Neurosteroid derivative solid dispersion, preparation method and application thereof, and therapeutic drug for central nervous system disorder related diseases

Abstract

The invention provides a neurosteroid derivative solid dispersion, a preparation method and application thereof, and a medicine containing a hot-melt extrusion solid dispersion, and belongs to the technical field of pharmacy. The preparation method comprises the following steps: carrying out melt extrusion on a raw material mixture at 125-160 DEG C to obtain the neurosteroid derivative solid dispersion, the mixed material comprises an active component, a plasticizer and a carrier material in a mass ratio of 10: (1-15): (10-90); the active component comprises at least one of a neurosteroid derivative (with a structure as shown in a formula 1), an isomer, a solvate 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 the polyethylene glycol is 1t; 6000, 6000; active components in the neurosteroid derivative solid dispersion exist in an amorphous state. The neurosteroid derivative in the neurosteroid derivative solid dispersion disclosed by the invention has relatively high oral bioavailability. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical technology, in particular to a neurosteroid derivative solid dispersion, a preparation method and application thereof, and a medicine containing the hot-melt extrusion solid dispersion. Background Art

[0002] Neurosteroids are steroid hormone derivatives that do not have hormonal effects. They can affect neuronal excitability by regulating ionotropic receptors and can bind to GABA-A receptors. Dehydroepiandrosterone, 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 brexolone, ganaxolone, sulanoside, antelopeside, and alfalone.

[0003] Neurosteroids generally have the defects of poor water solubility and low solubility, which leads to insufficient bioavailability of the drugs in the human body and brings limitations to their clinical application. Summary of the invention

[0004] The purpose of the present invention is to provide a neurosteroid derivative solid dispersion, a preparation method and application, and a therapeutic drug for central nervous system disorder-related diseases. The neurosteroid derivative in the neurosteroid derivative solid dispersion provided by the present invention has a high oral bioavailability.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for preparing a neurosteroid derivative solid dispersion, comprising the following steps:

[0007] Melting and extruding the raw material mixture at 125-160° C. to obtain the neurosteroid derivative solid dispersion;

[0008] The mixed material comprises an active ingredient, a plasticizer and a carrier material, wherein the mass ratio of the active ingredient, the plasticizer and the carrier material is 10:1-15:10-90;

[0009] The active ingredient includes at least one of a neurosteroid derivative, an isomer, a solvate and a pharmaceutically acceptable salt thereof, and the neurosteroid derivative has a structure shown in Formula 1:

[0010]

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

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

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

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

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

[0016]

[0017] 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.

[0018] Preferably, the carrier material comprises one or more of copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl macrogol glyceride, polyvinyl alcohol, polyvinyl pyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivatives, starch and starch derivatives.

[0019] Preferably, the copovidone comprises PVP-VA64.

[0020] The present invention provides a neurosteroid derivative solid dispersion prepared by the preparation method described in the above technical scheme.

[0021] The present invention provides the use of the neurosteroid derivative solid dispersion described in the above technical solution in the preparation of therapeutic drugs for central nervous system disorder-related diseases.

[0022] The present invention provides a therapeutic drug for central nervous system disorder-related diseases, and the preparation raw materials include the neurosteroid derivative solid dispersion described in the above technical solution and pharmaceutically acceptable excipients.

[0023] Preferably, the pharmaceutically acceptable excipients include one or more of a diluent, a disintegrant, a glidant and a lubricant; the therapeutic drug for central nervous system disorder-related conditions is an oral drug, and the dosage form of the oral drug includes tablets, capsules or granules.

[0024] The invention provides a method for preparing a neurosteroid derivative solid dispersion, comprising the following steps: melt-extruding a raw material mixture at 125-160° C. to obtain the neurosteroid derivative solid dispersion; the mixture comprises an active ingredient, a plasticizer and a carrier material, and the mass ratio of the active ingredient, the plasticizer and the carrier material is 10:1-15:10-90; the active ingredient comprises at least one of a neurosteroid derivative, an isomer, a solvate 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 the polyethylene glycol is less than 6000; and the active ingredient in the neurosteroid derivative solid dispersion exists in an amorphous state. The present invention melt-extrudes the active ingredients, plasticizers and carrier materials in suitable proportions under suitable temperature conditions, and the active ingredients in the obtained neurosteroid derivative solid dispersion exist in an amorphous state, that is, the active ingredients are in a solid dispersion state, which overcomes the common defects of poor water solubility and low solubility of neurosteroid derivatives. The solid dispersion of neurosteroid derivatives and pharmaceutically acceptable excipients are used to prepare drugs, and the oral bioavailability is high, and the active ingredients have a suitable dissolution rate and a high absolute solubility. The results of the test example show that the film-coated tablets prepared by the solid dispersion of neurosteroid derivatives of the present invention have a solubility of more than 80% at 45 minutes and a solubility of more than 93% at 120 minutes, and the oral absorption bioavailability is significantly higher than that of the raw material.

[0025] In addition, the present invention adopts a hot melt extrusion method to prepare the neurosteroid derivative solid dispersion, which is simple and can realize continuous industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the XRD pattern of the API;

[0027] Figure 2 This is the XRD pattern of the blank excipient (the mass ratio of PEG3350 to PVP-VA64 is 1:5);

[0028] Figure 3 XRD pattern of the hot melt extruded solid dispersion prepared in Example 4;

[0029] Figure 4 It is a dissolution curve diagram of the raw material drug in Test Example 1, and the film-coated tablets prepared in Examples 1 to 9 and Comparative Examples 1 to 4;

[0030] Figure 5 This is the drug-time curve diagram of each experimental group in Test Example 2. DETAILED DESCRIPTION

[0031] The present invention provides a method for preparing a neurosteroid derivative solid dispersion, comprising the following steps:

[0032] Melting and extruding the raw material mixture at 125-160° C. to obtain the neurosteroid derivative solid dispersion;

[0033] The raw material mixture includes an active ingredient, a plasticizer and a carrier material, and the mass ratio of the active ingredient, the plasticizer and the carrier material is 10:1-15:10-90;

[0034] The active ingredient includes at least one of a neurosteroid derivative, an isomer, a solvate and a pharmaceutically acceptable salt thereof, and the neurosteroid derivative has a structure shown in Formula 1:

[0035]

[0036] In Formula 1, R1 is selected from -H or C1-C12 alkyl; R2 is selected from R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO2)- or R-CH(OH)-, and R is selected from -H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0037] The plasticizer is selected from one or more of polyethylene glycol, poloxamer and Tween, and the average molecular weight of the polyethylene glycol of the plasticizer is less than 6000;

[0038] The active ingredient in the neurosteroid derivative solid dispersion exists in an amorphous state.

[0039] In the present invention, unless otherwise specified, the materials used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.

[0040] The present invention firstly describes in detail the raw material mixture required for preparing the neurosteroid derivative solid dispersion.

[0041] In the present invention, the raw material mixture includes an active ingredient, a plasticizer and a carrier material, and the mass ratio of the active ingredient, the plasticizer and the carrier material is 10:1-15:10-90; wherein the mass ratio of the active ingredient to the plasticizer is 10:1-15, specifically 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10, 10:11, 10:1 2, 10:13, 10:14 or 10:15; the mass ratio of the active ingredient to the carrier material is 10:10-90, 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.

[0042] In the present invention, the active ingredient includes at least one of a neurosteroid derivative, its isomer, solvate and pharmaceutically acceptable salt, and can be specifically a neurosteroid derivative. In the present invention, the neurosteroid derivative has a structure shown in Formula 1, wherein R1 is selected from -H or C1-C12 alkyl, the C1-C12 alkyl is preferably C1-C6 alkyl, and more preferably C1-C3 alkyl, and can be specifically methyl, ethyl or propyl; R2 is selected from R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO2)- or R-CH(OH)-, the R is selected from -H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, and is preferably C1-C6 alkyl, the C1-C6 alkyl is preferably C1-C3 alkyl, and can be specifically methyl, ethyl or propyl. As an embodiment of the present invention, the R1 is -H, R2 is R-(C=O)-, and R is C1-C3 alkyl. As an embodiment of the present invention, the neurosteroid derivative has a structure shown in Formula 2:

[0043]

[0044] In the present invention, the plasticizer is selected from one or more of polyethylene glycol, poloxamer and Tween, and can be polyethylene glycol, poloxamer or Tween in particular; the average molecular weight of the polyethylene glycol is less than 6000, and can further be 400-4000, and can be 3350 in particular. As an embodiment of the present invention, the polyethylene glycol can include one or more of PEG3350, PEG400 and PEG4000, and can be PEG3350 in particular; the poloxamer can include poloxamer 188 and / or poloxamer 407, and can be poloxamer 188 in particular; the Tween can include one or more of Tween 80, Tween 20 and Tween 40, and can be Tween 80 in particular.

[0045] As an embodiment of the present invention, the carrier material may include one or more of copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glyceride, polyvinyl alcohol, polyvinyl pyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivative, starch and starch derivative, and may specifically be copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glyceride, polyvinyl alcohol, polyvinyl pyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivative, starch or starch derivative. As an embodiment of the present invention, the copolyvidone may include PVP-VA64; the cellulose derivative may include hydroxypropyl methylcellulose (HPMC); the starch derivative may include pregelatinized starch.

[0046] As an embodiment of the present invention, the raw material mixture can be an active ingredient, polyethylene glycol (specifically PEG3350) and copolyvidone (specifically PVP-VA64), and the mass ratio of the active ingredient, polyethylene glycol and copolyvidone can be 10:1-15:10-90, and can further be 10:5-15:40-80, specifically 10:5:80, 10:10:30, 10:15:40, 10:10:50 or 10:10:70.

[0047] As an embodiment of the present invention, the raw material mixture can also be an active ingredient, polyethylene glycol (specifically PEG3350) and a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The mass ratio of the active ingredient, polyethylene glycol and the polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer can be 10:1 to 15:10 to 90, and can further be 10:5 to 15:40 to 80, and can specifically be 10:5:80 or 10:10:50.

[0048] As an embodiment of the present invention, the raw material mixture can also be an active ingredient, poloxamer (specifically poloxamer 188) and a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the mass ratio of the active ingredient, poloxamer and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer can be 10:1-15:10-90, further can be 10:5-15:40-80, specifically can be 10:10:50.

[0049] As an embodiment of the present invention, the raw material mixture can 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 can be 10:1-15:10-90, further can be 10:5-15:40-80, specifically can be 10:10:50.

[0050] The preparation method of the neurosteroid derivative solid dispersion of the present invention is described in detail below.

[0051] The invention melt-extrudes the raw material mixture under the condition of 125-160 DEG C to obtain the neurosteroid derivative solid dispersion.

[0052] As an embodiment of the present invention, the active ingredient, the plasticizer and the carrier material can be sieved separately, and the sieve materials are collected and mixed to obtain the raw material mixture; the mesh number of the sieve used for sieving can be 40 to 80 meshes, specifically 40 meshes, 60 meshes or 80 meshes; the mixing time can be 10 to 15 minutes.

[0053] As an embodiment of the present invention, the melt extrusion is performed in a twin-screw hot melt extruder, and the temperature of the twin-screw hot melt extruder is preset before the melt extrusion, wherein the temperature of the melt extrusion is 125-160° C., specifically 125° C., 130° C., 135° C., 140° C., 145° C., 150° C. or 155° C. As an embodiment of the present invention, 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.

[0054] In an embodiment of the present invention, when 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, and after screw extrusion and melting, a transparent strip-shaped extrudate is extruded from the die head of the twin-screw hot melt extruder, and then cooled, cut, crushed and sieved in sequence to obtain the neurosteroid derivative solid dispersion. In an embodiment of the present invention, the feed rate of the raw material mixture can be 5 to 10 g / min, specifically 5 g / min, 6 g / min, 7 g / min, 8 g / min, 9 g / min or 10 g / min. In an embodiment of the present invention, the cutting equipment can be specifically a pelletizer; the mesh number of the sieve used for sieving can be 20 to 40 meshes, specifically 20 meshes, 30 meshes or 40 meshes.

[0055] In the embodiment of the present invention, the melting temperature of the active ingredient, such as the compound of the structure shown in Formula 2, is about 170°C. The addition of the carrier material can reduce the melting temperature of the active ingredient, and the use of the plasticizer can improve the moldability. By controlling the ratio of the active ingredient, the plasticizer and the carrier material within the above range, it is possible to prevent the melting temperature of the active ingredient from being increased due to the low proportion of the carrier material, which may increase the drug impurities, and 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.

[0056] The present invention provides a neurosteroid derivative solid dispersion prepared by the preparation method described in the above technical scheme.

[0057] The present invention provides the use of the neurosteroid derivative solid dispersion described in the above technical solution in the preparation of therapeutic drugs for central nervous system disorder-related diseases.

[0058] As an embodiment of the present invention, the central nervous system disorder-related disorders may include postpartum depression, clinical depression, atypical depression, major depressive disorder, bipolar disorder, mood disorders, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorder, NMDA hypofunction, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female pediatric epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease.

[0059] The present invention provides a therapeutic drug for central nervous system disorder-related diseases, and the preparation raw materials include the neurosteroid derivative solid dispersion described in the above technical solution and pharmaceutically acceptable excipients.

[0060] As an embodiment of the present invention, the pharmaceutically acceptable excipients include one or more of a diluent, a disintegrant, a glidant and a lubricant, and specifically can be a diluent, a disintegrant, a glidant and a lubricant. In the embodiment of the present invention, the diluent can include one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and sodium chloride, and specifically can be microcrystalline cellulose; the disintegrant can include one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone, and specifically can be cross-linked polyvinylpyrrolidone; the glidant can include colloidal silicon dioxide; the lubricant can include magnesium stearate and / or sodium fumarate, and specifically can be magnesium stearate.

[0061] As an embodiment of the present invention, the therapeutic drug for the central nervous system disorder-related disease 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.

[0062] As an embodiment of the present invention, when the therapeutic drug for central nervous system disorder-related diseases is a film-coated tablet, the preparation method of the film-coated tablet may include the following steps:

[0063] The neurosteroid derivative solid dispersion, diluent, disintegrant, glidant and lubricant are mixed and compressed into tablets, and then film-coated with a gastric soluble coating premix to obtain the film-coated tablets.

[0064] As an embodiment of the present invention, the mass ratio of the neurosteroid derivative solid dispersion, diluent, disintegrant, glidant 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, glidant and lubricant can be 5-10 min.

[0065] As an embodiment of the present invention, the tablet weight during tableting can be specifically 225-400 mg, specifically 225 mg, 300 mg, 325 mg, 350 mg, 375 mg or 400 mg; the present invention has no special limitation on the specific operating conditions of the tableting, and the conditions familiar to those skilled in the art can be used.

[0066] The present invention does not specifically limit the specific type of the gastric-soluble coating premix, and a gastric-soluble coating premix familiar to those skilled in the art can be used. The present invention does not specifically limit the specific operating conditions of the film coating, and conditions familiar to those skilled in the art can be used; in the embodiment of the present invention, after the film coating, the coating weight gain can be 3-5%, specifically 4%.

[0067] The present invention mixes the neurosteroid derivative with a carrier material and a plasticizer, and then melt-extrudes the mixture, so that the drug molecules are dispersed in the carrier material in an amorphous state to form a solid dispersion state, and then fully mixed with a diluent, a disintegrant, a glidant and a lubricant, and directly pressed into tablets, and coated with a film coating for moisture-proofing. The tablets prepared by this method have high oral bioavailability, and the active ingredients have a suitable dissolution rate and a high absolute solubility. In addition, the present invention adopts a hot melt extrusion method, which is simple and can realize continuous industrial production.

[0068] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0069] Example 1

[0070] The compound of formula 2 (10 g), plasticizer PEG3350 (5 g) and carrier material PVP-VA64 (80 g) were sieved through an 80-mesh sieve, and the sieve residues were mixed for 15 minutes to obtain a mixed material;

[0071] The temperature of the twin-screw hot melt extruder is set to 125°C, and the screw speed is set to 50rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 5g / min, and melt-extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 20-mesh sieve, and the sieved material is a granular hot-melt extruded solid dispersion;

[0072] Take 95g of the hot-melt extruded solid dispersion, add 50g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 400mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0073] Example 2

[0074] The compound of formula 2 (10 g), plasticizer PEG3350 (10 g) and carrier material PVP-VA64 (30 g) were sieved through an 80-mesh sieve, and the sieve residues were mixed for 15 minutes to obtain a mixed material;

[0075] The temperature of the twin-screw hot melt extruder is set to 130°C, and the screw speed is set to 100rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 7g / min, and melt extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 40-mesh sieve. The sieved material is a granular hot-melt extruded solid dispersion;

[0076] Take 50 g of the hot-melt extruded solid dispersion, add 30 g of microcrystalline cellulose, 6 g of cross-linked polyvinylpyrrolidone, 3 g of colloidal silicon dioxide and 1 g of magnesium stearate, mix for 10 minutes, directly compress the tablets according to a tablet weight of 225 mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0077] Example 3

[0078] The compound of formula 2 (10 g), plasticizer PEG3350 (15 g) and carrier material PVP-VA64 (40 g) were sieved through an 80-mesh sieve, and the sieve residues were mixed for 15 minutes to obtain a mixed material;

[0079] The temperature of the twin-screw hot melt extruder is set to 145°C, and the screw speed is set to 150rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 10g / min, and melt extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 40-mesh sieve, and the sieved material is a granular hot-melt extruded solid dispersion;

[0080] Take 65g of the hot-melt extruded solid dispersion, add 60g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 350mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0081] Example 4

[0082] The compound of formula 2 (10 g), plasticizer PEG3350 (10 g) and carrier material PVP-VA64 (50 g) were sieved through an 80-mesh sieve, and the sieve residues were mixed for 15 minutes to obtain a mixed material;

[0083] The temperature of the twin-screw hot melt extruder is set to 135°C, and the screw speed is set to 100rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 7g / min, and melt extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 30-mesh sieve. The sieved material is a granular hot-melt extruded solid dispersion;

[0084] Take 70g of the hot-melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 325mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0085] Example 5

[0086] The compound of formula 2 (10 g), plasticizer PEG3350 (10 g) and carrier material PVP-VA64 (70 g) were sieved through an 80-mesh sieve, and the sieve residues were mixed for 15 minutes to obtain a mixed material;

[0087] The temperature of the twin-screw hot melt extruder is set to 140°C, and the screw speed is set to 100rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 7g / min, and melt extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 40-mesh sieve. The sieved material is a granular hot-melt extruded solid dispersion;

[0088] Take 90g of the hot-melt extruded solid dispersion, add 55g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 400mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0089] Example 6

[0090] The compound of formula 2 (10 g), plasticizer PEG3350 (5 g) and carrier material polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (80 g) were sieved with 80 meshes respectively, and the sieve contents were mixed for 15 minutes to obtain a mixed material;

[0091] The temperature of the twin-screw hot melt extruder is set to 130°C, and the screw speed is set to 50rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 5g / min, and melt-extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 40-mesh sieve, and the sieved material is a granular hot-melt extruded solid dispersion;

[0092] Take 95g of the hot-melt extruded solid dispersion, add 50g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 400mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0093] Example 7

[0094] The compound of formula 2 (10 g), plasticizer PEG3350 (10 g) and carrier material polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (50 g) were sieved with 80 meshes respectively, and the sieve contents were mixed for 15 minutes to obtain a mixed material;

[0095] The temperature of the twin-screw hot melt extruder is set to 145°C, and the screw speed is set to 150rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 10g / min, and melt-extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 20-mesh sieve, and the sieved material is a granular hot-melt extruded solid dispersion;

[0096] Take 70g of the hot-melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 325mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0097] Example 8

[0098] The compound of formula 2 (10 g), poloxamer 188 (10 g) and a carrier material polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (50 g) were respectively passed through an 80-mesh sieve, and the sieve residues were mixed for 15 minutes to obtain a mixed material;

[0099] The temperature of the twin-screw hot melt extruder is set to 140°C, and the screw speed is set to 150rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 10g / min, and melt extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 20-mesh sieve. The sieved material is a granular hot-melt extruded solid dispersion;

[0100] Take 70g of the hot-melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 325mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0101] Example 9

[0102] The compound of formula 2 (10 g), Tween 80 (10 g) and carrier material PVP-VA64 (50 g) were sieved with 80 meshes respectively, and the sieve residues were mixed for 15 minutes to obtain a mixed material;

[0103] The temperature of the twin-screw hot melt extruder is set to 135°C, and the screw speed is set to 100rpm. After the temperature rises to the set value and stabilizes, the mixed material is added to the twin-screw hot melt extruder from the feed port at a feeding rate of 7g / min, and melt-extruded to obtain a strip-shaped extrudate; the extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer, and passed through a 20-mesh sieve. The sieved material is a granular hot-melt extruded solid dispersion;

[0104] Take 70g of the hot-melt extruded solid dispersion, add 45g of microcrystalline cellulose, 10g of cross-linked polyvinylpyrrolidone, 4g of colloidal silicon dioxide and 1g of magnesium stearate, mix for 10min, directly compress the tablets according to a tablet weight of 325mg, and use a gastric soluble coating premix for film coating. The coating weight gain is 4% to obtain a film-coated tablet.

[0105] Comparative Example 1

[0106] The method of Example 4 was followed, except that the plasticizer PEG3350 was omitted from the mixed material for hot melt extrusion, and the reduced weight was supplemented with the carrier material PVP-VA64.

[0107] Comparative Example 2

[0108] The method of Example 4 is used as reference, except that the plasticizer PEG3350 is replaced by PEG6000 in the mixed material for hot melt extrusion.

[0109] Comparative Example 3

[0110] The method of Example 4 was followed, except that the temperature of the twin-screw hot melt extruder was set to 120°C.

[0111] Comparative Example 4

[0112] The method of Example 4 was used, except that the carrier material PVP-VA64 was omitted from the mixed material for hot melt extrusion, and the reduced weight was supplemented with plasticizer PEG3350.

[0113] Test Example 1 Powder X-ray Diffraction (XRD) Detection

[0114] The raw material, blank excipient (PEG3350 and PVP-VA64 mass ratio of 1:5) and the hot-melt extruded solid dispersion prepared in Example 4 were taken as test samples, and the crystal state of the above test samples was studied by powder X-ray diffraction.

[0115] Figure 1 is the XRD pattern of the raw material drug, Figure 2 This is the XRD pattern of the blank excipient (the mass ratio of PEG3350 to PVP-VA64 is 1:5). Figure 3The XRD pattern of the hot-melt extruded solid dispersion prepared in Example 4. The results show that the XRD pattern of the API has abundant characteristic peaks, proving that the API is in a crystalline state; the XRD pattern of the blank excipient has no characteristic peaks, and the characteristic peaks of the raw materials in the XRD pattern of the hot-melt extruded solid dispersion prepared in Example 4 completely disappear, indicating that the API therein is completely transformed into an amorphous state.

[0116] Test Example 2 Dissolution curve test

[0117] The raw material drug (the structural compound shown in Formula 2), the film-coated tablets prepared in Examples 1 to 9 and Comparative Examples 1 to 4 were subjected to dissolution curve testing, and the dissolution determination method was as follows:

[0118] Weigh 25 mg of the raw material drug, 1 film-coated tablet prepared in Examples 1 to 9 and Comparative Examples 1 to 4 (equivalent to 25 mg of the raw material drug), and use 900 mL of phosphate buffer (measure 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, 112.0 mL of 0.2 mol / L sodium hydroxide solution, dilute to 1000 mL with water, add 10 g of sodium dodecyl sulfate, shake well, and dissolve by ultrasound) as the dissolution medium. The speed is 100 rpm. Take 10 mL of solution at 5 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min, respectively, and supplement the dissolution medium at the same temperature and volume at the same time. Filter the taken solution through a 0.45 μm filter membrane, take the filtrate, record the chromatogram at 195 nm by high performance liquid chromatography, calculate the cumulative dissolution by peak area according to the external standard method, and draw the dissolution curve. Results are shown in Figure 4 , the corresponding specific data are shown in Table 1. Table 1 Dissolution of the raw materials and the film-coated tablets prepared in the examples and comparative examples (unit: %) As can be seen from Table 1, the present invention adopts a hot melt extrusion process to prepare a solid dispersion, so that the drug molecules are dispersed in a plasticizer and a carrier material in an amorphous state to form a solid dispersion state, and then fully mixed with a certain amount of diluent, disintegrant, glidant and lubricant, directly tableted, and film-coated with a gastric soluble coating premix to obtain a film-coated tablet, which greatly improves the dissolution rate and absolute solubility of the active ingredient (i.e., the structural compound shown in Formula 2), and the solubility reaches more than 80% at 45 minutes. In Comparative Example 1, no plasticizer PEG3350 was added, and the dissolution rate of the active ingredient was slow, with a solubility of only 53.16% at 45 min. In Comparative Example 2, plasticizer PEG6000 was used, which had a large molecular weight, resulting in a slow dissolution rate of the active ingredient, and a solubility of only 45.23% at 120 min. In Comparative Example 3, the temperature of melt extrusion was low, which would also reduce the dissolution rate of the active ingredient to a certain extent, and the solubility was only 75.05% at 120 min. In Comparative Example 4, no carrier material was added, which greatly reduced the dissolution rate of the active ingredient, and the solubility was only 15.93% at 120 min.

[0119] Test Example 3 Pharmacokinetic Test

[0120] In order to investigate the oral absorption and bioavailability improvement of the hot-melt extruded solid dispersion of the present invention in animals, the drug substance, the film-coated tablets prepared in Example 4 and Example 7 were selected for pharmacokinetic test of oral gavage in female SD rats, and the drug substance aqueous solution was administered by tail vein injection as a control to calculate the bioavailability.

[0121] 1. Experimental drugs:

[0122] Drug substance solution: Disperse fully with 0.5wt% CMC-Na solution to prepare a suspension with a concentration of 1.0mg / mL.

[0123] Example 4 Preparation solution: After the preparation is finely ground, it is fully dispersed in 0.5wt% CMC-Na solution to prepare a suspension with a raw material drug concentration of 1.0 mg / mL.

[0124] Example 7 Preparation solution: After the preparation is finely ground, it is fully dispersed in 0.5wt% CMC-Na solution to prepare a suspension with a raw material drug concentration of 1.0 mg / mL.

[0125] Aqueous solution of raw drug (tail vein): Dissolve in 30 wt% sulfobutyl ether-β-cyclodextrin aqueous solution to prepare a solution with a concentration of 0.3 mg / mL.

[0126] 2. Experimental Animals:

[0127] SD female rats, weighing 200-220 g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0128] 3. Test methods:

[0129] 20 SD female rats were randomly divided into 4 groups, 5 rats in each group, as the raw material drug group (10 mg / kg), Example 4 group (10 mg / kg), Example 7 group (10 mg / kg), and tail vein group (3 mg / kg). The raw material drug group, Example 4 group, and Example 7 group were all administered by oral gavage according to the designed dose, and blood was collected from the orbital venous plexus at 0 time (before administration), 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, and 24h after administration; the tail vein group was administered by tail vein injection, and blood was collected from the orbital venous plexus at 0 time, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h after administration. After the blood was anticoagulated with heparin and centrifuged, the plasma was separated for testing.

[0130] Accurately measure 50 μL of plasma sample, add 200 μL of protein precipitant (acetonitrile-isopropanol solution containing 100 ng / mL of HRN01-d3, the volume ratio of acetonitrile to isopropanol in the acetonitrile-isopropanol solution is 1:1), vortex mix for 1 min, transfer all samples to the phospholipid-free plate, place a 96-well plate underneath, place it under a positive pressure device for 5 min (N2 pressure is less than 0.01 MPa), take all the filtrate, detect it by LC-MS / MS, and calculate the concentration of the raw material drug in each plasma sample by the standard curve method.

[0131] 4. Test results:

[0132] The test results of the drug substance concentration (ng / mL) in the plasma samples of each test group at different times are shown in Table 2.

[0133] Table 2 Detection results of drug concentration (ng / mL) in plasma samples of each test group at different times

[0134]

[0135]

[0136] Figure 5 The drug-time curves of each experimental group are shown in Table 3. The drug-time curve data were statistically analyzed using Phoenix WinNonlin, version 8.3.5 software, and the pharmacokinetic parameter results are shown in Table 3. As shown in Table 3, compared with the raw material drug, the film-coated tablets prepared in Examples 4 and 7 of the present invention significantly improved the oral absorption bioavailability of the raw material drug.

[0137] Table 3 Pharmacokinetic parameters of each test group

[0138]

[0139] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

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

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

3. The preparation method according to claim 2, characterized in that: The neurosteroid derivative has a 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; and 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 copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl macrogol glyceride, polyvinyl alcohol, polyvinyl pyrrolidone, 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 copolyvidone includes PVP-VA64.

7. A neurosteroid derivative solid dispersion prepared by the preparation method according to any one of claims 1 to 6.

8. Use of the neurosteroid derivative solid dispersion according to claim 7 in the preparation of therapeutic drugs for central nervous system disorder-related diseases.

9. A therapeutic drug for central nervous system disorder-related diseases, wherein the raw materials for preparation include the neurosteroid derivative solid dispersion according to claim 7 and pharmaceutically acceptable excipients.

10. The therapeutic drug for central nervous system disorder-related diseases according to claim 9, characterized in that: The pharmaceutically acceptable excipients include one or more of a diluent, a disintegrant, a glidant and a lubricant; the therapeutic drug for central nervous system disorder-related diseases is an oral drug, and the dosage form of the oral drug includes tablets, capsules or granules.

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