteric-coated capsules, etc.), pills (micro-pellets, dripping pills), granules, dry suspensions, powders, oral liquid preparations (solutions, suspensions, emulsions).

[0115] According to the different pharmaceutical dosage forms, other suitable pharmaceutical carriers can be selectively contained, such as diluents, fillers, disintegrants, surfactants, suspending agents, binders, lubricants, colorants, flavoring agents, etc. The "selectively contained" means that one or several of them can be selected, or none of them can be selected.

[0116] Tablets, capsules, pills, granules, dry suspensions, powders, and oral liquid preparations for oral administration are generally present in unit dosage and contain usual excipients such as diluents, fillers, disintegrants, surfactants, suspending agents, binders, lubricants, colorants, taste modifiers, and the like.

[0117] wherein the content of the compound of Formula A or a pharmaceutically acceptable salt thereof provided by the solid dispersion of the compound of Formula A in the unit formulation is 0.01 mg to 1000 mg, or 0.01 mg to 500 mg, or 0.1 mg to 500 mg, or 1 mg to 400 mg, 2 mg to 300 mg, or 10 mg to 200 mg, or 50 mg to 100 mg.

[0118] Suitable fillers or diluents used include lactose, mannitol, sorbitol, microcrystalline cellulose, starch, modified starch, dextrin, cyclodextrin and its derivatives, calcium phosphate, sucrose, polyethylene glycol (polyethylene glycol of various molecular weights), pregelatinized starch, xylitol, fructose, maltitol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, and the like; the disintegrants include sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, corn starch, microcrystalline cellulose, carboxymethyl cellulose calcium, and the like; the surfactants include sodium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, polysorbate (polysorbate of various types), fatty acid sorbitan (fatty acid sorbitan of various types), and the like; the suspending agents include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, gum arabic, xanthan gum, sodium carboxymethyl cellulose, and the like; the binders include povidone, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum, and the like; the lubricants include talc, sodium stearyl fumarate, and the like. In addition, preservatives such as sodium benzoate, potassium sorbate, methyl paraben, propyl paraben, and the like can also be included; stabilizers and antioxidants such as calcium disodium edetate, sodium sulfite, vitamin C, vitamin E, and the like can also be included; taste modifiers such as maltitol, steviol, aspartame, fructose, sucrose, sodium saccharin, orange flavor, strawberry flavor, and the like can also be included; and other conventional, appropriate additives can also be included.

[0119] In a preferred embodiment of the present application, the pharmaceutical preparation is an oral preparation, and the other pharmaceutically acceptable carrier is at least one selected from the group consisting of mannitol, microcrystalline cellulose, lactose, starch, and dextrin, more preferably at least one selected from the group consisting of mannitol and microcrystalline cellulose. The weight of the other pharmaceutically acceptable carrier in the composition is 0.1% to 80%, preferably 20% to 80%, of the weight of the solid dispersion.

[0120] The pharmaceutical composition is prepared by using the preparation means commonly used in the art. Specifically, for tablets, dry granulation, wet granulation, or direct compression can be used; for capsules, dry granulation, wet granulation, or direct filling of powder can be used.

[0121] When preparing drop pills, the polyethylene glycol (such as PEG 3000, PEG 4000, PEG 6000, PEG 8000, etc.) which is solid at room temperature is heated and melted, and then the solid dispersion is dissolved or dispersed in the polyethylene glycol to form a liquid mixture, which is then dropped and cooled to obtain drop pills. Alternatively, the solid dispersion of the compound of formula A is heated and melted, and then dropped and cooled to obtain drop pills. Of course, other pharmaceutical excipients such as disintegrants, surfactants, lubricants, etc. can be added as needed in the above preparation.

[0122] It should also be understood that when the pharmaceutical dosage form is a tablet, it can be film-coated. The tablets can be coated (enteric coating or gastric soluble film coating) according to methods well known in the art. The materials for film coating include suitable coating agents such as Opadry, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc. They can also contain plasticizers such as polyethylene glycol, triethyl citrate, etc. The color of the coating film can be various, such as orange, white, blue, etc.

[0123] Specifically, granules or dry suspensions are obtained by uniformly mixing the solid dispersion of the compound of formula A of the present application and the pharmaceutical carrier, which includes but is not limited to the following substances: lactose, mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, cyclodextrin and its derivatives, calcium phosphate, sucrose, talc, sodium stearyl fumarate, etc., and then using wet granulation or dry granulation. If necessary, tablets can be further obtained by tabletting, or capsules can be obtained by filling hollow capsules.

[0124] Injection can be obtained by uniformly mixing the solid dispersion of the compound of formula A and suitable injection pharmaceutical carriers according to the preparation method of injection, wherein the pharmaceutical carriers include but are not limited to the following substances as fillers or excipients: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose, sodium chloride.

[0125] If necessary, other pharmaceutical excipients can be added to the above preparation method according to the different pharmaceutical dosage forms and the need to ensure the quality of the pharmaceutical agent.

[0126] In another aspect, the present application provides the use of the pharmaceutical composition and the solid dispersion described in the present application in the preparation of a medicament for the treatment of any one or more of neuropsychiatric diseases selected from schizophrenia, depression, anxiety, sleep disorder, cognitive disorder, neurodegenerative disease, bipolar disorder, post-traumatic stress syndrome, addictive disease, withdrawal syndrome or attention deficit, preferably any one or more of depression, cognitive disorder, anxiety, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder, more preferably depression; further, the depression is selected from mild depression, moderate depression, severe depression, depression accompanied by other mental disorders and recurrent depression; and the mental disorder is selected from one or more of sleep disorder, cognitive disorder, anxiety, obsessive-compulsive disorder, affective disorder or personality disorder, preferably cognitive disorder, anxiety or sleep disorder.

[0127] In some embodiments, the solid dispersion of the prepared vortioxetine prodrug (compound shown in formula A) is found to have significantly improved pharmacokinetic performance in vivo compared with the vortioxetine prodrug (compound shown in formula A) in PK tests in male rats, such as significantly increased brain-blood ratio of vortioxetine, reduced peripheral exposure and improved bioavailability.

[0128] In some embodiments, the solid dispersion of the prepared vortioxetine prodrug (compound shown in formula A) is further compressed into tablets, and the in vivo pharmacokinetic properties thereof are investigated. The results show that the solid dispersion composition of the vortioxetine prodrug (compound shown in formula A) provided by the present application can significantly improve the in vivo bioavailability of the vortioxetine prodrug (compound shown in formula A), which is of great clinical significance for significantly improving the convenience of drug administration for patients and improving patient compliance, especially for patients with severe depression who need long-term medication and are often accompanied by anorexia and suicidal tendency.

[0129] In other embodiments, the prepared solid dispersion of the vortioxetine prodrug (compound shown in formula A) is also subjected to stability investigation. After being placed under accelerated conditions (40℃±2℃, 25%±5%RH) for 3 months, the prepared solid dispersion of the vortioxetine prodrug is still in an amorphous state, and the in vitro dissolution rate does not change significantly, indicating that the solid dispersion of the vortioxetine prodrug (compound shown in formula A) provided by the present application has good stability, and is suitable for the development of solid dispersion preparations of the vortioxetine prodrug (compound shown in formula A) and application in clinical practice.

[0130] The solid dispersion of the compound of formula A or the pharmaceutical composition comprising the same of the present application has no characteristic peaks of the crystalline state of the compound of formula A or the pharmaceutically acceptable salt thereof in the X-ray powder diffraction spectrum expressed by the angle 2θ using Cu-Kα radiation after deducting the background peaks of the pharmaceutical adjuvant, indicating that the compound of formula A or the pharmaceutically acceptable salt thereof is in an amorphous state. The compound of formula A or the pharmaceutically acceptable salt thereof of the present application is in an amorphous state, the molecules are in a highly disordered state, the surface free energy of the substance is greater, the molecules in the solid substance have higher energy than the molecules in the crystalline solid substance, and the molecules are more easily dispersed, increasing the dissolution and improving the bioavailability of the compound of formula A or the pharmaceutically acceptable salt thereof.

[0131] In a specific embodiment of the present application, it is proved that the combination of the amorphous compound of formula A or the pharmaceutically acceptable salt thereof prepared by the present application and the pharmaceutical adjuvant is crystallized under accelerated test conditions (40±2℃, humidity 25%±5%), the solid dispersion and the pharmaceutical composition of the amorphous compound of formula A or the pharmaceutically acceptable salt thereof and the pharmaceutical adjuvant of the present application can maintain good physical and chemical stability, and will have a broad application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0132] Figure 1 is the X-ray powder diffraction pattern (XRPD pattern) of the solid dispersion of the vortioxetine prodrug compound A prepared in Example 1 of the present application, which is placed in 40℃±2℃, 25%±5% humidity on the 0th day, the 30th day, and the 90th day for detection;

[0133] Figure 2 is the XRPD pattern of the capsule containing the solid dispersion of the vortioxetine prodrug compound A prepared in Example 1 of the present application, which is placed in 40℃±2℃, 25%±5% humidity on the 0th day, the 30th day, and the 90th day for detection, and the XRPD pattern of the adjuvants mannitol and microcrystalline cellulose.

[0134] From Figure 2 It can be seen that after deducting the XRPD diffraction peaks of the adjuvants mannitol and microcrystalline cellulose, the capsule containing the solid dispersion of the vortioxetine prodrug compound A is placed in 40℃±2℃, 25%±5% humidity on the 0th day, the 30th day, and the 90th day for detection, and no crystalline diffraction peaks are observed.

[0135] EXAMPLE

[0136] The following experiments are used to further verify the significant advantages of the solid dispersion of the vortioxetine prodrug (compound shown in formula A) and water-soluble carrier materials (polyvinylpyrrolidone, poloxamer, polyethylene glycol, sorbitol) and surfactants (polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer) in improving the solubility and dissolution rate, stability, brain-blood ratio, reducing peripheral exposure, and improving bioavailability of the vortioxetine prodrug (compound shown in formula A).

[0137] Unless specifically stated otherwise, in the following examples, specific techniques or conditions are not explicitly described, and those skilled in the art can perform them according to the common techniques or conditions in the art or according to the product instructions. The used drugs, reagents or instruments are not marked with the manufacturer, and are all conventional products available in the market.

[0138] Specific preparation methods of the solid dispersion and oral solid preparation:

[0139] (1) Dissolve the vortioxetine prodrug (compound shown in formula A), surfactant, and water-soluble carrier material in the same solvent;

[0140] (2) Spray dry the above solution to prepare a solid dispersion;

[0141] (3) Add appropriate excipients to prepare an oral solid preparation.

[0142] Among them, the spray drying inlet temperature is 55-61℃, the outlet temperature is 35-45℃, the atomization pressure is 0.1-0.2MPa, the average liquid feeding amount is 8.2-11.3(ml / min), the average drying air flow is 0.5-0.65m 3 / min (220V, 50Hz), and the cooling temperature is -7℃.

[0143] The present application uses an X-ray powder diffractometer (Aeris DY883, Panalytical, Netherlands) to collect data from the sample. The method parameters of the X-ray powder diffraction are as follows: Cu / Kα is used as the ray source, the working voltage and current are 40Kv and 20mA respectively, and the 2θ scanning range is 3-40°.

[0144] Reagents

[0145] Vortioxetine prodrug compound A (self-made), Tween 80 (abbreviation TW80, Nanjing Well Pharmaceutical Co., Ltd.), PVP K30 (Boai Xin Kaiyuan Medical Technology Group Co., Ltd.), mannitol (Rohogert), microcrystalline cellulose (DFE), lactose (DFE), magnesium stearate (Anhui Shanhe Pharmaceutical Auxiliary Material Co., Ltd.), starch (Anhui Shanhe Pharmaceutical Auxiliary Material Co., Ltd.), dextrin (Anhui Shanhe Pharmaceutical Auxiliary Material Co., Ltd.).

[0146] Apparatus

[0147] Spray dryer (Yamato DL310+GAS410), magnetic stirrer (Yihua Instruments Co., Ltd.), HPLC (Agilent), dissolution tester (Tianjin Tianda Tianfa Science and Technology Development Co., Ltd.)

[0148] Auxiliary material and amount screening example

[0149] Prescription and amount of batches 1-6 solid dispersions

[0150]

[0151]

[0152] Note: " / " means no.

[0153] According to the above prescription, the materials were weighed and stirred in a water bath at 40°C to prepare a uniform solution to be sprayed dry, and then sprayed dry. The inlet air temperature of the spray dryer was 56-59°C, the outlet air temperature was 40°C, the average liquid flow rate was 9.7 ml / min, the atomization pressure was 0.12 MPa, the average drying air flow rate was 0.59 m 3 / min (220V, 50Hz), and the cooling temperature was -7°C. Six batches of solid dispersions were obtained.

[0154] Solubility test:

[0155] The 1-6 batches of solid dispersions of vortioxetine prodrug compound A were placed under the same conditions for solubility test:

[0156] 300mg of sample was added to 4ml of corresponding solvent (pH 1.2, pH 4.5, pH 6.8 buffer salt solution) to make it supersaturated. After stirring for 24h, 2ml was taken, centrifuged, filtered, and then determined by HPLC method (injection amount 5ul, ordinary C18 column).

[0157] The test results are shown in the following table: solubility results of batches 1-6 solid dispersions

[0158]

[0159] Note: " / " means not tested.

[0160] Comparing the above 1-6 batches, it can be seen that the batch 1 only added water-soluble carrier material PVP30, without adding surfactant Tween 80, and the solubility of the prepared solid dispersion of compound A is very small. While adding water-soluble carrier PVP30 and surfactant Tween 80, the solubility of the prepared solid dispersion of compound A is better. From batch 1 to batch 3, it can be seen that with the increase of the amount of surfactant, the solubility of the solid dispersion is gradually improved; from batch 3 and batch 4, it can be seen that when the amount of surfactant increases to a certain amount, the effect on the solubility of the solid dispersion is no longer obvious. Comparing batch 6 with batch 5, it can be seen that when the amount of surfactant (TW80) and water-soluble carrier material PVP30 is the same, the additional increase of water-soluble carrier material mannitol does not obviously improve the solubility of the solid dispersion.

[0161] Example 1, preparation of vortioxetine prodrug compound A solid dispersion and capsule

[0162] (1) Preparation of solid dispersion

[0163] Prescription:

[0164] Ingredients Amount Vortioxetine prodrug Compound A 5g PVP K30 10g TW80 0.5g 95% ethanol 150ml

[0165] Preparation method:

[0166] The materials are weighed according to the above prescription, stirred in a 40℃ water bath, and configured into a uniform solution to be sprayed and dried, and then sprayed and dried. The inlet air temperature of the spray drying is 56-59℃, the outlet air temperature is 40℃, the average liquid feeding amount is 9.7ml / min, the atomization pressure is 0.12Mpa, the average drying air flow is 0.59m 3 / min (220V, 50Hz), and the cooling temperature is -7℃.

[0167] (2) Preparation of capsule

[0168] Take 100 parts by weight of the vortioxetine prodrug compound A solid dispersion prepared in step (1), add 100 parts by weight of microcrystalline cellulose and 100 parts by weight of mannitol, mix uniformly, and then fill into capsules.

[0169] Example 2, preparation of vortioxetine prodrug compound A solid dispersion

[0170] Prescription:

[0171] Ingredients Amount Vortioxetine prodrug Compound A 5g PVP K30 20g TW60 0.25g 95% ethanol 400ml

[0172] Preparation method:

[0173] The materials are weighed according to the above prescription, stirred in a 40°C water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-60°C, an outlet air temperature of 42°C, an average liquid feed rate of 9.7 ml / min, an atomization pressure of 0.12 Mpa, an average drying air flow of 0.59 m 3 / min (220V, 50Hz), and a cooling temperature of -7°C.

[0174] Example 3, Preparation of a Vortioxetine Prodrug Compound A Solid Dispersion

[0175] Prescription:

[0176] Ingredients Amount Vortioxetine prodrug Compound A 5g PVP K30 30g TW40 1g 95% ethanol 800ml

[0177] Preparation method:

[0178] The materials are weighed according to the above prescription, stirred in a 40°C water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-60°C, an outlet air temperature of 42°C, an average liquid feed rate of 9.7 ml / min, an atomization pressure of 0.12 Mpa, an average drying air flow of 0.59 m 3 / min (220V, 50Hz), and a cooling temperature of -7°C.

[0179] Example 4, Preparation of a Vortioxetine Prodrug Compound A Solid Dispersion

[0180] Prescription:

[0181] Ingredients Amount Vortioxetine prodrug Compound A 5g PVP K30 15g TW20 1.5g 95% ethanol 500ml

[0182] Preparation method:

[0183] The materials are weighed according to the above prescription, stirred in a 40°C water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-60°C, an outlet air temperature of 42°C, an average liquid feed rate of 9.7 ml / min, an atomization pressure of 0.12 Mpa, an average drying air flow of 0.59 m 3 / min (220V, 50Hz), and a cooling temperature of -7°C.

[0184] Example 5, Preparation of a Vortioxetine Prodrug Compound A Solid Dispersion

[0185] Prescription:

[0186] Formulation Amount Vortioxetine prodrug Compound A 5g PVP K90 1g TW80 1g 80% ethanol 400ml

[0187] Preparation method:

[0188] The materials are weighed according to the above prescription, stirred in a 40°C water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-61°C, an outlet air temperature of 43°C, an average liquid feed rate of 11.3 ml / min, an atomization pressure of 0.12 Mpa, an average drying air flow of 0.59 m 3 / min (220V, 50Hz), and a cooling temperature of -7°C.

[0189] Example 6, Preparation of a Vortioxetine Prodrug Compound A Solid Dispersion

[0190] Prescription:

[0191] Formulation Amount Vortioxetine prodrug Compound A 5g Hydroxypropyl methylcellulose 5g Poloxamer 1g 95% ethanol 200ml

[0192] Preparation method:

[0193] The materials are weighed according to the above prescription, stirred in a 40°C water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-61°C, an outlet air temperature of 43°C, an average liquid feed rate of 11.3 ml / min, an atomization pressure of 0.12 Mpa, an average drying air flow of 0.59 m 3 / min (220V, 50Hz), and a cooling temperature of -7°C.

[0194] Example 7, Preparation of a Vortioxetine Prodrug Compound A Solid Dispersion

[0195] Prescription:

[0196] Formulation Amount Vortioxetine prodrug Compound A 5g PEG 2000 5g Poloxamer 0.5g 95% ethanol 200ml

[0197] Preparation method:

[0198] The materials are weighed according to the above prescription, stirred in a 40°C water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-61°C, an outlet air temperature of 43°C, an average liquid feed rate of 11.3 ml / min, an atomization pressure of 0.12 Mpa, an average drying air flow of 0.59 m 3 / min (220V, 50Hz), and a cooling temperature of -7°C.

[0199] Example 8, Preparation of a Vortioxetine Prodrug Compound A Solid Dispersion

[0200] Prescription:

[0201] Ingredients Amount Vortioxetine prodrug Compound A 5g Hydroxypropyl cellulose 5g Triethanolamine oleate 0.1g 90% ethanol 200ml

[0202] Preparation method:

[0203] The materials are weighed according to the above prescription, stirred in a 40℃ water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-60℃, an outlet air temperature of 42℃, an average liquid feed rate of 9.7ml / min, an atomization pressure of 0.15Mpa, an average drying air flow of 0.59m 3 / min (220V, 50Hz), and a cooling temperature of -7℃.

[0204] Example 9, Preparation of Vortioxetine Prodrug Compound A Solid Dispersion and Capsules

[0205] (1) Solid dispersion preparation:

[0206] Prescription:

[0207] Ingredients Amount Vortioxetine prodrug Compound A 5g Hydroxypropyl cellulose 5g Tween 80 0.2g 90% ethanol 200ml

[0208] Preparation method: The materials are weighed according to the above prescription, stirred in a 40℃ water bath, and configured into a uniform solution to be spray dried, and then spray dried, with an inlet air temperature of 58-60℃, an outlet air temperature of 42℃, an average liquid feed rate of 11.3ml / min, an atomization pressure of 0.15Mpa, an average drying air flow of 0.65m 3 / min (220V, 50Hz), and a cooling temperature of -7℃.

[0209] (2) Capsule preparation: 100 parts by weight of the above solid dispersion, 100 parts by weight of lactose, and 100 parts by weight of microcrystalline cellulose are mixed uniformly, and then encapsulated.

[0210] Example 10, Preparation of Vortioxetine Prodrug Compound A Solid Dispersion and Tablets

[0211] (1) Solid dispersion preparation:

[0212] Prescription:

[0213] Ingredients Amount Vortioxetine prodrug Compound A 5g PVP K30 5g Tween 80 0.2g 90% ethanol 200ml

[0214] Preparation method: The preparation is performed according to the preparation method of the solid dispersion in Example 9.

[0215] (2) Tablet preparation: 100 parts by weight of the above solid dispersion, 50 parts by weight of starch, 50 parts by weight of lactose, and 100 parts by weight of microcrystalline cellulose are granulated with an appropriate amount of 95% ethanol, dried at 50℃, sieved through a 24 mesh screen, 0.3 parts of stearic acid is added, and mixed uniformly, and then compressed into tablets.

[0216] Example 11, Preparation of Vortioxetine Prodrug Compound A Solid Dispersion and Capsules

[0217] (1) Solid dispersion preparation:

[0218] Formulation:

[0219] Ingredients Amount Vortioxetine prodrug Compound A 5g Sorbitol 20g Tween 80 0.3g 85% ethanol 300ml

[0220] Preparation method: refer to the preparation method of solid dispersion in Example 9.

[0221] (2) Capsule preparation: take 100 parts by weight of the above solid dispersion, add 100 parts by weight of lactose, 100 parts by weight of microcrystalline cellulose, mix evenly, and then fill into capsules.

[0222] Example 12, preparation of vortioxetine prodrug compound A solid dispersion and capsule

[0223] (1) Solid dispersion preparation:

[0224] Formulation:

[0225] Formulation Amount Vortioxetine prodrug Compound A 5g PVP K30 15g Tween 20 1g 85% ethanol 300ml

[0226] Preparation method: according to the above formulation, weigh the materials, stir in a 40℃ water bath, and prepare a uniform solution for spray drying. Then spray dry, with an inlet air temperature of 58-60℃, an outlet air temperature of 42℃, an average liquid feed rate of 9.7ml / min, an atomization pressure of 0.1Mpa, an average drying air flow of 0.53m 3 / min (220V, 50Hz), and a cooling temperature of -7℃.

[0227] (2) Capsule preparation: take 100 parts by weight of the above solid dispersion, add 100 parts by weight of dextrin, 100 parts by weight of microcrystalline cellulose, granulate with appropriate 95% ethanol, dry at 50℃, sieve through a 24 mesh screen, mix evenly, and then fill into capsules.

[0228] Example 13, solubility test

[0229] The vortioxetine prodrug compound A solid dispersions prepared in Examples 1, 3, 4, 5, and 7 were placed in the same conditions as vortioxetine prodrug compound A for solubility testing:

[0230] 300mg of sample was added to 4ml of corresponding solvent (pH1.2, pH4.5, pH6.8 buffer salt solution) to make it supersaturated. After stirring for 24h, 2ml was taken, centrifuged, filtered, and then determined by HPLC method (injection amount 5ul, ordinary C18 column). The test results are shown in Table 1 below:

[0231] Table 1: Solubility test results of solid dispersion and compound A

[0232]

[0233] Note: " / " means not detected.

[0234] From the results of Table 1, it can be seen that the solubility of the solid dispersion of the present application for Compound A is obviously improved.

[0235] The following takes the solid dispersion of the vortioxetine prodrug Compound A prepared in Example 1 and the capsule as an example to study the dissolution, stability and in vivo bioavailability.

[0236] Example 14, dissolution test

[0237] The capsule containing the solid dispersion of the vortioxetine prodrug Compound A prepared in Example 1 is taken to test the dissolution of the capsule.

[0238] The dissolution test method: the paddle method is used to test the dissolution of Compound A in the capsule containing the solid dispersion of the vortioxetine prodrug Compound A in pH 1.2 (hydrochloric acid solution) and pH 6.8 phosphate buffer (37℃, dissolution medium 900mL, rotation speed 75rpm), respectively. 5ml is taken at 10min, 20min, 30min, respectively, and the content is tested after centrifugation without replenishing the liquid, which is determined by HPLC method.

[0239] The HPLC determination conditions: the mobile phase is acetonitrile, the injection amount is 5ul, the C18 chromatographic column is used, the column temperature is 30℃, and the wavelength is 254nm.

[0240] The test results are shown in Table 2 below.

[0241] Table 2 dissolution test results

[0242] Sampling time (min) pH 1.2 pH 6.8 10 79.79％ 81.86％ 20 85.62％ 86.07％ 30 85.50％ 86.31％

[0243] Example 15, stability study

[0244] The solid dispersion and the capsule prepared in Example 1 are respectively placed at 40℃±2℃, 25% humidity, and the XRPD detection is carried out at 0th day, 30th day, 90th day, respectively. In the process of detecting the crystal form of the capsule, mannitol and microcrystalline cellulose are used as auxiliary materials for comparison; the detection results are shown in Figure 1 and Figure 2 From Figure 1 and Figure 2 it can be seen that the solid dispersion and the capsule prepared by the method of Example 1 of the present application have good stability, and still maintain the amorphous state after being placed at 40℃±2℃, 25% humidity for 90 days.

[0245] Example 16, in vivo bioavailability study

[0246] Objective: To compare the pharmacokinetic characteristics of Compound A and Compound A solid dispersion prepared in Example 1 in rats by LC-MS-MS method.

[0247] Chromatographic conditions: Column: WELCH Xtimate-C18 column (50 x 2.1 mm, 3.5 mm); Mobile phase: A: water solution (0.1% formic acid); B: acetonitrile (0.1% formic acid); Gradient elution (0.10-0.80 min, 10% B-95% B; 0.80-1.80 min, 95% B-95% B; 1.80-1.81 min, 95% B-10% B; 1.81-3.00 min, 10% B-10% B); Flow rate: 350 μL·min-1; Column temperature: 30 °C.

[0248] Mass spectrometric conditions: Electrospray ion source (ESI), positive ion scan multiple reaction monitoring mode (MRM). Ion source temperature: 500 °C; Ion spray voltage: 5000 V; Atomizer (GS1): 50 psi; Auxiliary gas (GS2): 35 psi; Collision gas (CAD): High; Curtain gas (CUR): 25 psi. The ion pairs used for quantitative analysis were m / z 299.3→109.2 (vortioxetine), 455.3→165.1 (internal standard verapamil), respectively.

[0249] Plasma sample processing: Take 20 μL of the plasma sample, place it in a 2.0 mL centrifuge tube, add 200 μL of precipitant solution (acetonitrile solution containing 60.0 ng·mL-1 of dexamethasone, 5.0 ng·mL-1 of verapamil, 30.0 ng·mL-1 of buspirone solution), vortex for 3 min, centrifuge (12,000 rpm) for 3 min, transfer 75 μL of supernatant to a 96-well plate, add 75 μL of water solution, mix well, and take 10 μL for LC-MS / MS analysis. -1

[0250] Brain tissue sample processing: Take 50 μL of the brain tissue sample, place it in a 2.0 mL centrifuge tube, add 500 μL of precipitant solution (acetonitrile solution containing 60.0 ng·mL-1 of dexamethasone, 5.0 ng·mL-1 of verapamil, 30.0 ng·mL-1 of buspirone solution), vortex for 3 min, centrifuge (12,000 rpm) for 3 min, transfer 75 μL of supernatant to a 96-well plate, add 75 μL of water solution, mix well, and take 10 μL for LC-MS / MS analysis. -1 -1 -1

[0251] Preparation of test samples:

[0252] ​​​​Vortioxetine prodrug compound A, 90% PEG400 + 10% water as solvent; vortioxetine prodrug compound A solid dispersion prepared in Example 1, pure water as solvent, adding the appropriate amount of solvent, fully dissolved and mixed to prepare each group of administration solution. When preparing the test sample, the theoretical sample amount was calculated according to the designed concentration and the required volume, and the dose was 10 mg / kg (calculated as vortioxetine). The prepared drug solution was labeled for standby. If the test sample is not well dissolved or uniformly suspended, it can be appropriately vortexed or ultrasonicated.

[0253] Test design:

[0254] Each group took 18 healthy male rats, 3 animals at each time point, a total of 6 time points (0.5, 1, 2, 4, 6, 10 h), and each group was given a single intragastric administration at the same dose of 10 mg / kg vortioxetine. At the designated time point after administration, plasma and whole brain tissue samples were collected. Then the API-4000 QTRAP LC-MS-MS was used to determine the concentration of the compound (vortioxetine prodrug compound A and vortioxetine) in the sample. The relevant PK parameters were calculated using WinNonLin software, and the pharmacokinetic parameters are reported as follows: AUC (0-t), AUC (0-∞), MRT (0-t), Cmax, Tmax, T1 / 2.

[0255] Brain-blood ratio (B / P) = AUC0-last (brain tissue) / AUC0-last (plasma)

[0256] The results are as follows:

[0257]

[0258] Note: Compound A* refers to vortioxetine prodrug compound A; Example 1 refers to the solid dispersion of vortioxetine prodrug compound A prepared in Example 1.

[0259] From the above results, it can be seen that compared with vortioxetine prodrug compound A, the solid dispersion of vortioxetine prodrug compound A prepared by the present application can significantly improve the brain-blood ratio of vortioxetine in rats, reduce the peripheral exposure, and improve the bioavailability.

[0260] Example 17, screening of solid preparation adjuvants

[0261] Samples 1-5 are samples obtained by mixing the solid dispersion prepared in Example 1 with mannitol, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate in a weight ratio of 1:1, respectively;

[0262] Sample 6-10 is based on the complete material (including solid dispersion, mannitol, microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate, gelatin capsule shell) to reduce one material, for example, sample 6 is the complete material reduced in gelatin capsule shell, that is, the sample does not contain gelatin capsule shell, and other materials are all;

[0263] Among them, in the complete material, the weight ratio of solid dispersion to mannitol, microcrystalline cellulose and sodium carboxymethyl starch is 1:1, and the weight ratio of solid dispersion to magnesium stearate is 1:0.1.

[0264] The sample 1-10 was placed at 60℃ for 30 days, and the purity of compound A in the sample was detected by HPLC method, and the test results are shown in the following table:

[0265]

[0266] From the above results, it can be seen that when one or more of mannitol, microcrystalline cellulose and capsule shell are contained in the composition, the stability of compound A in the composition is better than that containing other auxiliary materials; and sodium carboxymethyl starch and magnesium stearate have a greater impact on the stability of compound A.

[0267] The above examples are the preferred embodiments of the present application, but the embodiments of the present application are not limited by the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application are equivalent replacement methods, and are all included in the protection scope of the present application.

Claims

1. A solid dispersion of a compound as shown in Formula A, characterized in that, The mixture includes the compound of formula A or its pharmaceutically acceptable salt, surfactant, and water-soluble carrier material; wherein the weight ratio of the compound of formula A to the water-soluble carrier material is 1:(0.2–6); and the weight ratio of the compound of formula A to the surfactant is 1:(0.01–0.5). The surfactant is selected from at least one of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. The water-soluble carrier material is selected from at least one of the following: polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, PEG2000, sorbitol, and mannitol.

2. The solid dispersion according to claim 1, characterized in that, The surfactant is polysorbate 80.

3. The solid dispersion according to claim 1, characterized in that, The water-soluble carrier material is at least one of polyvinylpyrrolidone K30 and polyvinylpyrrolidone K90.

4. The solid dispersion according to any one of claims 1 to 3, characterized in that, The weight ratio of the compound shown in Formula A to the surfactant is 1:(0.02~0.3).

5. The solid dispersion according to any one of claims 1 to 3, characterized in that, The weight ratio of the compound shown in Formula A to the water-soluble carrier material is 1:(1-6).

6. The solid dispersion according to claim 1, characterized in that, The water-soluble carrier material is selected from polyvinylpyrrolidone K30, and the surfactant is selected from polysorbate 80. The weight ratio of the compound shown in Formula A to polysorbate 80 is 1:(0.04-0.1); the weight ratio of the compound shown in Formula A to polyvinylpyrrolidone K30 is 1:(1-6).

7. A method for preparing the solid dispersion according to any one of claims 1 to 6, comprising: (1) Dissolve the compound shown in Formula A or its pharmaceutically acceptable salt, surfactant, and water-soluble carrier material in the same solvent in proportion; (2) The solution obtained in step (1) is spray-dried, freeze-dried or hot-melt extruded to prepare a solid dispersion; The solvent is ethanol.

8. The method according to claim 7, characterized in that, The spray dryer has an inlet temperature of 50–65°C, an outlet temperature of 30–50°C, and an atomization pressure of 0.1–0.3 MPa.

9. A pharmaceutical composition, characterized in that, It comprises the solid dispersion according to any one of claims 1 to 6 and at least one other pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that, The other pharmaceutically acceptable carrier is selected from at least one of mannitol, microcrystalline cellulose, lactose, starch, or dextrin.

11. The pharmaceutical composition according to claim 9, characterized in that, The other pharmaceutically acceptable carrier is selected from at least one of mannitol or microcrystalline cellulose.

12. The pharmaceutical composition according to claim 9, characterized in that, In a unit formulation, the amount of the compound of formula A provided by a solid dispersion of the compound or its pharmaceutically acceptable salt is 0.01 mg to 1000 mg.

13. The pharmaceutical composition according to claim 9, characterized in that, In a unit formulation, the amount of the compound of formula A provided by a solid dispersion of the compound or its pharmaceutically acceptable salt is 0.1 mg to 500 mg, or 10 mg to 200 mg.

14. A method for preparing the pharmaceutical composition according to claim 9, characterized in that, The solid dispersion according to any one of claims 1 to 6 is mixed with other pharmaceutically acceptable carriers to prepare a pharmaceutically acceptable dosage form, wherein the dosage form is a tablet, capsule, pill, granule, dry suspension, powder, oral liquid, or injection.

15. Use of a pharmaceutical composition according to any one of claims 9 to 13 and a solid dispersion according to any one of claims 1 to 6 in the preparation of a medicament for treating neuropsychiatric disorders, wherein the neuropsychiatric disorders are selected from one or more of schizophrenia, depression, anxiety disorder, sleep disorder, cognitive impairment, neurodegenerative disease, bipolar disorder, post-traumatic stress disorder, addictive disorder, withdrawal syndrome, or attention deficit.

16. The use according to claim 15, characterized in that, The neuropsychiatric disorders mentioned are selected from any one or more of the following: depression, cognitive impairment, anxiety disorder, schizophrenia, sleep disorder, neurodegenerative disease, or bipolar disorder.

17. The use according to claim 15, characterized in that, The neuropsychiatric disorder mentioned is depression.

18. The use according to claim 17, characterized in that, The depression is selected from mild depression, moderate depression, severe depression, depression with other mental disorders, and recurrent depression; the mental disorder is selected from one or more of sleep disorders, cognitive disorders, anxiety disorders, obsessive-compulsive disorders, affective disorders, or personality disorders.

19. The use according to claim 18, characterized in that, The mental disorder is selected from cognitive impairment, anxiety disorder, or sleep disorder.

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