CN115702897A

CN115702897A - Pharmaceutical composition containing vortioxetine prodrug or salt thereof

Info

Publication number: CN115702897A
Application number: CN202210930484.4A
Authority: CN
Inventors: 蒋钰; 张玲; 涂碧云; 卜淼淼; 王楠; 周珺; 陈帅
Original assignee: Suzhou Enhua Biomedical Technology Co ltd; Nhwa Pharmaceutical Corp
Current assignee: Suzhou Enhua Biomedical Technology Co ltd; Nhwa Pharmaceutical Corp
Priority date: 2021-08-09
Filing date: 2022-08-04
Publication date: 2023-02-17

Abstract

The present invention relates to a pharmaceutical composition comprising a vortioxetine prodrug or a salt thereof; in particular to a solid dispersion containing vortioxetine prodrug compound A or pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The solid dispersion comprises a compound shown as a formula A, a surfactant and a water-soluble carrier material; the solid dispersion has improved solubility and dissolution, can obviously improve the cerebral blood ratio and the bioavailability of active ingredients compared with the compound shown in the formula A, and has good stability.

Description

Pharmaceutical composition containing vortioxetine prodrug or salt thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing a vortioxetine prodrug or a pharmaceutically acceptable salt thereof, in particular to a solid dispersion containing the vortioxetine prodrug or the pharmaceutically acceptable salt thereof.

Background

Vortioxetine (vortioxetine) is a new drug for the treatment of depression, developed by dandelin north drug (Lundbeck) in combination with japan wutian drug (Takeda), is a potent 5-hydroxytryptamine reuptake inhibitor (SSRIs) with very high affinity (Ki =1.6 nM) for the 5-hydroxytryptamine transporter (SERT) in humans, but with little affinity for the norepinephrine transporter (Ki =113 nM) and dopamine transporter (Ki =1000 nM). Furthermore, vortioxetine is also a 5-HT1A receptor agonist, a 5-HT1B receptor partial agonist, a 5-HT1D,5-HT3 and 5-HT7 receptor antagonist. Approved by the FDA for marketing at 30/9/2013 under the trade name brinellix, for use in the treatment of Major Depressive Disorder (MDD).

The common adverse reactions of vortioxetine are gastrointestinal side reactions such as nausea, constipation and vomiting, which are the main side effects of SSRIs antidepressants. The 5mg vortioxetine group had a high incidence of adverse reactions compared to the placebo group, both nausea (19.4 vs9.4%) and diarrhea (11.4 vs7.0%), with a further increase in the dose administered, a higher incidence of gastrointestinal side effects (J. Pharmacology & therapeutics,2015, 145.

WO2021115372A1 discloses that vortioxetine is connected with different fat-soluble side chains to prepare vortioxetine prodrug, which can obviously improve the cerebral blood ratio of vortioxetine, reduce the exposure amount of the periphery, has the potential effect of improving gastrointestinal side effects of vortioxetine, and has a significant brain-targeted drug delivery effect; meanwhile, the provided prodrug compound has good pharmacokinetic properties.

Although the fat-soluble side chain is introduced to prepare the fat-soluble prodrug, the membrane penetration capacity is improved, the drug can more easily enter brain tissues through BBB, the brain/blood ratio of the drug is increased, and the drug has the targeted drug delivery effect of the central nervous system. However, the solubility of the drug is significantly reduced due to the introduction of a fat-soluble side chain, and for example, vortioxetine prodrug compound a is slightly soluble in methanol or ethanol and is almost insoluble in an aqueous medium. Low solubility in aqueous media will be the major rate-limiting factor in the onset of drug action in the oral route of administration,

disclosure of Invention

The present inventors have found that the compound represented by formula a has low solubility in an aqueous medium due to the introduction of a fat-soluble side chain, which limits the development of oral formulations. In order to solve the above technical problems, the present inventors have found that the above problems can be well solved by preparing a solid dispersion by mixing a compound represented by formula a or a pharmaceutically acceptable salt thereof with a suitable pharmaceutical carrier.

The invention uses the solid dispersion technology to improve the solubility of the vortioxetine prodrug compound, in particular to the compound shown in the formula A, in an aqueous medium, thereby improving the bioavailability of oral administration.

In another aspect the invention aims to provide a pharmaceutical composition comprising said solid dispersion and the related process of preparation.

The invention provides a solid dispersion of a compound shown as a formula A or a pharmaceutically acceptable salt thereof, which comprises the compound shown as the formula A or the pharmaceutically acceptable salt thereof, a surfactant and a water-soluble carrier material; wherein the weight ratio of the compound shown in the formula A to the water-soluble carrier material is 1: (0.1-10); the weight ratio of the compound shown in the formula A to the surfactant is 1: (0.01-1) of,

in one embodiment of the invention, the surfactant has a Hydrophilic Lipophilic Balance (HLB) of greater than 8, preferably greater than or equal to 10, more preferably greater than or equal to 15, such as 15, 16, or 17, and the like.

In one embodiment of the invention, 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.

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

preferably, the water-soluble cellulose derivative is selected from at least one of Hydroxypropylmethylcellulose (HPMC), or Hydroxypropylcellulose (HPC);

preferably, the saccharide is at least one selected from fructose, sucrose, lactose, galactose, mannitol, sorbitol and xylitol;

preferably, the organic acid is at least one selected from citric acid, tartaric acid, fumaric acid, maleic acid and succinic acid.

In one embodiment of the invention, the surfactant is at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, preferably polysorbate 80; the water-soluble carrier material is at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, PEG2000, sorbitol and mannitol, preferably at least one of povidone K30 and povidone K90.

In a preferred embodiment of the present invention, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.02 to 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 to 0.3), more preferably 1:0.1.

in a preferred embodiment of the invention, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (0.2 to 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).

In a preferred embodiment of the present invention, the solid dispersion comprises a compound represented by formula a or a pharmaceutically acceptable salt thereof, polysorbate 80, and povidone K30; wherein the weight ratio of the compound shown in the formula A to polysorbate 80 is 1: (0.01 to 1), preferably 1: (0.01 to 0.5), more preferably 1: (0.02 to 0.3), for example, 1:0.1; the weight ratio of the compound shown in the formula A to the povidone K30 is 1: (0.1 to 10), preferably 1: (1 to 6), more preferably 1:2.

the invention also provides a preparation method of the solid dispersion, which comprises the following steps: (1) Dissolving a compound shown as a formula A or pharmaceutically acceptable salt, a surfactant and a water-soluble carrier material in the same solvent; (2) Carrying out spray drying, freeze drying or hot-melt extrusion on the solution obtained in the step (1) to prepare a solid dispersion;

wherein the solvent is at least one of alcohols, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, sulfoxides, carboxylic acids and water containing 1-6 carbon atoms, and preferably the solvent is methanol, ethanol or acetone.

Further preferably, in the above method, the temperature of the air inlet of the spray drying is 50-65 ℃, the temperature of the air outlet is 30-50 ℃, and the atomization pressure is 0.1-0.3 MPa.

In a third aspect, the present invention also provides a pharmaceutical composition comprising the solid dispersion of the present invention and at least one other pharmaceutically acceptable carrier.

In general, the dosage of the pharmaceutical excipients in the pharmaceutical composition can be reasonably adjusted according to the type, specification and the like of the preparation, and in the present invention, the preferred pharmaceutical composition is an oral preparation, wherein the weight of the other pharmaceutically acceptable carriers is 0.1% to 80% of the weight of the solid dispersion, such as 1% to 80%,1% to 70%,10% to 80%,15% to 80%,20% to 80%, preferably 20% to 80%.

Further, in the above pharmaceutical composition, the other pharmaceutically acceptable carrier is at least one selected from the group consisting of excipients, propellants, solubilizers, solubilizing agents, emulsifying agents, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, penetration enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickening agents, encapsulation agents, humectants, absorbents, diluents, flocculants and deflocculants agents, antioxidants, adsorbents, filter aids, and release retardants.

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

Further preferably, the pharmaceutical composition comprises a solid dispersion comprising compound a or a pharmaceutically acceptable salt thereof according to the present invention and mannitol and/or microcrystalline cellulose; more preferably, the weight ratio of the solid dispersion to mannitol in the composition is 1:0.1 to 10, for example, more preferably 1:1 to 5; the weight ratio of the solid dispersion to the microcrystalline cellulose is 1:0.1 to 5, preferably 1:0.1 to 1. For example, the pharmaceutical composition, wherein the solid dispersion of the compound of formula a or a pharmaceutically acceptable salt thereof provides a content of the compound of formula a in a unit formulation of 0.01mg to 1000mg, preferably 0.1mg to 500mg, or 10mg to 200mg.

The fourth aspect of the invention also provides a preparation method of the pharmaceutical composition, which comprises the step of mixing the solid dispersion with other pharmaceutically acceptable carriers to prepare a pharmaceutically acceptable pharmaceutical dosage form, preferably the pharmaceutical dosage form is an oral preparation, and more preferably tablets, capsules, pills, granules, dry suspensions, powders and oral liquids.

The fifth aspect of the invention also provides the use of the pharmaceutical composition and the solid dispersion in the preparation of a medicament for treating neuropsychiatric diseases, wherein the neuropsychiatric diseases are any one or more of schizophrenia, depression, anxiety, sleep disorders, cognitive disorders, neurodegenerative diseases, bipolar disorders, post-traumatic stress syndrome, addictive diseases, withdrawal syndromes or attention deficit, preferably any one or more of depression, cognitive disorders, anxiety, schizophrenia, sleep disorders, neurodegenerative diseases or bipolar disorders, and more preferably depression.

Further, the depression is selected from mild depression, moderate depression, major depression, depression with other mental disorders, and recurrent depression; the psychiatric disorder is selected from one or more of a sleep disorder, cognitive disorder, anxiety disorder, obsessive compulsive disorder, affective disorder or personality disorder, preferably the psychiatric disorder is selected from a cognitive disorder, anxiety disorder or sleep disorder.

Detailed Description

The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

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 invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

Definition of terms

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about", "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.

The "pharmaceutically acceptable carrier" in the present invention refers to a pharmaceutical excipient or excipient that can be used for dilution, filling, adhesion, disintegration, lubrication, coloring, flavoring, wetting, etc., in addition to the main ingredients in a pharmaceutical preparation (or composition), and the pharmaceutically acceptable carrier can also form a dispersion system or a multi-component system of a solid dispersion of the compound represented by formula a or a pharmaceutically acceptable salt thereof together with the surfactant and the water-soluble carrier material in the solid dispersion.

The medicine composition refers to a semi-finished product, a preparation composition and the like containing a medicine active component and a pharmaceutic adjuvant component.

AUC means the area under the plasma concentration-time curve, cmax means the peak plasma concentration.

h means hours, g means grams, μ l means microliters, min means minutes, DEG C means centigrade, mg means milligrams, mL means milliliters, rpm means revolutions per minute.

In general, the term "solid dispersion" refers to a system in the solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein refers to a stable solid dispersion comprising an amorphous drug substance and one or more polymers or carriers. Further, the term "solid dispersion" as used herein 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 drug substance in a substantially amorphous solid form, i.e., at least about 80% of the drug substance in the dispersion is in an 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.

In one embodiment of the invention, the invention provides a solid dispersion of a compound shown as a formula A, which comprises the compound shown as the formula A or pharmaceutically acceptable salt thereof, a surfactant and a water-soluble carrier material; wherein the weight ratio of the compound shown in the formula A to the water-soluble carrier material is 1: (0.1-10); the weight ratio of the compound shown in the formula A to the surfactant is 1: (0.01-1) of,

in one embodiment of the present invention, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (0.2 to 8);

preferably, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (0.2 to 6);

preferably, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (1-6);

preferably, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (1-5);

preferably, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (1-4);

preferably, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (2-3);

preferably, the weight ratio of the compound of formula a to the water-soluble carrier material is 1:2.

also, the weight ratio of the compound represented by formula a to the surfactant is preferably 1: (0.01-0.5); preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.04-0.3);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.05-0.1);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.05-0.2);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.05-0.3);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.05-0.4);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.06-0.3);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.04-0.2);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.02-0.3);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.02-0.2);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.1 to 0.3);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1: (0.1 to 0.2);

preferably, the weight ratio of the compound represented by formula a to the surfactant is 1:0.1;

wherein the surfactant has a hydrophilic-lipophilic balance (HLB) value of greater than 8, preferably greater than or equal to 10, and more preferably greater than or equal to 15. For the use of two or more surfactants whose mixture HLB value should satisfy this requirement, the theoretical HLB value of the mixed surfactant can be calculated, for example, as follows:

HLB _mixing ＝(aX+bY+cZ)/(X+Y+Z)

Wherein a, b and c are respectively HLB values of the surfactants x, y and z; x, Y and Z are relative molecular masses of the surfactants X, Y and Z.

In a specific embodiment of the present invention, 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.

The polysorbate 80, namely TW80, is also called Tween 80;

the Poloxamer, named Poloxamer in English, is an alpha-hydrogen-omega-hydroxypoly (oxyethylene) a-poly (oxypropylene) b-poly (oxyethylene) c block copolymer, and is a novel high-molecular nonionic surfactant. Depending on their molecular weight, there are different types, such as 188, 407, 124, 128, 108, 237, 338, etc., and the "poloxamer" of the present invention includes all types and mixtures of any of the different types thereof, preferably type 188, 407 is used, such as the more common type 188 under the trade name pluronic f68; wherein the water-soluble carrier material is selected from at least one of water-soluble cellulose derivatives, saccharides, organic acids, urea, povidone, copovidone and polyethylene glycol;

further, the water-soluble cellulose derivative is selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC);

the polyethylene glycol is a mixture formed by condensation polymerization of ethylene oxide and water, and has a molecular formula of HO (CH) ₂ CH ₂ O) nH, wherein n represents the average number of oxyethylene groups, the English abbreviation is PEG, polyethylene glycol has various molecular weights and physical properties, the polyethylene glycol with the molecular weight of 100-700 is liquid at normal temperature and normal pressure, the polyethylene glycol with the molecular weight of more than 1000 is solid, and the polyethylene glycol has very good hydrophilicity, is a pharmaceutical adjuvant which is commonly used in pharmaceutics, and is safe and nontoxic. The solid dispersion of the invention selectively uses polyethylene glycol which is solid at normal temperature and normal pressure, such as PEG1000, PEG1500, PEG2000, PEG3000, PEG4000, PEG5000, PEG6000, PEG7000, PEG8000, PEG9000, PEG10000, PEG15000, PEG20000 and the like, and the mixture of any two or more of the above; PEG2000 and PEG4000 are preferably used.

The saccharide is selected from fructose, sucrose, lactose, galactose, mannitol, sorbitol, and xylitol; preferably, sorbitol or mannitol is used.

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

The povidone, also called polyvinylpyrrolidone, abbreviated as PVP in the English, is a homopolymer of 1-vinyl-2-pyrrolidone, and has different types such as K30, K32, K25, K29, K90, K17, C15, C30 and the like according to different molecular weights, and the polyvinylpyrrolidone in the invention includes all types and a mixture of any different types, and preferably K30, K25 and K90 are used.

In a preferred embodiment of the present invention, the solid dispersion of the compound of formula a comprises:

components	Weight (parts)
		Vortioxetine prodrug compound A	1
PVP K30	4
		TW60	0.05

components	Weight (parts)
		Vortioxetine prodrug compound A	1
PVP K30	6
		TW40	0.2

components	Weight (parts)
		Vortioxetine prodrug compound A	1
PVP K30	3
		TW20	0.3

components	Weight (parts)
		Vortioxetine prodrug compound A	1
PVP K90	0.2
		TW80	0.2

components	Weight (parts)
		Vortioxetine prodrug compound A	1
Hydroxypropyl methylcellulose	1
		Poloxamers	0.2

components	Weight (parts)
		Vortioxetine prodrug compound A	1
PEG 2000	1
		Poloxamers	0.1

components	Weight (parts)
		Vortioxetine prodrug compound A	1
Hydroxypropyl cellulose	1
		Oleic acid triethanolamine	0.02

components	Weight (parts)
		Vortioxetine prodrug compound A	1
Hydroxypropyl cellulose	1
		Tween 80	0.04

components	Weight (parts)
		Vortioxetine prodrug compound A	1
PVP K30	1
		Tween 80	0.04

components	Weight (parts)
		Vortioxetine prodrug compound A	1
Sorbitol	4
		Tween 80	0.06

the "vortioxetine prodrug", "compound a", "compound shown in formula a", and "vortioxetine prodrug compound a" mentioned in the present invention may be substituted with each other, and all refer to compounds having the following structures:

the compound shown in the formula A or the pharmaceutically acceptable salt thereof in the solid dispersion of the compound shown in the formula A and the pharmaceutical composition containing the solid dispersion of the compound shown in the formula A are in an amorphous state, and a crystal characteristic peak of the compound shown in the formula A or the pharmaceutically acceptable salt thereof is absent after a background peak of a pharmaceutical excipient is subtracted in an X-ray powder diffraction spectrum of the solid dispersion or the pharmaceutical composition.

The invention defines the mass ratio range of the compound shown in the formula A or the pharmaceutically acceptable salt thereof and one or more water-soluble carrier materials selected from water-soluble cellulose derivatives, saccharides, organic acids, urea, povidone, copovidone and polyethylene glycol and one or more surfactants selected from polysorbate, triethanolamine oleate and poloxamer, and is based on the consideration of improving the contribution degree of the solubility and the solubility of the compound shown in the formula A or the pharmaceutically acceptable salt thereof and the factors of improving the pharmacokinetic property and the bioavailability of the active ingredients in the solid dispersion by the pharmaceutical application of the solid dispersion, if the dosage of the one or more water-soluble carrier materials selected from the water-soluble cellulose derivatives, the saccharides, the organic acids, the urea, the povidone, the copovidone and the polyethylene glycol and the one or more surfactants selected from polysorbate, triethanolamine oleate and poloxamer is too small, the dispersion degree and the dissolution degree and the solubility of the compound shown in the formula A or the pharmaceutically acceptable salt thereof in the solid dispersion are incomplete and are not remarkably improved, and the medicinal effect is not good; if the dosage of the water-soluble carrier material selected from one or more of water-soluble cellulose derivatives, saccharides, organic acids, urea, povidone, copovidone and polyethylene glycol and the dosage of the surfactant selected from one or more of polysorbate, triethanolamine oleate and poloxamer are excessive, the compound shown in the formula A or the pharmaceutically acceptable salt thereof has low drug content in the dispersion and has no appreciable contribution degree on improving the dissolution rate, solubility, bioavailability, pharmacokinetic property and the like, and the subsequent application and cost accounting in the production of the preparation composition are not facilitated.

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

In a more specific embodiment of the present invention, in the solid dispersion, the surfactant is polysorbate 80; the water-soluble carrier material is povidone K30 or povidone K90, wherein the weight ratio of the compound shown in the formula A to the polysorbate 80 is 1: (0.01 to 1), preferably 1: (0.02 to 0.3), more preferably 1: (0.04 to 0.1), for example, 1:0.1; the weight ratio of the compound shown in the formula A to the povidone K30 or K90 is 1: (0.1 to 10), preferably 1: (1 to 6), more preferably 1:2.

the solid dispersion of the compound shown in the formula a can be prepared by a conventional preparation method in the art according to a specific prescription, such as a solvent method, a solvent deposition method, a spray drying method, a fluidized bed method, a freeze drying method and the like, preferably a spray drying method.

In one embodiment of the present invention, the method for preparing the solid dispersion comprises: (1) Dissolving a compound shown as a formula A or pharmaceutically acceptable salt thereof, a surfactant and a water-soluble carrier material in the same solvent according to a weight ratio; (2) Carrying out spray drying, freeze drying or hot-melt extrusion on the solution obtained in the step (1) to prepare a solid dispersion;

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

In another aspect of the invention, the use of the vortioxetine prodrug and the solid dispersion of the compound represented by formula a is provided. The specific scheme is as follows:

the application of the solid dispersion of the compound shown in the formula A in preparing a pharmaceutical preparation of the compound shown in the formula A. The compound solid dispersion shown in the formula A can be further prepared into oral preparations with other pharmaceutically acceptable carriers, such as tablets (common tablets, dispersible tablets, sustained release tablets, enteric-coated tablets, effervescent tablets, orally disintegrating tablets, chewable tablets, irregular tablets and the like), capsules (hard capsules, soft capsules, enteric-coated capsules and the like), pills (pellets, dropping pills), granules, dry suspensions, powders and oral liquid (solutions, suspensions and emulsions).

Other suitable pharmaceutical carriers such as diluents, fillers, disintegrants, surfactants, suspending agents, binders, lubricants, coloring agents, flavoring agents, etc. may optionally be included according to the pharmaceutical dosage form. The term "optionally contains" means that one or more of them may be selected or not.

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

Wherein in a unit preparation, the solid dispersion of the compound shown in the formula A or the pharmaceutically acceptable salt thereof provides the compound shown in the formula A with the content of 0.01-1000 mg, or 0.01-500 mg, or 0.1-500 mg, or 1-400mg, 2mg-300 mg, or 10-200 mg, or 50-100 mg.

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 glycols of various molecular weights), pregelatinized starch, xylitol, fructose, maltitol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, and the like; the disintegrant includes sodium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, corn starch, microcrystalline cellulose, calcium carboxymethylcellulose, etc.; the surfactant includes sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, polysorbates (various types of polysorbates), sorbitan fatty acids (various types of sorbitan fatty acids), and the like; suspending agents include, but are not limited to, hydroxypropylmethyl cellulose, ethyl cellulose, gum arabic, xanthan gum, sodium carboxymethyl cellulose, and the like; the binder includes povidone, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum, and the like; such lubricants include talc, sodium stearyl fumarate, and the like. In addition, preservatives such as sodium benzoate, potassium sorbate, methylparaben, propylparaben, and the like; stabilizers and antioxidants such as sodium calcium edetate, sodium sulfite, vitamin C, vitamin E, and the like; taste modifiers such as maltitol, stevia, aspartame, fructose, sucrose, saccharin sodium, orange flavor, strawberry flavor, and the like; other conventional, appropriate additives may also be included.

In a preferred embodiment of the present invention, the pharmaceutical formulation is an oral formulation, and the other pharmaceutically acceptable carrier is selected from at least one of mannitol, microcrystalline cellulose, lactose, starch, dextrin, and more preferably at least one of mannitol or microcrystalline cellulose. The weight of the other pharmaceutically acceptable carriers in the composition is 0.1-80% of the weight of the solid dispersion, preferably 20-80%.

The pharmaceutical composition is prepared by adopting a preparation means commonly used in the field, and specifically, for tablets, the pharmaceutical composition can be prepared by adopting a dry granulation method and a wet granulation method, and can also be prepared by adopting a direct compression method; for capsules, dry granulation, wet granulation or direct powder filling may be used.

When preparing the dripping pill, heating and melting polyethylene glycol (such as PEG3000, PEG4000, PEG6000, PEG8000, etc.) and poloxamer which are solid at normal temperature, dissolving or dispersing the solid dispersion in the polyethylene glycol and poloxamer to form a liquid mixture, dripping the liquid mixture by a dripping machine, and cooling to obtain the dripping pill; or heating and melting the solid dispersion of the compound shown in the formula A, dripping by using a dripping machine, and cooling to obtain the dripping pill. Of course, other pharmaceutical excipients, such as a disintegrant, a surfactant, a lubricant, and the like, can also be added in the preparation according to needs.

It will also be appreciated that where the pharmaceutical dosage form is a tablet, it may be film coated. Tablets may be coated (enteric or gastric film coatings) according to methods well known in the art, and materials for film coating include suitable coating agents, such as opadry, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, and the like; plasticizers such as polyethylene glycol, triethyl citrate, and the like may also be included. The coating film may be of various colors, such as orange, white, blue, etc.

Specifically, the solid dispersion of the compound represented by formula a of the present invention and a pharmaceutically acceptable carrier are uniformly mixed, and then wet granulation or dry granulation is adopted to obtain granules or dry suspension, and further tabletting is carried out to obtain tablets or hollow capsules are filled to obtain capsules as required, wherein the pharmaceutically acceptable carrier 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.

The injection can be prepared by mixing the solid dispersion of the compound shown in the formula A and a suitable injection pharmaceutical carrier uniformly, wherein the pharmaceutical carrier comprises but is not limited to the following substances as fillers or excipients: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose and sodium chloride.

If necessary, other proper pharmaceutical excipients can be added in the preparation method according to different pharmaceutical dosage forms and the requirement of ensuring the quality of the medicament.

In another aspect, the invention provides the use of the pharmaceutical composition and the solid dispersion in the preparation of a medicament for treating neuropsychiatric diseases, wherein the neuropsychiatric diseases are selected from any one or more of schizophrenia, depression, anxiety, sleep disorders, cognitive disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, withdrawal syndrome or attention deficit disorder, preferably any one or more of depression, cognitive disorders, anxiety, schizophrenia, sleep disorders, neurodegenerative diseases or bipolar disorder, and more preferably depression; further said depression is selected from the group consisting of mild depression, moderate depression, major depression, depression with other psychiatric disorders, and recurrent depression; the mental disorder is selected from one or more of sleep disorder, cognitive disorder, anxiety disorder, obsessive compulsive disorder, affective disorder or personality disorder, preferably cognitive disorder, anxiety disorder or sleep disorder.

In some embodiments, the solid dispersion of vortioxetine prodrug (compound of formula a) prepared by the present invention is found to have significantly improved pharmacokinetic properties in vivo, such as significantly increased cerebral blood ratio of vortioxetine, reduced peripheral exposure, and improved bioavailability, compared to vortioxetine prodrug (compound of formula a) in PK experiments in male rats.

In some examples, the solid dispersions of vortioxetine prodrug (compound of formula a) prepared by the present invention were further compressed into tablets and examined for its pharmacokinetic properties in vivo. The result shows that the solid dispersion composition of the vortioxetine prodrug (the compound shown in the formula A) provided by the invention can obviously improve the bioavailability of the vortioxetine prodrug (the compound shown in the formula A) in vivo, which has great clinical significance for obviously improving the convenience of taking medicines for patients and improving the compliance of the patients, especially for patients with severe depression who need to take medicines for a long time and are often accompanied with inappetence and suicidal tendency.

In other embodiments, the prepared solid dispersion of the vortioxetine prodrug (the compound shown in formula a) is subjected to stability study, and after the prepared solid dispersion of the vortioxetine prodrug (the compound shown in formula a) is placed for 3 months under an accelerated condition (40 ℃ ± 2 ℃,25% ± 5% rh), the prepared solid dispersion of the vortioxetine prodrug is still in an amorphous state, and the in vitro dissolution rate is not significantly changed, which indicates that the solid dispersion of the vortioxetine prodrug (the compound shown in formula a) provided by the invention has good stability, and is suitable for being developed into a solid dispersion preparation of the vortioxetine prodrug (the compound shown in formula a) and applied to clinic.

The solid dispersion of the compound shown in the formula A or the pharmaceutical composition containing the solid dispersion of the compound shown in the formula A uses Cu-Kalpha radiation, and has no characteristic peak of a crystalline state of the compound shown in the formula A or pharmaceutically acceptable salt thereof in an X-ray powder diffraction spectrum expressed by an angle 2 theta, wherein the characteristic peak is obtained by deducting a background peak of a pharmaceutic adjuvant from the crystalline state of the compound shown in the formula A or the pharmaceutically acceptable salt thereof, and the compound shown in the formula A or the pharmaceutically acceptable salt thereof is in an amorphous state. The compound shown in the formula A or the pharmaceutically acceptable salt thereof is in an amorphous state, molecules are in a highly disordered state, the surface free energy of the substance is larger, the molecules in the solid substance have higher energy than those in the crystalline solid substance, the molecules are easier to disperse, the dissolution rate is increased, and the bioavailability of the compound shown in the formula A or the pharmaceutically acceptable salt thereof is improved.

In a specific embodiment of the present invention, it is proved that the compound represented by formula a in an amorphous state or a pharmaceutically acceptable salt thereof prepared by the present invention and a pharmaceutical excipient crystallize and precipitate under accelerated test conditions (40 ± 2 ℃ and humidity of 25% ± 5%), and the solid dispersion and the pharmaceutical composition of the compound represented by formula a in an amorphous state or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient can maintain good physical stability and chemical stability, and have a broad application prospect.

Drawings

FIG. 1 is an X-ray powder diffraction pattern (XRPD pattern) of a solid dispersion of vortioxetine prodrug compound A prepared according to example 1 of the present invention, measured at 40 ℃. + -. 2 ℃ and 25%. + -. 5% humidity at day 0, day 30 and day 90;

figure 2 is an XRPD pattern of a capsule body containing a solid dispersion of vortioxetine prodrug compound a prepared according to example 1 of the present invention tested at 40 ℃ ± 2 ℃ and 25% ± 5% humidity at day 0, day 30 and day 90, and of adjuvants mannitol and microcrystalline cellulose.

As can be seen from fig. 2, after XRPD diffraction peaks of mannitol and microcrystalline cellulose as auxiliary materials are removed, no crystalline form diffraction peak appears when a capsule body containing vortioxetine prodrug compound a solid dispersion is placed at 40 ℃ ± 2 ℃ and 25% ± 5% humidity for detection at

days

0, 30 and 90.

Examples

The following experiments further demonstrate the remarkable advantages of the solid dispersion of the vortioxetine prodrug (compound shown in formula a) of the present invention, the water-soluble carrier material (polyvinylpyrrolidone, poloxamer, polyethylene glycol, sorbitol,) and the surfactant (polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer) in improving the solubility and dissolution rate, stability, cerebral blood ratio, reducing the exposure of the periphery, improving the bioavailability, and the like of the vortioxetine prodrug (compound shown in formula a).

Unless otherwise indicated, specific techniques or conditions are not explicitly described in the following examples, and those skilled in the art may follow those techniques or conditions commonly employed in the art or in the product specification. The medicines, reagents or instruments used are not indicated by manufacturers, and are all conventional products which are commercially available.

The specific preparation method of the solid dispersion and the oral solid preparation comprises the following steps:

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

(2) Spray drying the solution to prepare a solid dispersion;

(3) Adding appropriate adjuvants to make into oral solid preparation.

Wherein the temperature of an air inlet of the spray drying is 55-61 ℃, the temperature of an air outlet is 35-45 ℃, the atomization pressure is 0.1-0.2 MPa, the average liquid delivery amount is 8.2-11.3 (ml/min), and the average dry air volume is 0.5-0.65 m ³ At a cooling temperature of-7 ℃ per min (220V, 50Hz).

The invention uses an X-ray powder diffractometer (Aeris DY883, pa.Naceae) to collect data of samples. The method parameters of X-ray powder diffraction are as follows: cu/K alpha is used as a ray source, the working voltage and the current are respectively 40Kv and 20mA, and the 2 theta scanning range is 3-40 degrees.

Reagent

Vortioxetine prodrug compound a (self-made), tween 80 (TW 80, tokyo wil pharmaceutical industry, ltd), PVP K30 (boehai new open source medical science and technology group, ltd), mannitol (rosigate), microcrystalline cellulose (DFE), lactose (DFE), magnesium stearate (anhui mountain river pharmaceutic adjuvant, ltd), starch (anhui mountain river pharmaceutic adjuvant, ltd), dextrin (anhui mountain river pharmaceutic adjuvant, ltd).

Device

Spray dryer (Yamaoto DL310+ GAS 410), magnetic stirrer (Yuehua instruments Co., ltd.), HPLC (Agilent), dissolution apparatus (Tianjin Tiandada Tianfa scientific and technological development Co., ltd.)

Screening examples for auxiliary materials and amounts

Recipe and dosage of batch 1-6 solid dispersion

Note that: "/" indicates none.

Weighing the above materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, and spray drying at inlet air temperature of 56-59 deg.C, outlet air temperature of 40 deg.C, average liquid delivery amount of 9.7ml/min, atomization pressure of 0.12Mpa, and average dry air flow of 0.59m ³ At a cooling temperature of-7 ℃ per min (220V, 50Hz). 1 to 6 batches of solid dispersions were obtained.

And (3) testing the solubility:

the solid dispersions of vortioxetine prodrug compound a, which yielded 1 to 6 batches, were subjected to solubility tests under the same conditions, respectively:

300mg of the sample was added to 4ml of the corresponding solvent (pH 1.2, pH4.5, pH6.8 buffered saline) to supersaturate the mixture, and after stirring for 24 hours, 2ml of the mixture was centrifuged, filtered and then subjected to HPLC (sample size: 5ul, normal C18 column).

The results are shown in the following table: solubility results for batches 1-6 solid dispersions

Note that: "/" indicates no detection.

Comparing the above 1-6 batches, it can be seen that the solubility of the prepared solid dispersion of compound A is very low when only the water-soluble carrier material PVP30 is added in batch 1 and the surfactant Tween 80 is not added. And the solid dispersion of the compound A prepared by adding the water-soluble carrier PVP30 and the surfactant Tween 80 has better solubility. As can be seen from batches 1 to 3, the solubility of the solid dispersion gradually increased with increasing amounts of surfactant added; it can further be seen from batches 3 and 4 that the effect on the solubility of the solid dispersion is no longer significant after the amount of surfactant has been increased to a certain amount. It can be seen that when the surfactant (TW 80) and PVP30 were used in the same amount as in batch 6 compared to batch 5, the additional addition of mannitol, a water-soluble carrier material, did not significantly improve the solubility of the solid dispersion.

Example 1 preparation of solid dispersions and capsules of vortioxetine prodrug compound a

(1) Preparation of solid dispersions

Prescription:

components	Dosage of
		Vortioxetine prodrug compound A	5g
PVP K30	10g
		TW80	0.5g
95% ethanol	150ml

The preparation method comprises the following steps:

weighing the above materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, spray drying at inlet air temperature of 56-59 deg.C, outlet air temperature of 40 deg.C, average liquid delivery amount of 9.7ml/min, atomization pressure of 0.12Mpa, and average dry air flow of 0.59m ³ At a cooling temperature of-7 ℃ per min (220V, 50Hz).

(2) Preparation of capsules

And (2) taking 100 parts by weight of the vortioxetine prodrug compound A solid dispersion prepared in the step (1), adding 100 parts by weight of microcrystalline cellulose and 100 parts by weight of mannitol, uniformly mixing, and encapsulating to obtain the vortioxetine prodrug compound A.

Example 2 preparation of solid Dispersion of Vortioxetine prodrug Compound A

Prescription:

components	Dosage of
		Vortioxetine prodrug compound A	5g
PVP K30	20g
		TW60	0.25g
95% ethanol	400ml

The preparation method comprises the following steps:

weighing the materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, spray drying at inlet air temperature of 58-60 deg.C, outlet air temperature of 42 deg.C, average liquid delivery amount of 9.7ml/min, atomization pressure of 0.12Mpa, and average dry air flow of 0.59m ³ At a cooling temperature of-7 ℃ per min (220V, 50Hz).

Example 3 preparation of solid Dispersion of Vortioxetine prodrug Compound A

Prescription:

components	Amount of the composition
		Vortioxetine prodrug compound A	5g
PVP K30	30g
		TW40	1g
95% ethanol	800ml

The preparation method comprises the following steps:

weighing the above materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, and spray drying at inlet air temperature of 57-61 deg.C, outlet air temperature of 43 deg.C, average liquid delivery amount of 11.3ml/min, atomization pressure of 0.12Mpa, and average dry air flow of 0.59m ³ Min (220V, 50Hz), cooling temperature of-7 ℃.

Example 4 preparation of solid Dispersion of Vortioxetine prodrug Compound A

Prescription:

components	Dosage of
		Vortioxetine prodrug compound A	5g
PVP K30	15g
		TW20	1.5g
95% ethanol	500ml

The preparation method comprises the following steps:

weighing the materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, spray drying at inlet air temperature of 58-59 deg.C, outlet air temperature of 40 deg.C, average liquid delivery amount of 9.7ml/min, atomization pressure of 0.10Mpa, and average dry air flow of 0.59m ³ Min (220V, 50Hz), cooling temperature of-7 ℃.

Example 5 preparation of solid Dispersion of Vortioxetine prodrug Compound A

Prescription:

prescription	Dosage of
		Vortioxetine prodrug compound A	5g
PVP K90	1g
		TW80	1g
80% of BAlcohol(s)	400ml

The preparation method comprises the following steps:

weighing the materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, and spray drying at air inlet temperature of 58-61 deg.C, air outlet temperature of 43 deg.C, average liquid delivery amount of 11.3ml/min, atomization pressure of 0.12Mpa, and average dry air flow of 0.59m ³ At a cooling temperature of-7 ℃ per min (220V, 50Hz).

Example 6 preparation of solid Dispersion of Vortioxetine prodrug Compound A

Prescription:

prescription	Dosage of
		Vortioxetine prodrug compound A	5g
Hydroxypropyl methylcellulose	5g
		Poloxamers	1g
95% ethanol	200ml

The preparation method comprises the following steps:

weighing the materials according to the above formula, and placing in a water bath at 40 deg.CStirring to obtain uniform solution to be spray dried, and spray drying at inlet air temperature of 58-61 deg.C, outlet air temperature of 43 deg.C, average liquid delivery rate of 11.3ml/min, atomization pressure of 0.12Mpa, and average dry air flow rate of 0.59m ³ Min (220V, 50Hz), cooling temperature of-7 ℃.

Example 7 preparation of solid Dispersion of Vortioxetine prodrug Compound A

Prescription:

prescription	Amount of the composition
		Vortioxetine prodrug compound A	5g
PEG
	2000	5g
Poloxamers			0.5g
	95% ethanol	200ml

The preparation method comprises the following steps:

weighing the above materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, spray drying at inlet air temperature of 56-58 deg.C, outlet air temperature of 38 deg.C, average liquid delivery amount of 9.7ml/min, atomization pressure of 0.15Mpa, and average dry air flow of 0.59m ³ Min (220V, 50Hz), cooling temperature of-7 ℃.

Example 8 preparation of solid Dispersion of Vortioxetine prodrug Compound A

Prescription:

components	Dosage of
		Vortioxetine prodrug compound A	5g
Hydroxypropyl cellulose	5g
		Oleic acid triethanolamine	0.1g
90% ethanol	200ml

The preparation method comprises the following steps:

weighing the materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, spray drying at inlet air temperature of 58-60 deg.C, outlet air temperature of 42 deg.C, average liquid delivery amount of 9.7ml/min, atomization pressure of 0.15Mpa, and average dry air flow of 0.59m ³ Min (220V, 50Hz), cooling temperature of-7 ℃.

Example 9 preparation of solid dispersions and capsules of vortioxetine prodrug compound a

(1) Preparation of solid dispersion:

prescription:

components	Amount of the composition
		Vortioxetine prodrug compound A	5g
Hydroxypropyl cellulose	5g
		Tween 80	0.2g
90% ethanol	200ml

The preparation method comprises the following steps: weighing the materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, spray drying at inlet air temperature of 58-60 deg.C, outlet air temperature of 42 deg.C, average liquid delivery amount of 11.3ml/min, atomization pressure of 0.15Mpa, and average dry air flow of 0.65m ³ At a cooling temperature of-7 ℃ per min (220V, 50Hz).

(2) Preparing capsules: and (3) taking 100 parts by weight of the solid dispersion, adding 100 parts by weight of lactose and 100 parts by weight of microcrystalline cellulose, uniformly mixing, and encapsulating.

Example 10 preparation of solid dispersions and tablets of vortioxetine prodrug compound a

(1) Preparation of solid dispersion:

prescription:

components	Dosage of
		Vortioxetine prodrug compound A	5g
PVP K30	5g
		Tween 80	0.2g
90% ethanol	200ml

The preparation method comprises the following steps: the preparation was carried out by referring to the method for preparing a solid dispersion in example 9.

(2) Preparation of tablets: taking 100 parts by weight of the solid dispersion, adding 50 parts by weight of starch, 50 parts by weight of lactose and 100 parts by weight of microcrystalline cellulose, granulating with a proper amount of 95% ethanol, drying at 50 ℃, finishing by using a 24-mesh screen, adding 0.3 part of stearic acid, uniformly mixing and tabletting.

Example 11 preparation of solid dispersions and capsules of vortioxetine prodrug compound a

(1) Preparation of solid dispersion:

prescription:

components	Amount of the composition
		Vortioxetine prodrug compound A	5g
Sorbitol	20g
		Tween 80	0.3g
85% ethanol	300ml

The preparation method comprises the following steps: reference example 9 was prepared as the method for preparing the solid dispersion.

(2) Preparing capsules: taking 100 parts by weight of the solid dispersion, adding 100 parts by weight of lactose and 100 parts by weight of microcrystalline cellulose, uniformly mixing, and encapsulating.

Example 12 preparation of solid dispersions and capsules of vortioxetine prodrug compound a

(1) Preparation of solid dispersion:

prescription:

prescription	Dosage of
		Vortioxetine prodrug compound A	5g
PVP K30	15g
		Tween
20	1g
		85% ethanol	300ml

The preparation method comprises the following steps: weighing the above materials according to the above formula, stirring in 40 deg.C water bath to obtain uniform solution to be spray dried, spray drying at inlet air temperature of 58-60 deg.C, outlet air temperature of 42 deg.C, average liquid delivery amount of 9.7ml/min, atomization pressure of 0.1Mpa, and average dry air flow of 0.53m ³ At a cooling temperature of-7 ℃ per min (220V, 50Hz).

(2) Preparing capsules: taking 100 parts by weight of the solid dispersoid, adding 100 parts by weight of dextrin and 100 parts by weight of microcrystalline cellulose, granulating with a proper amount of 95% ethanol, drying at 50 ℃, finishing by using a 24-mesh screen, uniformly mixing, and encapsulating.

Example 13 solubility assay

The solid dispersion of vortioxetine prodrug compound a prepared in example 1,3,4,5,7 and vortioxetine prodrug compound a were subjected to solubility test under the same conditions, respectively:

300mg of the sample was added to 4ml of the corresponding solvent (pH 1.2, pH4.5, pH6.8 buffered saline) to supersaturate the mixture, and after stirring for 24 hours, 2ml of the mixture was centrifuged, filtered and then subjected to HPLC (sample size: 5ul, normal C18 column). The results are shown in table 1 below:

table 1: solid dispersion and measurement result of solubility of Compound A

Remarking: "/" indicates no detection.

As can be seen from the results of the test in Table 1, the solid dispersion prepared by the method of the present invention has a significant improvement in the solubility improvement of Compound A.

The dissolution rate, stability and in vivo bioavailability of vortioxetine prodrug compound a solid dispersion and capsule prepared in example 1 were used as examples.

Example 14 dissolution test

The capsules containing vortioxetine prodrug compound a solid dispersion prepared in example 1 were taken and tested for dissolution.

The dissolution rate detection method comprises the following steps: the dissolution of the capsules containing the vortioxetine prodrug compound a solid dispersion in ph1.2 (hydrochloric acid solution) and ph6.8 phosphate buffer (37 ℃, 900mL dissolution medium, 75 rpm) was measured by the paddle method, and the capsules were sampled at 10min,20min,30min, 5mL each time, centrifuged to measure the content, without solution replacement, and measured by the HPLC method.

Determination conditions by HPLC method: the mobile phase is acetonitrile, the sample introduction amount is 5ul, the chromatographic column is C18, the column temperature is 30 ℃, and the wavelength is 254nm.

The results of the measurements are shown in Table 2 below.

TABLE 2 dissolution test results

Sampling time (min)	pH1.2	pH6.8
			10	79.79％	81.86％
20	85.62％	86.07％
			30	85.50％	86.31％

Example 15 stability study

Placing the solid dispersion and the capsule prepared in the example 1 at 40 +/-2 ℃ and 25% humidity respectively, detecting by XRPD on the 0 th day, the 30 th day and the 90 th day respectively, and adopting mannitol and microcrystalline cellulose as auxiliary material contrast in the capsule crystal form detection process; as shown in FIGS. 1 and 2, it can be seen from FIGS. 1 and 2 that the solid dispersion and the capsule prepared by the method of example 1 of the present invention have good stability and remain amorphous after standing for 90 days at 40 ℃. + -. 2 ℃ and 25% humidity.

Example 16 in vivo bioavailability study

The purpose is as follows: pharmacokinetic profiles of vortioxetine prodrug compound a and the solid dispersion of vortioxetine prodrug compound a prepared in example 1 were examined in rats using LC-MS method.

Chromatographic conditions are as follows: the chromatographic column is a WELCH Xtimate-C18 column (50X 2.1mm, 3.5mm); mobile phase: a: aqueous solution (0.1% formic acid); b: acetonitrile (0.1% formic acid); gradient elution (0.10-0.80min, 10% B-95% B-0.80-1.80min, 95% B-95% B1.80-1.81min, 95% B-10% B-1.81-3.00min, 10% B-10% B; flow rate: 350 mu L min-1; column temperature: at 30 ℃.

Mass spectrum conditions: electrospray ion source (ESI) was used, positive ion scanning multiple reaction monitoring mode (MRM). Ion source temperature: 500 ℃; ion ejection voltage: 5000V; nebulizer (GS 1): 50psi; auxiliary gas (GS 2): 35psi; collision gas (CAD): high; air curtain gas (CUR): 25psi. The ion pairs used for the quantitative analysis were m/z 299.3 → 109.2 (vortioxetine), 455.3 → 165.1 (internal standard verapamil), respectively.

Treatment of plasma samples: collecting 20 μ L of plasma sample, placing in 2.0mL centrifuge tube, adding 200 μ L precipitant solution (acetonitrile solution containing 60.0 ng/mL-1 dexamethasone, 5.0 ng/mL-1 verapamil, and 30.0 ng/mL ^-1 Buspirone solution), vortexing for 3min, centrifuging (12,000rpm) for 3min, transferring 75 μ L of supernatant to 96-well plate, adding 75 μ L of aqueous solution, and mixingAfter homogenization, 10. Mu.L of the suspension was analyzed by LC-MS/MS.

Treatment of brain tissue samples: a brain tissue sample (50. Mu.L) was taken, placed in a 2.0mL centrifuge tube, and 500. Mu.L of a precipitant solution (acetonitrile solution containing 60.0 ng. Multidot.mL) was added ^-1 Dexamethasone, 5.0 ng.mL ^-1 Verapamil, 30.0 ng/mL ^-1 The buspirone solution) for 3min, centrifuging (12,000rpm) for 3min, taking 75 mu L of supernatant, transferring the supernatant to a 96-well plate, adding 75 mu L of aqueous solution, fully mixing, taking 10 mu L, and performing LC-MS/MS analysis.

Preparing a test sample:

taking vortioxetine prodrug compound a, with 90% by weight of peg400+10% of water as vehicle; the solid dispersion of vortioxetine prodrug compound a prepared in example 1 is prepared by using pure water as a solvent, adding a proper volume of solvent, fully dissolving and mixing to prepare each group of administration solutions. When preparing a test sample, calculating theoretical sample weight according to designed concentration and required volume, and administering according to the dosage of 10mg/kg (calculated by vortioxetine). And sticking the prepared liquid medicine with a label for later use. If the test sample is not well dissolved or is not uniformly suspended, appropriate vortexing or sonication can be performed.

And (3) experimental design:

each group was administered a single gavage of 18 healthy male rats, 3 animals per time point, 6 time points (0.5, 1, 2, 4, 6, 10 h) at the same dose of vortioxetine at 10 mg/kg. Plasma, whole brain tissue samples were collected at the indicated time points after dosing. The concentrations of compounds (vortioxetine prodrug compound a and vortioxetine) in the samples were then determined using API-4000QTRAP LC-MS. Relevant PK parameters were calculated using WinNonLin software, and pharmacokinetic parameters are reported below: AUC (0-T), AUC (0- ∞), MRT (0-T), cmax, tmax, T1/2.

Cerebral blood ratio (B/P) = AUC0-last (brain tissue)/AUC 0-last (plasma)

The results are as follows:

and (3) annotation: compound a refers to vortioxetine prodrug compound a; example 1 refers to a solid dispersion of vortioxetine prodrug compound a prepared in example 1.

From the results, compared with vortioxetine prodrug compound A, the solid dispersion of vortioxetine prodrug compound A prepared by the invention can obviously improve the cerebral blood ratio of vortioxetine in rats, reduce the exposure amount of vortioxetine in the periphery and improve the bioavailability.

Example 17 solid formulation adjuvant screening

Samples 1-5 are solid dispersions prepared for example 1 with mannitol, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate, respectively, in a weight ratio of 1:1 mixing the obtained samples;

samples 6-10 were samples obtained by reducing one material based on the complete material (including solid dispersion, mannitol, microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate, gelatin capsule shell), e.g., sample 6 was a complete material with a reduced gelatin capsule shell, i.e., the sample did not contain a gelatin capsule shell, and all other materials were present;

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

placing the samples 1-10 at 60 ℃ for 30 days, and detecting the purity of the compound A in the samples by an HPLC method, wherein the test results are shown in the following table:

from the 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 the compound A in the composition is better than that of the compound A containing other auxiliary materials; while sodium carboxymethyl starch and magnesium stearate have a greater effect on the stability of compound a.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. A solid dispersion of a compound shown as a formula A is characterized by comprising the compound shown as the formula A or pharmaceutically acceptable salt thereof, a surfactant and a water-soluble carrier material; wherein the weight ratio of the compound shown in the formula A to the water-soluble carrier material is 1: (0.1-10); the weight ratio of the compound shown in the formula A to the surfactant is 1: (0.01-1):

more preferably, the surfactant has a hydrophilic-lipophilic balance (HLB) of greater than 8, preferably greater than or equal to 10, and more preferably greater than or equal to 15.

2. The solid dispersion of claim 1, wherein 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.

3. The solid dispersion according to claim 1, characterized in that the water-soluble carrier material is selected from at least one of water-soluble cellulose derivatives, sugars, organic acids, urea, povidone, copovidone, polyethylene glycol;

preferably, the water-soluble cellulose derivative is selected from: at least one of Hydroxypropylmethylcellulose (HPMC), or Hydroxypropylcellulose (HPC);

preferably, the saccharide is selected from at least one of fructose, sucrose, lactose, galactose, mannitol, sorbitol, or xylitol;

4. The solid dispersion according to claim 1, wherein the surfactant is at least one of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, preferably polysorbate 80;

the water-soluble carrier material is at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, PEG2000, sorbitol and mannitol, preferably at least one of povidone K30 and povidone K90.

5. The solid dispersion according to any one of claims 1 to 4, wherein the weight ratio of the compound represented by formula A to the surfactant is 1: (0.02-0.3);

further preferably, the weight ratio of the compound of formula a to the water-soluble carrier material is 1: (0.2 to 6), preferably 1: (1-6).

6. The solid dispersion according to claim 1, wherein the water-soluble carrier material is povidone K30 and the surfactant is polysorbate 80, wherein the weight ratio of the compound of formula A to polysorbate 80 is 1:

(0.04-0.1); the weight ratio of the compound shown in the formula A to the povidone K30 is 1: (1 to 10), preferably 1: (1-6).

7. A method for preparing the solid dispersion of any one of claims 1 to 6, comprising: (1) Dissolving a compound shown as a formula A or pharmaceutically acceptable salt, a surfactant and a water-soluble carrier material thereof in the same solvent according to a ratio; (2) Carrying out spray drying, freeze drying or hot-melt extrusion on the solution obtained in the step (1) to prepare a solid dispersion;

preferably, the solvent is at least one of alcohols containing 1 to 6 carbon atoms, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, sulfoxides, carboxylic acids, and water, and more preferably, the solvent is ethanol.

8. The method of claim 7, wherein the temperature of the air inlet of the spray drying is 50-65 ℃, the temperature of the air outlet is 30-50 ℃, and the atomization pressure is 0.1-0.3 MPa.

9. A pharmaceutical composition comprising the solid dispersion of any one of claims 1 to 6 and at least one other pharmaceutically acceptable carrier;

preferably, the other pharmaceutically acceptable carrier is selected from at least one of excipients, propellants, solubilizers, solubilizing agents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-binders, integration agents, permeation enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulation agents, humectants, absorbents, diluents, flocculants and deflocculants, antioxidants, adsorbents, filter aids, release retardants;

further preferably, the other pharmaceutically acceptable carrier is selected from at least one of mannitol, microcrystalline cellulose, lactose, starch or dextrin; more preferably, the other pharmaceutically acceptable carrier is selected from at least one of mannitol or microcrystalline cellulose.

10. The pharmaceutical composition according to claim 9, 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 0.01mg to 1000mg, preferably 0.1mg to 500mg, or 10mg to 200mg, in a unit formulation.

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

12. Use of a pharmaceutical composition according to any one of claims 9 to 10 and a solid dispersion according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a neuropsychiatric disorder selected from any one or more of schizophrenia, depression, anxiety, sleep disorders, cognitive disorders, neurodegenerative disorders, bipolar disorder, post traumatic stress syndrome, addictive disorders, withdrawal syndrome or attention deficit disorder; preferably any one or more of depression, cognitive disorders, anxiety disorders, schizophrenia, sleep disorders, neurodegenerative diseases or bipolar disorder, more preferably depression;

further preferably, the depression is selected from mild depression, moderate depression, major depression, depression with other psychiatric disorders, and recurrent depression; the psychiatric disorder is selected from one or more of sleep disorders, cognitive disorders, anxiety disorders, obsessive compulsive disorders, affective disorders or personality disorders, more preferably the psychiatric disorder is selected from cognitive disorders, anxiety disorders or sleep disorders.