Solid dispersion of neurosteroid derivative, preparation method therefor, and use thereof, and drug for treating diseases related to central nervous system disorders

Abstract

The present application provides a solid dispersion of a neurosteroid derivative, a preparation method therefor, and use thereof, and a drug containing a hot-melt extruded solid dispersion, and belongs to the technical field of pharmaceuticals. In the present application, a raw material mixture is melt-extruded at 125-160 °C to obtain the solid dispersion of the neurosteroid derivative. The raw material mixture comprises an active ingredient, a plasticizer, and a carrier material in a mass ratio of 10:1-15:10-90. The active ingredient comprises at least one of the neurosteroid derivative (having a structure represented by formula 1), an isomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof. The plasticizer is selected from one or more of polyethylene glycol, poloxamer, and Tween, and the average molecular weight of polyethylene glycol is <6000. The active ingredient in the solid dispersion of the neurosteroid derivative is present in an amorphous form. The neurosteroid derivative in the solid dispersion of the neurosteroid derivative of the present application has relatively high oral bioavailability.

Description

Solid dispersions of neurosteroid derivatives, their preparation methods and applications; therapeutic drugs for central nervous system disorders.

[0001] This application claims priority to Chinese Patent Application No. CN202411783308.8, filed on December 6, 2024, entitled "Solid Dispersion of Neurosteroid Derivatives and its Preparation Method and Application, and a Therapeutic Drug for Central Nervous System Disorders", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical technology, and in particular to solid dispersions of neurosteroid derivatives, their preparation methods and applications, and drugs containing hot-melt extruded solid dispersions. Background Technology

[0003] Neurosteroids are steroid hormone derivatives that do not have hormonal effects. They affect neuronal excitability by modulating ionotropic receptors and can bind to GABA-A receptors. Dehydroepiandrosterone (DHEA), progesterone, and their metabolites can regulate the expression of GABA-A receptor subunits through genetic mechanisms, thereby affecting neurotransmitters. Currently developed neurosteroid drugs targeting GABA-A receptors include brinolone, ganexolone, sulfanolone, antacidone, and afadolone.

[0004] Neurosteroids generally suffer from poor water solubility and low soluble content, resulting in insufficient bioavailability in the human body and limiting their clinical application. Summary of the Invention

[0005] The purpose of this application is to provide solid dispersions of neurosteroid derivatives, their preparation methods and applications, and therapeutic drugs for central nervous system disorders. The neurosteroid derivatives in the solid dispersions provided in this application have high oral bioavailability.

[0006] To achieve the above-mentioned objectives, this application provides the following technical solution:

[0007] This application provides a method for preparing a solid dispersion of a neurosteroid derivative, comprising the following steps:

[0008] The raw material mixture was melt-extruded at 125–160°C to obtain the solid dispersion of the neurosteroid derivative.

[0009] The raw material mixture includes active ingredients, plasticizers, and carrier materials, and the mass ratio of the active ingredients, plasticizers, and carrier materials is 10:1 to 15:10 to 90.

[0010] The active ingredient comprises at least one of a neurosteroid derivative, its isomer, a solvate, and a pharmaceutically acceptable salt, wherein the neurosteroid derivative has the structure shown in Formula 1:

[0011] In Formula 1, R1 is selected from -H or C1 to C12 alkyl; R2 is selected from R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO2)- or R-CH(OH)-, wherein R is selected from -H, C1 to C6 alkyl, C2 to C6 alkenyl or C2 to C6 alkynyl;

[0012] The plasticizer is selected from one or more of polyethylene glycol, poloxamer and Tween, wherein the average molecular weight of the polyethylene glycol is <6000;

[0013] The active ingredient in the solid dispersion of the neurosteroid derivative exists in an amorphous state.

[0014] Preferably, R1 is -H, R2 is R-(C=O)-, and R is a C1 to C3 alkyl group.

[0015] Preferably, the neurosteroid derivative has the structure shown in Formula 2:

[0016] Preferably, the polyethylene glycol includes one or more of PEG3350, PEG400 and PEG4000; the poloxamer includes poloxamer 188 and / or poloxamer 407; and the Tween includes one or more of Tween 80, Tween 20 and Tween 40.

[0017] Preferably, the carrier material comprises one or more of the following: copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glycerol, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polylactic acid, polyhydroxyacetic acid, lactic acid-hydroxyacetic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivatives, starch, and starch derivatives.

[0018] Preferably, the copolyvinylpyrrolidone comprises PVP-VA64.

[0019] Preferably, the raw material mixture comprises an active ingredient, polyethylene glycol, and copovidone; the polyethylene glycol is PEG3350, and the copovidone is PVP-VA64.

[0020] Preferably, the raw material mixture is an active ingredient, a graft copolymer of polyethylene glycol and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol; the polyethylene glycol is PEG3350.

[0021] Preferably, the raw material mixture is an active ingredient, poloxamer, and a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol; wherein the poloxamer is poloxamer 188.

[0022] Preferably, the raw material mixture comprises an active ingredient, Tween, and copovidone; the Tween is Tween 80, and the copovidone is PVP-VA64.

[0023] Preferably, the melt extrusion is carried out in a twin-screw hot melt extruder, wherein the screw speed of the twin-screw hot melt extruder is 50 to 200 rpm.

[0024] Preferably, the feeding rate of the raw material mixture is 5 to 10 g / min.

[0025] This application provides a solid dispersion of neurosteroid derivatives prepared by the preparation method described in the above technical solution.

[0026] This application provides the application of the neurosteroid derivative solid dispersion described above in the preparation of therapeutic drugs for central nervous system disorders.

[0027] Preferably, the central nervous system disorder-related conditions may include postpartum depression, clinical depression, atypical depression, severe depressive disorder, bipolar disorder, mood disorder, anxiety, post-traumatic stress disorder, premenstrual anxiety disorder, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder, social anxiety disorder, memory loss, poor stress tolerance, Niemann-Pick II type C disease or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorder, NMDA insufficiency, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease.

[0028] This application provides a therapeutic drug for central nervous system disorders, the raw materials of which include the neurosteroid derivative solid dispersion described in the above technical solution and pharmaceutically acceptable excipients.

[0029] Preferably, the pharmaceutically acceptable excipients include one or more of diluents, disintegrants, glidants, and lubricants.

[0030] Preferably, the diluent includes one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sodium chloride.

[0031] Preferably, the disintegrant comprises one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone.

[0032] Preferably, the flow aid comprises colloidal silica.

[0033] Preferably, the lubricant comprises magnesium stearate and / or sodium fumarate.

[0034] Preferably, the treatment for central nervous system disorders is an oral medication.

[0035] Preferably, the dosage form of the oral medication includes tablets, capsules, or granules.

[0036] Preferably, the tablet is a film-coated tablet, and the method for preparing the film-coated tablet includes the following steps:

[0037] The solid dispersion of neurosteroid derivatives, diluent, disintegrant, glidant and lubricant are mixed and compressed into tablets, which are then coated with a gastric-soluble coating premix to obtain the film-coated tablets.

[0038] Preferably, the mass ratio of the neurosteroid derivative solid dispersion, diluent, disintegrant, flow aid, and lubricant is 65–95:45–60:8–12:3–5:0.5–1.5.

[0039] Preferably, the tablet weight during compression is 225–400 mg.

[0040] Preferably, the weight gain of the film coating is 3-5%.

[0041] This application provides a method for preparing a solid dispersion of a neurosteroid derivative, comprising the following steps: melt extruding a raw material mixture at 125–160°C to obtain the solid dispersion of the neurosteroid derivative; the raw material mixture comprises an active ingredient, a plasticizer, and a carrier material, wherein the mass ratio of the active ingredient, plasticizer, and carrier material is 10:1–15:10–90; the active ingredient comprises at least one selected from neurosteroid derivatives, their isomers, solvates, and pharmaceutically acceptable salts; the plasticizer is selected from one or more selected from polyethylene glycol, poloxamer, and Tween, wherein the average molecular weight of the polyethylene glycol is <6000; the active ingredient in the solid dispersion of the neurosteroid derivative exists in an amorphous state. This application involves melt extruding a suitable ratio of active ingredient, plasticizer, and carrier material under appropriate temperature conditions to obtain a solid dispersion of neurosteroid derivatives. The active ingredient exists in an amorphous state, i.e., in a solid dispersion state. This overcomes the common defects of poor water solubility and low dissolution of neurosteroid derivatives. Using this solid dispersion of neurosteroid derivatives with pharmaceutically acceptable excipients to prepare drugs results in high oral bioavailability and a suitable dissolution rate for the active ingredient, exhibiting a high absolute dissolution rate. Test results show that film-coated tablets prepared using the solid dispersion of neurosteroid derivatives described in this application achieve a dissolution rate of over 80% at 45 minutes and over 93% at 120 minutes, with significantly higher oral bioavailability than the active pharmaceutical ingredient.

[0042] Furthermore, this application employs a hot melt extrusion method to prepare solid dispersions of neurosteroid derivatives, which is both simple and allows for continuous industrial production. Attached Figure Description

[0043] Figure 1 shows the XRD pattern of the active pharmaceutical ingredient;

[0044] Figure 2 shows the XRD pattern of the blank excipient (PEG3350 to PVP-VA64 mass ratio of 1:5);

[0045] Figure 3 is the XRD pattern of the hot melt extruded solid dispersion prepared in Example 4;

[0046] Figure 4 shows the dissolution curves of the active pharmaceutical ingredient in Test Example 1, and the film-coated tablets prepared in Examples 1-9 and Comparative Examples 1-4.

[0047] Figure 5 shows the drug-time curves for each experimental group in Test Example 2. Detailed Implementation

[0048] This application provides a method for preparing a solid dispersion of a neurosteroid derivative, comprising the following steps:

[0049] The raw material mixture was melt-extruded at 125–160°C to obtain the solid dispersion of the neurosteroid derivative.

[0050] The raw material mixture includes active ingredients, plasticizers, and carrier materials, and the mass ratio of the active ingredients, plasticizers, and carrier materials is 10:1 to 15:10 to 90.

[0051] The active ingredient comprises at least one of a neurosteroid derivative, its isomer, a solvate, and a pharmaceutically acceptable salt, wherein the neurosteroid derivative has the structure shown in Formula 1:

[0052] In Formula 1, R1 is selected from -H or C1 to C12 alkyl; R2 is selected from R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO2)- or R-CH(OH)-, wherein R is selected from -H, C1 to C6 alkyl, C2 to C6 alkenyl or C2 to C6 alkynyl;

[0053] The plasticizer is selected from one or more of polyethylene glycol, poloxamer and Tween, wherein the average molecular weight of the polyethylene glycol in the plasticizer is <6000;

[0054] The active ingredient in the solid dispersion of the neurosteroid derivative exists in an amorphous state.

[0055] Unless otherwise specified, all materials used in this application are commercially available products well known to those skilled in the art or prepared using methods well known to those skilled in the art.

[0056] This application first provides a detailed description of the raw material mixture required for preparing the solid dispersion of the neurosteroid derivative.

[0057] In this application, the raw material mixture comprises an active ingredient, a plasticizer, and a carrier material, wherein the mass ratio of the active ingredient, plasticizer, and carrier material is 10:1 to 15:10 to 90; wherein the mass ratio of the active ingredient to the plasticizer is 10:1 to 15, specifically 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10, 10:11, or 10:1 2. 10:13, 10:14 or 10:15; the mass ratio of the active ingredient to the carrier material is 10:10 to 90, specifically 10:10, 10:15, 10:20, 10:25, 10:30, 10:35, 10:40, 10:45, 10:50, 10:55, 10:60, 10:65, 10:70, 10:75, 10:80, 10:85 or 10:90.

[0058] In this application, the active ingredient includes at least one of a neurosteroid derivative, its isomer, a solvate, and a pharmaceutically acceptable salt, specifically a neurosteroid derivative. In this application, the neurosteroid derivative has the structure shown in Formula 1, wherein R1 is selected from -H or C1-C12 alkyl, preferably C1-C6 alkyl, more preferably C1-C3 alkyl, specifically methyl, ethyl, or propyl; R2 is selected from R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO2)-, or R-CH(OH)-, wherein R is selected from -H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, preferably C1-C6 alkyl, and preferably C1-C3 alkyl, specifically methyl, ethyl, or propyl. As an embodiment of this application, R1 is -H, R2 is R-(C=O)-, and R is C1-C3 alkyl. As one embodiment of this application, the neurosteroid derivative has the structure shown in Formula 2:

[0059] In this application, the plasticizer is selected from one or more of polyethylene glycol, poloxamer, and Tween, specifically polyethylene glycol, poloxamer, or Tween; the average molecular weight of the polyethylene glycol is <6000, further 400-4000, specifically 3350. As an embodiment of this application, the polyethylene glycol may include one or more of PEG3350, PEG400, and PEG4000, specifically PEG3350; the poloxamer may include poloxamer 188 and / or poloxamer 407, specifically poloxamer 188; the Tween may include one or more of Tween 80, Tween 20, and Tween 40, specifically Tween 80.

[0060] As one embodiment of this application, the carrier material may include one or more of the following: copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glycerol, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivative, starch, and starch derivative. Specifically, it may be copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glycerol, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivative, starch, or starch derivative. As one embodiment of this application, the copovidone may include PVP-VA64; the cellulose derivative may include hydroxypropyl methylcellulose (HPMC); and the starch derivative may include pregelatinized starch.

[0061] As an embodiment of this application, the raw material mixture may be an active ingredient, polyethylene glycol (specifically PEG3350), and copovidone (specifically PVP-VA64). The mass ratio of the active ingredient, polyethylene glycol, and copovidone may be 10:1 to 15:10 to 90, and more specifically 10:5 to 15:40 to 80, or 10:5:80, 10:10:30, 10:15:40, 10:10:50, or 10:10:70.

[0062] As an embodiment of this application, the raw material mixture may also be an active ingredient, polyethylene glycol (specifically PEG3350), and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The mass ratio of the active ingredient, polyethylene glycol, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer may be 10:1 to 15:10 to 90, more specifically 10:5 to 15:40 to 80, and more specifically 10:5:80 or 10:10:50.

[0063] As an embodiment of this application, the raw material mixture may also be an active ingredient, poloxamer (specifically poloxamer 188), and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The mass ratio of the active ingredient, poloxamer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer may be 10:1 to 15:10 to 90, more specifically 10:5 to 15:40 to 80, and more specifically 10:10:50.

[0064] As an embodiment of this application, the raw material mixture may also be an active ingredient, Tween (specifically Tween 80) and copovidone (specifically PVP-VA64), and the mass ratio of the active ingredient, Tween and copovidone may be 10:1 to 15:10 to 90, further may be 10:5 to 15:40 to 80, and specifically may be 10:10:50.

[0065] The preparation method of the neurosteroid derivative solid dispersion described in this application is described in detail below.

[0066] In this application, the raw material mixture is melt-extruded at 125–160°C to obtain the solid dispersion of the neurosteroid derivative.

[0067] As one embodiment of this application, the active ingredient, plasticizer and carrier material can be sieved separately, and the undersize material can be collected and mixed to obtain the raw material mixture; the mesh size of the sieve used for sieving can be 40 to 80 mesh, specifically 40 mesh, 60 mesh or 80 mesh; the mixing time can be 10 to 15 minutes.

[0068] In one embodiment of this application, the melt extrusion is performed in a twin-screw hot melt extruder. The temperature of the twin-screw hot melt extruder is preset before melt extrusion, and the melt extrusion temperature is 125–160°C, specifically 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, or 155°C. In another embodiment of this application, the screw speed of the twin-screw hot melt extruder can be 50–200 rpm, specifically 50 rpm, 100 rpm, 150 rpm, or 200 rpm.

[0069] In this embodiment, after the temperature in the twin-screw hot melt extruder reaches the set value, the raw material mixture is added to the twin-screw hot melt extruder. After screw extrusion and melting, a transparent strip-shaped extrudate is extruded from the die head of the twin-screw hot melt extruder. This extrudate is then sequentially cooled, cut, pulverized, and sieved to obtain the neurosteroid derivative solid dispersion. In this embodiment, the feeding rate of the raw material mixture can be 5–10 g / min, specifically 5 g / min, 6 g / min, 7 g / min, 8 g / min, 9 g / min, or 10 g / min. In this embodiment, the cutting equipment can specifically be a pelletizer; the mesh size of the sieve used for sieving can be 20–40 mesh, specifically 20 mesh, 30 mesh, or 40 mesh.

[0070] In the embodiments of this application, the active ingredient, as shown in Formula 2, has a melting temperature of approximately 170°C. The addition of a carrier material can reduce the melting temperature of the active ingredient, and the use of a plasticizer can improve the moldability. By controlling the ratio of the active ingredient, plasticizer, and carrier material within the above range, it is possible to prevent the proportion of the carrier material from being too low, which could lead to an increase in the melting temperature of the active ingredient and potentially increase drug impurities. It is also possible to ensure that the extrudate is a transparent strip, thereby ensuring that the active ingredient in the solid dispersion of the neurosteroid derivative exists in an amorphous state.

[0071] This application provides a solid dispersion of neurosteroid derivatives prepared by the preparation method described in the above technical solution.

[0072] This application provides the application of the neurosteroid derivative solid dispersion described above in the preparation of therapeutic drugs for central nervous system disorders.

[0073] As one embodiment of this application, the central nervous system disorder-related conditions may include postpartum depression, clinical depression, atypical depression, severe depressive disorder, bipolar disorder, mood disorder, anxiety, post-traumatic stress disorder (PTSD), premenstrual anxiety disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, poor stress tolerance, Niemann-Pick II type C disease or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorder, NMDA insufficiency, migraine, status epilepticus, sleep disorder, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease.

[0074] This application provides a therapeutic drug for central nervous system disorders, the raw materials of which include the neurosteroid derivative solid dispersion described in the above technical solution and pharmaceutically acceptable excipients.

[0075] As one embodiment of this application, the pharmaceutically acceptable excipients include one or more of diluents, disintegrants, flow aids, and lubricants, specifically diluents, disintegrants, flow aids, and lubricants. In this embodiment, the diluent may include one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sodium chloride, specifically microcrystalline cellulose; the disintegrant may include one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone, specifically crospovidone; the flow aid may include colloidal silica; and the lubricant may include magnesium stearate and / or sodium fumarate stearate, specifically magnesium stearate.

[0076] As an embodiment of this application, the treatment drug for central nervous system disorders can be an oral drug, and the dosage form of the oral drug can include tablets, capsules or granules; the tablet can specifically be a film-coated tablet.

[0077] As an embodiment of this application, when the therapeutic drug for central nervous system disorders is a film-coated tablet, the method for preparing the film-coated tablet may include the following steps:

[0078] The neurosteroid derivative solid dispersion, diluent, disintegrant, glidant and lubricant are mixed and compressed into tablets, which are then coated with a gastric-soluble coating premix to obtain the film-coated tablets.

[0079] As an embodiment of this application, the mass ratio of the neurosteroid derivative solid dispersion, diluent, disintegrant, flow aid, and lubricant can be 65-95:45-60:8-12:3-5:0.5-1.5, specifically 95:50:10:4:1, 80:55:10:4:1, 65:60:10:4:1, 70:45:10:4:1, or 90:55:10:4:1; the mixing time of the neurosteroid derivative solid dispersion, diluent, disintegrant, flow aid, and lubricant can be 5-10 minutes.

[0080] As one embodiment of this application, the tablet weight during compression can be 225-400mg, specifically 225mg, 300mg, 325mg, 350mg, 375mg or 400mg; this application does not have any special limitation on the specific operating conditions for tablet compression, and conditions well known to those skilled in the art can be used.

[0081] This application does not specifically limit the type of gastric-soluble coating premix; any gastric-soluble coating premix known to those skilled in the art can be used. This application also does not specifically limit the specific operating conditions for the film coating; any conditions known to those skilled in the art can be used. In the embodiments of this application, after film coating, the coating weight gain can be 3-5%, specifically 4%.

[0082] This application involves mixing a neurosteroid derivative with a carrier material and a plasticizer, followed by melt extrusion to disperse drug molecules amorphously within the carrier material, forming a solid dispersion. This dispersion is then thoroughly mixed with a diluent, disintegrant, gliding agent, and lubricant, and directly compressed into tablets, which are then coated with a film for moisture protection. Tablets prepared using this method exhibit high oral bioavailability and the active ingredient demonstrates a suitable dissolution rate and high absolute dissolution. Furthermore, this application employs a hot melt extrusion method, which is simple and allows for continuous industrial production.

[0083] The technical solutions of this application will be clearly and completely described below with reference to the embodiments therein. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.

[0084] Example 1

[0085] The compound with the structure shown in Formula 2 (10g), plasticizer PEG3350 (5g) and carrier material PVP-VA64 (80g) were passed through an 80-mesh sieve respectively. The sieve-passed material was mixed for 15 minutes to obtain a mixture.

[0086] The twin-screw hot melt extruder is set to a temperature of 125℃ and a screw speed of 50 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 5 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled, cut into pellets, pulverized, and then passed through a 20-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0087] Take 95g of the hot melt extruded solid dispersion, add 50g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets according to 400mg tablet weight, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0088] Example 2

[0089] The compound with the structure shown in Formula 2 (10g), plasticizer PEG3350 (10g) and carrier material PVP-VA64 (30g) were passed through an 80-mesh sieve respectively. The sieve-passed material was mixed for 15 minutes to obtain a mixture.

[0090] The twin-screw hot melt extruder is set to a temperature of 130℃ and a screw speed of 100 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 7 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled, cut into pellets, pulverized, and then passed through a 40-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0091] Take 50g of the hot melt extruded solid dispersion, add 30g of microcrystalline cellulose, 6g of crospovidone, 3g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets at a tablet weight of 225mg, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0092] Example 3

[0093] The compound with the structure shown in Formula 2 (10g), plasticizer PEG3350 (15g) and carrier material PVP-VA64 (40g) were passed through an 80-mesh sieve respectively. The sieve-passing material was mixed for 15 minutes to obtain a mixture.

[0094] The twin-screw hot melt extruder is set to a temperature of 145℃ and a screw speed of 150rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 10g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled, cut into pellets, then crushed by a pulverizer, and passed through a 40-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0095] Take 65g of the hot melt extruded solid dispersion, add 60g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets according to 350mg tablet weight, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0096] Example 4

[0097] The compound with the structure shown in Formula 2 (10g), plasticizer PEG3350 (10g) and carrier material PVP-VA64 (50g) were passed through an 80-mesh sieve respectively. The sieve-passing material was mixed for 15 minutes to obtain a mixture.

[0098] The twin-screw hot melt extruder is set to a temperature of 135℃ and a screw speed of 100 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 7 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled, cut into pellets, pulverized, and then passed through a 30-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0099] Take 70g of the hot melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets at a tablet weight of 325mg, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0100] Example 5

[0101] The compound with the structure shown in Formula 2 (10g), plasticizer PEG3350 (10g) and carrier material PVP-VA64 (70g) were passed through an 80-mesh sieve respectively. The sieve-passing material was mixed for 15 minutes to obtain a mixture.

[0102] The twin-screw hot melt extruder is set to a temperature of 140℃ and a screw speed of 100 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 7 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled and then cut into pellets, then crushed by a pulverizer and passed through a 40-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0103] Take 90g of the hot melt extruded solid dispersion, add 55g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets according to 400mg tablet weight, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0104] Example 6

[0105] The compound with the structure shown in Formula 2 (10g), plasticizer PEG3350 (5g) and carrier material polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (80g) were respectively passed through an 80-mesh sieve. The sieve-passing material was mixed for 15 minutes to obtain a mixture.

[0106] The twin-screw hot melt extruder is set to a temperature of 130℃ and a screw speed of 50 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 5 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled and then cut into pellets by a pelletizer, then crushed by a pulverizer and passed through a 40-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0107] Take 95g of the hot melt extruded solid dispersion, add 50g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets according to 400mg tablet weight, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0108] Example 7

[0109] The compound with the structure shown in Formula 2 (10g), the plasticizer PEG3350 (10g) and the carrier material polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (50g) were respectively passed through an 80-mesh sieve. The sieve-passing material was mixed for 15 minutes to obtain a mixture.

[0110] The twin-screw hot melt extruder is set to a temperature of 145℃ and a screw speed of 150 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 10 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled, cut into pellets, pulverized, and then passed through a 20-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0111] Take 70g of the hot melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets at a tablet weight of 325mg, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0112] Example 8

[0113] The compound with the structure shown in Formula 2 (10g), poloxamer 188 (10g) and the carrier material polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (50g) were passed through an 80-mesh sieve respectively. The sieve-passing material was mixed for 15 minutes to obtain a mixture.

[0114] The twin-screw hot melt extruder is set to a temperature of 140℃ and a screw speed of 150 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 10 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled, cut into pellets, pulverized, and then passed through a 20-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0115] Take 70g of the hot melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets at a tablet weight of 325mg, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0116] Example 9

[0117] The compound with the structure shown in Formula 2 (10g), Tween 80 (10g) and the carrier material PVP-VA64 (50g) were passed through an 80-mesh sieve respectively. The sieve-passing material was mixed for 15 minutes to obtain a mixture.

[0118] The twin-screw hot melt extruder is set to a temperature of 135℃ and a screw speed of 100 rpm. After the temperature reaches the set value and stabilizes, the mixture is fed into the twin-screw hot melt extruder at a feeding rate of 7 g / min for melt extrusion to obtain strip-shaped extrudates. The extrudates are cooled, cut into pellets, pulverized, and then passed through a 20-mesh sieve. The material passing through the sieve is a granular hot melt extruded solid dispersion.

[0119] Take 70g of the hot melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of crospovidone, 4g of colloidal silica and 1g of magnesium stearate, mix for 10min, directly compress into tablets at a tablet weight of 325mg, and use a gastric-soluble coating premix for film coating, with a coating weight gain of 4%, to obtain film-coated tablets.

[0120] Comparative Example 1

[0121] The procedure is the same as in Example 4, except that the plasticizer PEG3350 is omitted from the mixture used for hot melt extrusion, and the reduced weight is compensated by the carrier material PVP-VA64.

[0122] Comparative Example 2

[0123] The procedure is the same as in Example 4, except that the plasticizer PEG3350 is replaced with PEG6000 in the mixture used for hot melt extrusion.

[0124] Comparative Example 3

[0125] The procedure is the same as in Example 4, except that the temperature of the twin-screw hot melt extruder is set to 120°C.

[0126] Comparative Example 4

[0127] The procedure is the same as in Example 4, except that the carrier material PVP-VA64 is omitted from the mixture used for hot melt extrusion, and the reduced weight is compensated by the plasticizer PEG3350.

[0128] Test Example 1: Powder X-ray Diffraction (XRD) Detection

[0129] The active pharmaceutical ingredient, blank excipient (PEG3350 and PVP-VA64 in a mass ratio of 1:5), and the hot melt extruded solid dispersion prepared in Example 4 were used as test samples. The crystallization state of the test samples was studied by powder X-ray diffraction.

[0130] Figure 1 shows the XRD pattern of the active pharmaceutical ingredient (API), Figure 2 shows the XRD pattern of the blank excipient (PEG3350 and PVP-VA64 in a mass ratio of 1:5), and Figure 3 shows the XRD pattern of the hot-melt extruded solid dispersion prepared in Example 4. The results indicate that the API has abundant characteristic peaks in its XRD pattern, proving that it is in a crystalline state; the blank excipient has no characteristic peaks in its XRD pattern; and the characteristic peaks of the API completely disappear in the XRD pattern of the hot-melt extruded solid dispersion prepared in Example 4, indicating that the API has completely transformed into an amorphous state.

[0131] Test Example 2 Dissolution Curve Test

[0132] Dissolution profiles were analyzed for the active pharmaceutical ingredient (the compound with the structure shown in Formula 2), the film-coated tablets prepared in Examples 1-9 and Comparative Examples 1-4, and the dissolution rate was determined using the following methods:

[0133] Accurately weigh 25 mg of the active pharmaceutical ingredient (API) and one film-coated tablet prepared in Examples 1-9 and Comparative Examples 1-4 (approximately equivalent to containing 25 mg of API). Use 900 mL of phosphate buffer (250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, 112.0 mL of 0.2 mol / L sodium hydroxide solution, diluted with water to 1000 mL, 10 g of sodium dodecyl sulfate added, shaken well, and sonicated to dissolve) as the dissolution medium at 100 rpm. Take 10 mL of solution at 5 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min, and simultaneously add the same volume and temperature of dissolution medium. Filter the collected solution through a 0.45 μm filter membrane, collect the filtrate, and record the chromatogram at 195 nm using high performance liquid chromatography (HPLC). Calculate the cumulative dissolution rate using the peak area according to the external standard method, and plot the dissolution curve. The results are shown in Figure 4, and the corresponding specific data are shown in Table 1.

[0134] Table 1. Dissolution rates (in %) of the active pharmaceutical ingredient and the film-coated tablets prepared in the examples and comparative examples.

[0135] As shown in Table 1, this application uses a hot melt extrusion process to prepare a solid dispersion, which disperses drug molecules in an amorphous form in plasticizers and carrier materials to form a solid dispersion. Then, it is thoroughly mixed with a certain amount of diluent, disintegrant, glidant and lubricant, directly compressed into tablets, and coated with a gastric-soluble coating premix to obtain film-coated tablets. This greatly improves the dissolution rate and absolute dissolution of the active ingredient (i.e., the compound with the structure shown in Formula 2), with a dissolution rate of over 80% after 45 minutes. In Comparative Example 1, without the plasticizer PEG3350, the dissolution rate of the active ingredient was slow, with a dissolution rate of only 53.16% at 45 min. In Comparative Example 2, the plasticizer PEG6000 was used, which has a larger molecular weight, resulting in a slower dissolution rate of the active ingredient, with a dissolution rate of only 45.23% at 120 min. In Comparative Example 3, the lower melt extrusion temperature also reduced the dissolution rate of the active ingredient to some extent, with a dissolution rate of only 75.05% at 120 min. In Comparative Example 4, without the addition of a carrier material, the dissolution rate of the active ingredient was greatly reduced, with a dissolution rate of only 15.93% at 120 min.

[0136] Test Example 3: Pharmacokinetic Study

[0137] To investigate the improvement in oral absorption and bioavailability of the hot-melt extruded solid dispersion in animals, pharmacokinetic studies were conducted on female SD rats using the active pharmaceutical ingredient, the film-coated tablets prepared in Examples 4 and 7, and the active pharmaceutical ingredient aqueous solution administered via tail vein injection as a control. Bioavailability was calculated.

[0138] 1. Investigational drug:

[0139] Active pharmaceutical ingredient solution: Disperse thoroughly with 0.5wt% CMC-Na solution to prepare a suspension with a concentration of 1.0 mg / mL.

[0140] Example 4 Formulation Solution: After grinding the formulation into a fine powder, it was fully dispersed in 0.5wt% CMC-Na solution to prepare a suspension with a raw material concentration of 1.0 mg / mL.

[0141] Example 7 Formulation Solution: After grinding the formulation into a fine powder, it was fully dispersed in 0.5wt% CMC-Na solution to prepare a suspension with a raw material concentration of 1.0 mg / mL.

[0142] Active pharmaceutical ingredient aqueous solution (tail vein): Dissolved in 30wt% sulfobutyl ether-β-cyclodextrin aqueous solution to prepare a solution with a concentration of 0.3mg / mL.

[0143] 2. Experimental animals:

[0144] Female SD rats, weighing 200–220 g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0145] 3. Test methods:

[0146] Twenty female SD rats were randomly divided into four groups of five each: the raw material group (10 mg / kg), the Example 4 group (10 mg / kg), the Example 7 group (10 mg / kg), and the tail vein group (3 mg / kg). Animals in the raw material group, Example 4 group, and Example 7 group were administered the drug orally via gavage at the designed dose. Blood samples were collected from the orbital venous plexus at 0 time (before administration) and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration. In the tail vein group, the drug was administered via tail vein injection, and blood samples were collected from the orbital venous plexus at 0 time and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. After heparin-anticoagulated centrifugation, plasma was separated for analysis.

[0147] Accurately measure 50 μL of plasma sample and add 200 μL of protein precipitant (acetonitrile-isopropanol solution containing 100 ng / mL HRN01-d3, wherein the volume ratio of acetonitrile to isopropanol in the acetonitrile-isopropanol solution is 1:1). Vortex mix for 1 min. Transfer all samples to a dephospholipid plate, place a 96-well plate underneath, and place under positive pressure for 5 min (N2 pressure below 0.01 MPa). Collect all filtrate and analyze using LC-MS / MS. Calculate the concentration of active pharmaceutical ingredient in each plasma sample using the standard curve method.

[0148] 4. Test Results:

[0149] The results of the detection of the concentration (ng / mL) of the active pharmaceutical ingredient in plasma samples at different time points in each experimental group are shown in Table 2.

[0150] Table 2. Results of drug concentration (ng / mL) in plasma samples from each experimental group at different time points.

[0151] Figure 5 shows the pharmacokinetic curves for each experimental group. The pharmacokinetic parameters of the above pharmacokinetic curves were statistically analyzed using Phoenix WinNonlin, version 8.3.5 software, and are shown in Table 3. As can be seen from Table 3, compared with the active pharmaceutical ingredient, the film-coated tablets prepared in Examples 4 and 7 of this application significantly improved the oral bioavailability of the active pharmaceutical ingredient.

[0152] Table 3. Pharmacokinetic parameters of each experimental group

[0153] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

1. A method for preparing a solid dispersion of a neurosteroid derivative, comprising the following steps: The raw material mixture was melt-extruded at 125–160°C to obtain the solid dispersion of the neurosteroid derivative. The raw material mixture includes active ingredients, plasticizers, and carrier materials, and the mass ratio of the active ingredients, plasticizers, and carrier materials is 10:1 to 15:10 to 90. The active ingredient comprises at least one of a neurosteroid derivative, its isomer, a solvate, and a pharmaceutically acceptable salt, wherein the neurosteroid derivative has the structure shown in Formula 1: In Formula 1, R1 is selected from -H or C1 to C12 alkyl; R2 is selected from R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO2)- or R-CH(OH)-, wherein R is selected from -H, C1 to C6 alkyl, C2 to C6 alkenyl or C2 to C6 alkynyl; The plasticizer is selected from one or more of polyethylene glycol, poloxamer and Tween, wherein the average molecular weight of the polyethylene glycol is <6000; The active ingredient in the solid dispersion of the neurosteroid derivative exists in an amorphous state.

2. The preparation method according to claim 1, characterized in that, R1 is -H, R2 is R-(C=O)-, and R is a C1 to C3 alkyl group.

3. The preparation method according to claim 2, characterized in that, The neurosteroid derivative has the structure shown in Formula 2:

4. The preparation method according to any one of claims 1 to 3, characterized in that, The polyethylene glycol includes one or more of PEG3350, PEG400 and PEG4000; the poloxamer includes poloxamer 188 and / or poloxamer 407; the Tween includes one or more of Tween 80, Tween 20 and Tween 40.

5. The preparation method according to claim 4, characterized in that, The carrier material includes one or more of the following: copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glycerol, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivatives, starch, and starch derivatives.

6. The preparation method according to claim 5, characterized in that, The copolyvinylpyrrolidone includes PVP-VA64.

7. The preparation method according to claim 5, characterized in that, The raw material mixture comprises active ingredients, polyethylene glycol, and copolyvinylpyrrolidone; the polyethylene glycol is PEG3350, and the copolyvinylpyrrolidone is PVP-VA64.

8. The preparation method according to claim 5, characterized in that, The raw material mixture comprises active ingredients, polyethylene glycol, and a graft copolymer of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol; the polyethylene glycol is PEG3350.

9. The preparation method according to claim 5, characterized in that, The raw material mixture is an active ingredient, poloxamer, and a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol; the poloxamer is poloxamer 188.

10. The preparation method according to claim 5, characterized in that, The raw material mixture consists of an active ingredient, Tween, and copovidone; the Tween is Tween 80, and the copovidone is PVP-VA64.

11. The preparation method according to claim 1, characterized in that, The melt extrusion is carried out in a twin-screw hot melt extruder, wherein the screw speed of the twin-screw hot melt extruder is 50 to 200 rpm.

12. The preparation method according to claim 1 or 11, characterized in that, The feeding rate of the raw material mixture is 5-10 g / min.

13. The solid dispersion of neurosteroid derivatives prepared by the preparation method according to any one of claims 1 to 12.

14. The use of the solid dispersion of the neurosteroid derivative according to claim 13 in the preparation of a therapeutic medicament for central nervous system disorders.

15. The application according to claim 14, characterized in that, The central nervous system disorders mentioned may include postpartum depression, clinical depression, atypical depression, severe depressive disorder, bipolar disorder, mood disorders, anxiety, post-traumatic stress disorder, premenstrual anxiety disorder, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder, social anxiety disorder, memory loss, poor stress tolerance, Niemann-Pick II type C disease or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorder, NMDA insufficiency, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease.

16. A therapeutic agent for a central nervous system disorder, comprising the solid dispersion of the neurosteroid derivative as described in claim 13 and pharmaceutically acceptable excipients.

17. The therapeutic agent for central nervous system disorders according to claim 16, characterized in that, Pharmaceutically acceptable excipients include one or more of diluents, disintegrants, glidants, and lubricants.

18. The therapeutic agent for central nervous system disorders according to claim 17, characterized in that, The diluent includes one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sodium chloride.

19. The therapeutic agent for central nervous system disorders according to claim 17, characterized in that, The disintegrant includes one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone.

20. The therapeutic agent for central nervous system disorders according to claim 17, characterized in that, The flow aid includes colloidal silica.

21. The therapeutic agent for central nervous system disorders according to claim 17, characterized in that, The lubricant includes magnesium stearate and / or sodium fumarate.

22. The therapeutic agent for central nervous system disorders according to any one of claims 16 to 21, characterized in that, The medications used to treat the central nervous system disorders are oral medications.

23. The therapeutic agent for central nervous system disorders according to claim 22, characterized in that, The dosage forms of the oral medication include tablets, capsules, or granules.

24. The therapeutic agent for central nervous system disorders according to claim 23, characterized in that, The tablet is a film-coated tablet, and the preparation method of the film-coated tablet includes the following steps: The solid dispersion of neurosteroid derivatives, diluent, disintegrant, glidant and lubricant are mixed and compressed into tablets, which are then coated with a gastric-soluble coating premix to obtain the film-coated tablets.

25. The therapeutic agent for central nervous system disorders according to claim 24, characterized in that, The mass ratio of the neurosteroid derivative solid dispersion, diluent, disintegrant, glidant, and lubricant is 65–95:45–60:8–12:3–5:0.5–1.

5.

26. The therapeutic agent for central nervous system disorders according to claim 24, characterized in that, The tablet weight during compression is 225–400 mg.

27. The therapeutic agent for central nervous system disorders according to claim 24, characterized in that, The weight gain of the film coating is 3-5%.

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