Neuroactive steroid solid dispersion, solid dispersion composition, preparation method and application thereof, and medicine containing solid dispersion

Abstract

The present invention provides a neuroactive steroid solid dispersion, a solid dispersion composition, a preparation method and application, and a drug containing the solid dispersion, and belongs to the field of pharmaceutical technology. The present invention melt-extrudes a raw material mixture to obtain a neuroactive steroid solid dispersion; the raw material mixture includes 10 to 70 parts of neuroactive steroids, 30 to 90 parts of carrier materials, and 0 to 60 parts of plasticizers by mass; the temperature of the melt extrusion is <160°C; the neuroactive steroid in the neuroactive steroid solid dispersion exists in an amorphous state, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is ≤200nm. The neuroactive steroid in the neuroactive steroid solid dispersion provided by the present invention has a high oral bioavailability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, in particular to a neuroactive steroid solid dispersion, a solid dispersion composition, a preparation method and application thereof, and a medicine containing the solid dispersion. Background Art

[0002] Neuroactive steroids (NAS) can affect central nervous system (CNS) function through multiple mechanisms, including interaction with GABA A Receptor binding exerts allosteric regulation. GABA A The receptor is an ionotropic channel receptor with γ-aminobutyric acid (GABA) as a ligand gate. As the main inhibitory neurotransmitter in the central nervous system, GABA can mediate GABA A The receptors thus affect the flow of ions inside and outside the nerve cell membrane, exerting physiological effects.

[0003] Extensive research on neuroactive steroids has shown that these compounds can act as GABA A Positive allosteric modulators (PAMs) of the receptor affect the flow of ions in and out of the neuronal cell membrane, thereby influencing a wide range of brain circuits that are critical for a variety of behavioral states. A Receptor dysregulation is a core factor in a range of neurological disorders, such as postpartum or postpartum depression, clinical depression, atypical depression, major depressive disorder, catatonic depression, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder, manic-depressive disorder, mood disorders, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), depression due to a chronic medical condition, refractory depression, suicidal tendencies, suicidal ideation or behavior, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder Disorders (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, menstrual epilepsy, pediatric epilepsy, epileptiform disorders, essential tremor, NMDA hypofunction, Tourette syndrome, migraine, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female pediatric epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease, etc. Currently developed or under development for GABA A Receptor-mediated neuroactive steroids include progesterone, pregnanolone, brexanolone, alfalone, sepnanolone, minaxolone, ganaxolone, and alfaxalone.

[0004] Among them, postpartum depression (PPD) is a psychiatric syndrome that occurs in women during the postpartum period. It is an obvious and easily identifiable severe depression that usually begins in the late pregnancy or within 4 weeks after delivery. It is the leading cause of postpartum suicide and a common complication of childbirth. A Allosteric modulators of GABA receptors that regulate GABA activity both inside and outside of synapses A Receptor function, thereby significantly improving certain symptoms of PPD such as mental stress and anxiety. Brexanolone is an endogenous neuroactive steroid with a chemical name of 3α-hydroxy-5α-pregnan-20-one and a molecular formula of C 21 H 34 O2, CAS registration number is 516-54-1, and the structural formula is as follows:

[0005] .

[0006] In March 2019, the U.S. FDA approved intravenous injection of brexanolone (Zulresso) for the treatment of PPD. Clinical trial results show that Zulresso has the advantages of rapid onset, long duration of action, good safety, and low incidence of adverse reactions in the treatment of PPD. Although Zulresso has many advantages, its administration route is invasive intravenous injection, which requires continuous injection for 60 hours and multiple adjustments of the dosage at different times (different doses are required for 0-4h, 4-24h, 24-52h, 52-56h, and 56-60h, respectively). This dosing regimen needs to be implemented by qualified medical staff in medical institutions that have passed the Risk Evaluation and Mitigation Strategy (REMS) certification, and frequent monitoring is required during the entire injection process, which will occupy more medical resources, have high costs, and will also affect availability. In addition, continuous intravenous infusion for 60 hours still has the problem of poor compliance for ordinary patients, and for PPD patients who are usually in the lactation period after childbirth, it will bring great challenges in terms of compliance.

[0007] Therefore, it is necessary to develop non-intravenous formulations of brexanolone in order to provide a convenient and more compliant dosing regimen for the treatment of PPD. Compared with other dosage forms, oral preparations have many advantages such as convenient administration, non-invasiveness, high patient compliance, low production cost, large drug loading, and relatively slow absorption. It is expected to solve the problem of excessive sedation when brexanolone is injected and the need for frequent monitoring during medication.

[0008] However, the development of oral preparations of brinolone faces many difficulties, such as poor water solubility and poor permeability through the small intestinal epithelial mucosa. brinolone also has a very important pharmacokinetic defect, that is, the original drug will be rapidly distributed or metabolized after entering the blood (its metabolites are inactive), resulting in a rapid decrease in blood drug concentration, which is not conducive to maintaining a certain blood drug concentration and efficacy. If it is directly dispersed in an oil solvent or dispersed in water in the presence of a solubilizer to make an ordinary preparation for oral administration, there are defects such as poor absorption and low bioavailability, and the oral bioavailability is even less than 5%. Summary of the invention

[0009] The purpose of the present invention is to provide a neuroactive steroid solid dispersion, a solid dispersion composition, a preparation method and application, and a drug containing the solid dispersion. The neuroactive steroid in the neuroactive steroid solid dispersion provided by the present invention has a high oral bioavailability.

[0010] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0011] The present invention provides a method for preparing a neuroactive steroid solid dispersion, comprising the following steps:

[0012] Melting and extruding the raw material mixture to obtain the neuroactive steroid solid dispersion;

[0013] The raw material mixture comprises, by weight, 10 to 70 parts of neuroactive steroid, 30 to 90 parts of carrier material, and 0 to 60 parts of plasticizer;

[0014] The temperature of the melt extrusion is less than 160°C;

[0015] The neuroactive steroid in the neuroactive steroid solid dispersion exists in an amorphous state, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is ≤200 nm.

[0016] Preferably, the neuroactive steroid comprises one or more of progesterone, pregnanolone, brexanolone, alfalone, sepnanolone, minaxolone, ganaxolone and alfaxalone;

[0017] 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 derivative, starch and starch derivative;

[0018] The plasticizer includes one or more of polyethylene glycol, poloxamer and Tween.

[0019] Preferably, the copovidone comprises PVP / VA64; the polyethylene glycol comprises PEG3350; the poloxamer comprises poloxamer 188; and the Tween comprises Tween 80.

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

[0021] The present invention provides a solid dispersion composition, comprising the following components in parts by mass:

[0022] The above technical solution comprises 10 to 100 parts of the neuroactive steroid solid dispersion, 0 to 50 parts of the sustained-release material, 0 to 10 parts of the disintegrant, 0 to 90 parts of the diluent, 0 to 10 parts of the glidant, and 0 to 2 parts of the lubricant, and the mass fractions of the sustained-release material, disintegrant, diluent, glidant and lubricant are not 0 at the same time.

[0023] Preferably, the sustained-release material comprises one or more of acrylic resin, polyethylene oxide, ethyl cellulose and hypromellose;

[0024] The disintegrant comprises one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone;

[0025] The diluent includes one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and sodium chloride;

[0026] The glidant includes colloidal silicon dioxide;

[0027] The lubricant includes magnesium stearate and / or sodium fumarate.

[0028] The present invention provides use of the neuroactive steroid solid dispersion described in the above technical solution or the solid dispersion composition described in the above technical solution in the preparation of therapeutic drugs for central nervous system disorder-related diseases.

[0029] Preferably, the central nervous system disorder-related conditions include postpartum or postpartum depression, clinical depression, atypical depression, major depressive disorder, catatonic depression, dysthymia, double depression, depressive personality disorder, recurrent brief depression, mild depressive disorder, bipolar disorder, manic-depressive disorder, mood disorder, anxiety, post-traumatic stress disorder, premenstrual dysphoric disorder, depression caused by chronic medical conditions, refractory depression, suicidal tendencies, suicidal ideas or behaviors, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder, social Anxiety disorders, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, catamenial epilepsy, pediatric epilepsy, epileptiform disorders, essential tremor, NMDA hypofunction, Tourette syndrome, migraine, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5-alpha reductase inhibitor-induced depression, infantile spasms, PCDH19 pediatric epilepsy in women, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease.

[0030] Preferably, the therapeutic drug is an oral drug, and the dosage form of the therapeutic drug includes tablets or capsules.

[0031] The present invention provides a medicine containing a solid dispersion, and the preparation raw materials include the neuroactive steroid solid dispersion described in the above technical solution or the solid dispersion composition described in the above technical solution.

[0032] The present invention provides a method for preparing a neuroactive steroid solid dispersion, comprising the following steps: melt-extruding a raw material mixture to obtain the neuroactive steroid solid dispersion; the raw material mixture comprises 10-70 parts of neuroactive steroid, 30-90 parts of carrier material, and 0-60 parts of plasticizer by weight; the temperature of the melt extrusion is less than 160°C; the neuroactive steroid in the neuroactive steroid solid dispersion exists in an amorphous state, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is ≤200nm. The neuroactive steroid in the neuroactive steroid solid dispersion provided by the present invention exists in an amorphous state (that is, the neuroactive steroid drug molecules are dispersed in the neuroactive steroid solid dispersion in an amorphous state), and the particle size of the neuroactive steroid is ≤200nm, which not only improves the water solubility and permeability of the neuroactive steroid, but also significantly improves the oral bioavailability of the neuroactive steroid in animals.

[0033] Furthermore, the carrier material of the present invention 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. The carrier material described in the above part of the present invention is a carrier material with a sustained release effect (referred to as a sustained release carrier material), such as acrylic resin, polyethylene oxide, ethyl cellulose, hydroxypropyl methylcellulose, copovidone, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene oxide, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer. When the sustained release carrier material is used to prepare a neuroactive steroid solid dispersion, it has a sustained release characteristic. When the neuroactive steroid solid dispersion is further used to prepare an oral drug (such as a tablet or capsule), the blood drug concentration after oral administration can be made more stable, which is conducive to maintaining the drug effect for a longer time, and avoids the animal central inhibition phenomenon caused by excessively high blood drug concentration. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the DSC diagram of the Brenolone API;

[0035] Figure 2 The DSC graph of the blank excipient (the mass ratio of PEG3350 to PVP / VA64 is 1:5);

[0036] Figure 3 The DSC graph of the physical mixture of brenosone and excipients (the mass ratio of brenosone, PEG3350 and PVP / VA64 is 1:1:5);

[0037] Figure 4 This is the DSC graph of the hot melt extruded solid dispersion of Brenolone (Formulation 6);

[0038] Figure 5 This is the DSC graph of the hot melt extruded solid dispersion of Brenolone (Formulation 7);

[0039] Figure 6 This is the XRD pattern of the Brenolone API;

[0040] Figure 7 This is the XRD pattern of the blank excipient (the mass ratio of PEG3350 to PVP / VA64 is 1:5);

[0041] Figure 8 It is the XRD pattern of the physical mixture of brenolon and excipients (the mass ratio of brenolon, PEG3350 and PVP / VA64 is 1:1:5);

[0042] Fig. 9 This is the XRD pattern of the hot melt extruded solid dispersion of Brenolone (Formulation 6);

[0043] Fig.10 This is the XRD pattern of the hot melt extruded solid dispersion of Brenolone (Formulation 7);

[0044] Fig.11 This is the particle size distribution diagram of the hot melt extruded solid dispersion of Brenolone (Formulation 7) after dispersion with water;

[0045] Fig.12 This is the particle size distribution diagram of the hot melt extruded solid dispersion of Brenolone (Formulation 22) after dispersion with water;

[0046] Fig.13 It is a drug-time curve of brenolon hot-melt extruded solid dispersion (Formulation 6, Formulation 7), brenolon hot-melt extruded solid dispersion composition (Composition 1, Composition 13) and brenolon raw material oral gavage administration;

[0047] Fig.14 This is the drug-time curve of Brenolone injected into the tail vein (3 mg / kg);

[0048] Fig.15 This is the concentration-time curve of brenosol nanosuspension and brenosol raw material for oral gavage administration. DETAILED DESCRIPTION

[0049] The present invention provides a method for preparing a neuroactive steroid solid dispersion, comprising the following steps:

[0050] Melting and extruding the raw material mixture to obtain the neuroactive steroid solid dispersion;

[0051] The raw material mixture comprises, by weight, 10 to 70 parts of neuroactive steroid, 30 to 90 parts of carrier material, and 0 to 60 parts of plasticizer;

[0052] The temperature of the melt extrusion is less than 160°C;

[0053] The neuroactive steroid in the neuroactive steroid solid dispersion exists in an amorphous state, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is ≤200 nm.

[0054] The present invention first describes the raw material mixture required for preparing the neuroactive steroid solid dispersion. In the present invention, the raw material mixture includes 10 to 70 parts of neuroactive steroids by mass, and specifically can be 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts or 70 parts. In the present invention, the neuroactive steroid preferably includes one or more of progesterone, pregnanolone, bryanolone, alfalone, sepnolone, minaxolone, ganaxolone and alfaxalone, more preferably progesterone, pregnanolone, bryanolone, alfalone, sepnolone, minaxolone, ganaxolone or alfaxalone, and more preferably bryanolone.

[0055] Based on the mass fraction of the neuroactive steroid, the raw material mixture of the present invention includes 30 to 90 parts of the carrier material, specifically 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts or 90 parts. In the present invention, the carrier material preferably includes copolyvidone (PVP / VA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), lauryl macrogol glyceride (Gelucire® 44 / 14), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-glycolic acid copolymer (PLGA), ethylene-vinyl acetate copolymer (EVA), acrylic resin (Eudragit), cellulose derivatives, starch and starch derivatives. One or more of them may be copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glyceride, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivatives, starch or starch derivatives. It may also be a mixture of copolyvidone and cellulose derivatives, or a mixture of copolyvidone and acrylic resin; the copolyvidone preferably includes PVP / VA64; the acrylic resin is preferably Eudragit RL100; the cellulose derivative preferably includes one or more of hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC) and methyl cellulose (MC); the starch derivative preferably includes cross-linked starch and / or carboxymethyl starch. The carrier material described in the above part of the present invention is a carrier material with a sustained release effect (referred to as a sustained release carrier material), such as acrylic resin, polyethylene oxide, ethyl cellulose, hydroxypropyl methylcellulose, copovidone, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene oxide, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer. When the sustained release carrier material is used to prepare a neuroactive steroid solid dispersion, it has a sustained release characteristic. When the neuroactive steroid solid dispersion is further used to prepare an oral drug (such as a tablet or capsule), the blood drug concentration after oral administration can be made more stable, which is conducive to maintaining the drug effect for a longer time, and avoids the animal central inhibition phenomenon caused by excessive blood drug concentration.

[0056] Based on the mass fraction of the neuroactive steroid, the raw material mixture of the present invention includes 0 to 60 parts of plasticizer, specifically 0.1 parts, 0.5 parts, 1 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts or 60 parts. In the present invention, the plasticizer preferably includes one or more of polyethylene glycol (PEG), poloxamer and Tween, more preferably polyethylene glycol, poloxamer or Tween; the polyethylene glycol preferably includes PEG3350; the poloxamer preferably includes poloxamer 188; the Tween preferably includes Tween 80.

[0057] The present invention melt-extrudes the raw material mixture to obtain the neuroactive steroid solid dispersion. The present invention preferably selects a suitable method according to the type of carrier material to prepare the neuroactive steroid solid dispersion, which is described in detail below.

[0058] In the present invention, when the carrier material is lauryl macrogol glyceride, the preparation method of the neuroactive steroid solid dispersion preferably comprises the following steps:

[0059] The raw material mixture is melt-extruded and then sieved while hot to obtain the neuroactive steroid solid dispersion.

[0060] In the present invention, the lauryl macrogol glyceride in the raw material mixture is preferably present in the form of a molten liquid, and the molten liquid is preferably obtained by heating and melting the lauryl macrogol glyceride, and the temperature of the heating and melting is preferably 60-90°C, specifically 60°C, 65°C, 70°C, 75°C, 80°C, 85°C or 90°C; the bruneolone is preferably crushed and sieved in sequence before use, and the mesh number of the sieve used for sieving is preferably 100-200 meshes; when the carrier material is lauryl macrogol glyceride, the raw material mixture is preferably a mixture of bruneolone and lauryl macrogol glyceride, that is, no plasticizer is added. In the present invention, the temperature of the melt extrusion is preferably <160°C, more preferably 60-80°C, specifically 60°C, 65°C, 70°C, 75°C or 80°C; in an embodiment of the present invention, the melt extrusion is preferably carried out in a twin-screw hot melt extruder (without the discharge port mold). In the present invention, the mesh size of the sieve used for hot sieving is preferably 20 to 80 meshes.

[0061] In the present invention, when lauryl macrogol glyceride is used as a carrier material to prepare a neuroactive steroid solid dispersion, the neuroactive steroid solid dispersion obtained after melt extrusion from a twin-screw hot melt extruder is in the form of milky white particles, and the neuroactive steroid exists in an amorphous state. The particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is ≤200nm, preferably 120~200nm, and specifically can be 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm or 200nm.

[0062] In the present invention, when the carrier material is a substance other than lauryl macrogol glyceride, the method for preparing the neuroactive steroid solid dispersion preferably comprises the following steps:

[0063] The raw material mixture is melt-extruded and then cooled, cut, crushed and sieved in sequence to obtain the neuroactive steroid solid dispersion.

[0064] In the present invention, each component in the raw material mixture is preferably crushed and sieved in sequence before use, and the mesh number of the sieve used for sieving is preferably 80-120 mesh, specifically 80 mesh, 100 mesh or 120 mesh. The temperature of the melt extrusion is preferably <160°C, more preferably 120-150°C, specifically 120°C, 125°C, 130°C, 135°C, 140°C, 145°C or 150°C; in an embodiment of the present invention, the melt extrusion is preferably carried out in a twin-screw hot melt extruder. After the melt extrusion of the present invention, a strip extrudate is preferably obtained, which is cut, crushed and sieved in sequence after cooling; in an embodiment of the present invention, the equipment used for cutting is preferably a pelletizer; the mesh number of the sieve used for sieving is preferably 20-80 mesh, specifically 20 mesh, 40 mesh or 80 mesh.

[0065] In the present invention, when a neuroactive steroid solid dispersion is prepared with a carrier material other than lauryl macrogol glyceride, the extrudate obtained after melt extrusion from a twin-screw hot melt extruder has a transparent strip appearance, and then is cut, crushed and sieved to obtain a white granular or powdered neuroactive steroid solid dispersion, wherein the neuroactive steroid exists in an amorphous state, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is ≤200nm, preferably 80~200nm, specifically 80nm, 90nm, 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm or 200nm.

[0066] In the present invention, when the neuroactive steroid is brexanolone, the prepared neuroactive steroid solid dispersion is brexanolone hot-melt extruded solid dispersion; the following takes brexanolone as an example to describe the brexanolone hot-melt extruded solid dispersion in the present invention in detail.

[0067] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenolide, polyethylene glycol and copovidone, the polyethylene glycol is preferably PEG3350, and the copovidone is preferably PVP / VA64; the mass ratio of brenolide, polyethylene glycol and copovidone is preferably 10:5~15:45~85, more preferably 10:10:50~80; the temperature of the melt extrusion is preferably 125~145°C, more preferably 130~140°C; the extrudate obtained after the melt extrusion has an appearance of transparent strips, wherein brenolide exists in an amorphous state, and the particle size of brenolide in the brenolide hot-melt extruded solid dispersion is 80~120nm.

[0068] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenolide and Soluplus, and the mass ratio of brenolide to Soluplus is preferably 10:30~40; the temperature of the melt extrusion is preferably 130~135°C; the extrudate obtained after the melt extrusion has an appearance of transparent strips, wherein brenolide exists in an amorphous state, and the particle size of brenolide in the brenolide hot-melt extruded solid dispersion is 80~120nm.

[0069] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenolide and Soluplus, and the mass ratio of brenolide to Soluplus is preferably 10:45~85, more preferably 10:50~80; the temperature of the melt extrusion is preferably 120~125°C; the extrudate obtained after the melt extrusion has an appearance of transparent strips, wherein brenolide exists in an amorphous state, and the particle size of brenolide in the brenolide hot-melt extruded solid dispersion is 80~120nm.

[0070] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenosolone, a plasticizer and Soluplus, the plasticizer is preferably polyethylene glycol or Tween, the polyethylene glycol is preferably PEG3350, and the Tween is preferably Tween 80; the mass ratio of brenosolone, plasticizer and Soluplus is preferably 10:5~15:45~60, more preferably 10:10:50~55; the temperature of the melt extrusion is preferably 120~125°C; the extrudate obtained after the melt extrusion has an appearance of transparent strips, wherein brenosolone exists in an amorphous state, and the particle size of brenosolone in the brenosolone hot-melt extruded solid dispersion is 80~120nm.

[0071] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenosolone, polyethylene glycol and a cellulose derivative, the polyethylene glycol is preferably PEG3350, and the cellulose derivative is preferably HPMC; the mass ratio of brenosolone, polyethylene glycol and cellulose derivative is preferably 10:5~15:45~55, more preferably 10:10:50; the temperature of the melt extrusion is preferably 140~145°C; the extrudate obtained after the melt extrusion has an appearance of transparent strips, wherein the brenosolone exists in an amorphous state, and the particle size of the brenosolone in the brenosolone hot-melt extruded solid dispersion is 80~120nm.

[0072] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenolide, polyethylene glycol, copolyvidone and a cellulose derivative, the polyethylene glycol is preferably PEG3350, the copolyvidone is preferably PVP / VA64, and the cellulose derivative is preferably HPMC; the mass ratio of brenolide, polyethylene glycol, copolyvidone and cellulose derivative is preferably 10:5~15:10~40:10~40, more preferably 10:10:20~25:25~40; the temperature of the melt extrusion is preferably 140~145°C; the extrudate obtained after the melt extrusion has an appearance of transparent strips, wherein brenolide exists in an amorphous state, and the particle size of brenolide in the brenolide hot-melt extruded solid dispersion is 80~120nm.

[0073] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenolide, polyethylene glycol, copolyvidone and acrylic resin, the polyethylene glycol is preferably PEG3350, the copolyvidone is preferably PVP / VA64, and the acrylic resin is preferably Eudragit RL100; the mass ratio of brenolide, polyethylene glycol, copolyvidone and acrylic resin is preferably 10:5~15:30~45:5~30, more preferably 10:10:25~40:10~25; the temperature of the melt extrusion is preferably 140~145°C; the extrudate obtained after the melt extrusion has an appearance of transparent strips, wherein the brenolide exists in an amorphous state, and the particle size of the brenolide in the brenolide hot-melt extruded solid dispersion is 80~120nm.

[0074] In an embodiment of the present invention, the raw material mixture is preferably a mixture of brenosone and Gelucire® 44 / 14, the mass ratio of brenosone to Gelucire® 44 / 14 is preferably 10:30~60, and the temperature of the melt extrusion is preferably 60~80°C; the brenosone hot-melt extruded solid dispersion has an appearance of milky white particles, brenosone exists in an amorphous state, and the particle size of brenosone in the brenosone hot-melt extruded solid dispersion is 120~200nm.

[0075] The present invention provides a neuroactive steroid solid dispersion prepared by the preparation method described in the above technical scheme.

[0076] The present invention provides a solid dispersion composition, comprising the following components in parts by mass:

[0077] The above technical solution comprises 10 to 100 parts of the neuroactive steroid solid dispersion, 0 to 50 parts of the sustained-release material, 0 to 10 parts of the disintegrant, 0 to 90 parts of the diluent, 0 to 10 parts of the glidant, and 0 to 2 parts of the lubricant, and the mass fractions of the sustained-release material, disintegrant, diluent, glidant and lubricant are not 0 at the same time.

[0078] In parts by mass, the solid dispersion composition of the present invention includes 10 to 100 parts of a neuroactive steroid solid dispersion, specifically 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 97 parts or 100 parts.

[0079] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of the present invention includes 0 to 50 parts of sustained-release material, specifically 0.1 parts, 0.5 parts, 1 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts or 50 parts. In the present invention, the sustained-release material preferably includes one or more of acrylic resin (Eudragit), polyoxyethylene (PEO), ethyl cellulose (EC) and hydroxypropyl methylcellulose (HPMC), more preferably acrylic resin, polyoxyethylene, ethyl cellulose or hydroxypropyl methylcellulose; the acrylic resin is preferably Eudragit RL100. In the present invention, when the carrier material used in preparing the neuroactive steroid solid dispersion includes a sustained-release carrier material, the mass fraction of the sustained-release material in the solid dispersion composition may be 0 or may not be 0, preferably 0 (i.e., no sustained-release material is added); when the carrier material used in preparing the neuroactive steroid solid dispersion does not include a sustained-release carrier material, the mass fraction of the sustained-release material in the solid dispersion composition may be 0 or may not be 0, preferably not 0 (i.e., a sustained-release material is added). When a sustained-release material is added to the solid dispersion composition of the present invention (especially when the carrier material used in preparing the neuroactive steroid solid dispersion does not include a sustained-release carrier material), and the solid dispersion composition is further used to prepare an oral drug (such as a tablet or capsule), the blood drug concentration after oral administration can be more stable, which is conducive to maintaining the drug effect for a longer time, and avoids the phenomenon of animal central inhibition caused by excessively high blood drug concentration.

[0080] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of the present invention includes 0 to 10 parts of a disintegrant, specifically 0.1 parts, 0.5 parts, 1 parts, 3 parts, 5 parts, 8 parts or 10 parts. In the present invention, the disintegrant preferably includes one or more of low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl starch (CMS-Na) and cross-linked polyvinylpyrrolidone (PVPP), more preferably low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone.

[0081] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of the present invention includes 0 to 90 parts of diluent, specifically 0.1 parts, 0.5 parts, 1 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts or 90 parts. In the present invention, the diluent preferably includes one or more of lactose, microcrystalline cellulose (MCC), anhydrous calcium hydrogen phosphate and sodium chloride, more preferably lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate or sodium chloride.

[0082] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of the present invention includes 0 to 10 parts of a glidant, specifically 0.1 parts, 0.5 parts, 1 parts, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts or 10 parts. In the present invention, the glidant preferably includes colloidal silicon dioxide.

[0083] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of the present invention includes 0 to 2 parts of lubricant, specifically 0.1 parts, 0.3 parts, 0.5 parts, 0.8 parts, 1 parts, 1.3 parts, 1.5 parts, 1.8 parts or 2 parts. In the present invention, the lubricant preferably includes magnesium stearate and / or sodium fumarate, more preferably magnesium stearate.

[0084] In the present invention, when the neuroactive steroid is brexanolone, the prepared neuroactive steroid solid dispersion is brexanolone hot-melt extruded solid dispersion; the following takes the neuroactive steroid as brexanolone as an example to describe in detail the solid dispersion composition prepared based on the brexanolone hot-melt extruded solid dispersion in the present invention.

[0085] In an embodiment of the present invention, the solid dispersion composition is preferably a mixture of a brenolide hot-melt extruded solid dispersion and a glidant, and the glidant is preferably colloidal silicon dioxide; the mass ratio of the brenolide hot-melt extruded solid dispersion to the glidant is preferably 97:1~5, more preferably 97:3.

[0086] In an embodiment of the present invention, the solid dispersion composition is preferably a mixture of brenolide hot-melt extruded solid dispersion and a diluent, and the diluent is preferably lactose; the mass ratio of the brenolide hot-melt extruded solid dispersion to the diluent is preferably 10:85~95, more preferably 10:90.

[0087] In an embodiment of the present invention, the solid dispersion composition is preferably a mixture of brenolide hot-melt extruded solid dispersion, a diluent and a glidant, the diluent is preferably lactose or MCC, and the glidant is preferably colloidal silicon dioxide; the mass ratio of the brenolide hot-melt extruded solid dispersion, the diluent and the glidant is preferably 50~70:25~50:1~10, more preferably 50~70:27~45:3~5.

[0088] In an embodiment of the present invention, the solid dispersion composition is preferably a mixture of brenolide hot-melt extruded solid dispersion, a diluent, a glidant and a lubricant, the diluent is preferably MCC, the glidant is preferably colloidal silicon dioxide, and the lubricant is preferably magnesium stearate; the mass ratio of the brenolide hot-melt extruded solid dispersion, the diluent, the glidant and the lubricant is preferably 30:60~70:3~7:0.5~3, more preferably 30:64:5:1.

[0089] In an embodiment of the present invention, the solid dispersion composition is preferably a mixture of brenolide hot-melt extruded solid dispersion, sustained-release material, diluent, glidant and lubricant, the sustained-release material is preferably HPMC, the diluent is preferably anhydrous calcium hydrogen phosphate, the glidant is preferably colloidal silicon dioxide, and the lubricant is preferably magnesium stearate; the mass ratio of the brenolide hot-melt extruded solid dispersion, sustained-release material, diluent, glidant and lubricant is preferably 30:35~45:20~30:3~7:0.5~3, more preferably 30:40:24:5:1.

[0090] In an embodiment of the present invention, the solid dispersion composition is preferably a mixture of brucerosol hot-melt extruded solid dispersion, a disintegrant, a diluent, a glidant and a lubricant, the disintegrant is preferably CMS-Na, L-HPC or PVPP, the diluent is preferably MCC, anhydrous calcium hydrogen phosphate or sodium chloride, the glidant is preferably colloidal silicon dioxide, and the lubricant is preferably magnesium stearate; the mass ratio of the brucerosol hot-melt extruded solid dispersion, disintegrant, diluent, glidant and lubricant is preferably 20~50:5~10:29~72:2~10:1~2, more preferably 20~30:5~8:55~72:2~5:1~2.

[0091] In an embodiment of the present invention, the solid dispersion composition is preferably a mixture of a bruceool hot-melt extruded solid dispersion, a sustained-release material, a diluent, a glidant and a lubricant, the sustained-release material is preferably Eudragit RL100, HPMC, EC or PEO, the diluent is preferably MCC or anhydrous calcium hydrogen phosphate, the glidant is preferably colloidal silicon dioxide, and the lubricant is preferably magnesium stearate; the mass ratio of the bruceool hot-melt extruded solid dispersion, the sustained-release material, the diluent, the glidant and the lubricant is preferably 20~60:20~50:17~37:2.5~5:0.5~1, and more preferably 20~30:30~50:24~34:2.5~5:0.5~1.

[0092] The present invention provides use of the neuroactive steroid solid dispersion described in the above technical solution or the solid dispersion composition described in the above technical solution in the preparation of therapeutic drugs for central nervous system disorder-related diseases.

[0093] In the present invention, the central nervous system disorder-related conditions preferably include postpartum or postpartum depression, clinical depression, atypical depression, major depressive disorder, catatonic depression, dysthymia, double depression, depressive personality disorder, recurrent brief depression, mild depressive disorder, bipolar disorder, manic-depressive disorder, mood disorder, anxiety, post-traumatic stress disorder, premenstrual dysphoric disorder, depression caused by chronic medical conditions, refractory depression, suicidal tendencies, suicidal ideas or suicidal behaviors, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder, Social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, catamenial epilepsy, pediatric epilepsy, epileptiform disorders, essential tremor, NMDA hypofunction, Tourette syndrome, migraine, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5-alpha reductase inhibitor-induced depression, infantile spasms, PCDH19 pediatric epilepsy in women, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease.

[0094] In the present invention, the therapeutic drug is preferably an oral drug, and the dosage form of the therapeutic drug preferably includes tablets or capsules.

[0095] In the present invention, the preparation method of the tablets preferably comprises the following steps: mixing the neuroactive steroid solid dispersion with excipients (the excipients are one or more of a sustained-release material, a disintegrant, a diluent, a glidant and a lubricant) and then tableting to obtain plain tablets; and film-coating the plain tablets with a gastric-soluble coating premix to obtain the tablets (specifically film-coated tablets).

[0096] In the present invention, the preparation method of the capsule preferably comprises the following steps: loading the neuroactive steroid solid dispersion into a hollow hard capsule to obtain the capsule; or mixing the neuroactive steroid solid dispersion with an excipient (the excipient is one or more of a sustained-release material, a disintegrant, a diluent, a glidant, and a lubricant) and loading the mixture into a hollow hard capsule to obtain the capsule. In the present invention, the hollow hard capsule is preferably a gelatin hollow hard capsule.

[0097] The present invention provides a drug containing a solid dispersion, wherein the raw materials for preparation include the neuroactive steroid solid dispersion described in the above technical solution or the solid dispersion composition described in the above technical solution. As an embodiment of the present invention, the drug containing a solid dispersion can specifically be a therapeutic drug for central nervous system disorder-related diseases described in the above technical solution.

[0098] 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.

[0099] Examples 1 to 4 and Comparative Examples 1 to 8

[0100] Using copolyvidone (PVP / VA64) as a carrier material and polyethylene glycol (PEG3350) as a plasticizer, the hot melt extrusion solid dispersion of brenolide was prepared in the following steps:

[0101] The brenolon, carrier material PVP / VA64 and plasticizer PEG3350 were crushed separately and passed through a 100-mesh sieve, and the sieve residues were mixed to obtain a mixed material;

[0102] The extrusion temperature of the twin-screw hot melt extruder is set. After the temperature reaches the set value and stabilizes, the mixed material is added into the twin-screw hot melt extruder from the feed port for melt extrusion to obtain a strip-shaped extrudate. The extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer and passed through an 80-mesh sieve. The sieved material is a powdered brenolon hot-melt extruded solid dispersion.

[0103] Table 1 shows the raw material ratio, melt extrusion temperature and extrudate properties of each prescription. As shown in Table 1, when PVP / VA64 is used as the carrier material to prepare the brenosol hot melt extrusion solid dispersion, when no plasticizer is added, the extrusion temperature is 150°C and still no transparent, uniform strip extrudate can be obtained. However, when the plasticizer PEG3350 is added, the extrusion temperature is 130°C and a transparent, uniform strip extrudate can be obtained, indicating that the addition of the plasticizer PEG3350 can significantly reduce the melting temperature of the mixed system of brenosol and PVP / VA64. By comparing prescription 4 and prescription 10, it can be seen that when no plasticizer is added, even if the amount of PVP / VA64 is increased, the melting temperature of the mixed system of brenosol and PVP / VA64 cannot be significantly reduced. At the same time, it can be seen from Table 1 that the extrusion temperature has a significant effect on the properties of the extrudate. As the extrusion temperature increases, the mixed system is in a completely molten state, which is conducive to making brenolide in an amorphous state in the solid dispersion; but the increase in temperature is not conducive to the chemical stability of brenolide.

[0104] Table 1 Raw material ratio, melt extrusion temperature and extrudate properties of recipes 1 to 12

[0105]

[0106] * Extrudate refers to the solid dispersion extruded from a twin-screw hot melt extruder without further cutting or crushing. All extrudates in this test are in the form of strips, and the column "Extrudate Properties" only describes whether the strip is transparent, translucent or opaque.

[0107] Test Example 1 Characterization of the properties of brenolon hot melt extruded solid dispersion

[0108] In this test example, the presence of brenolon in the brenolon hot-melt extruded solid dispersion was determined by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD); and high performance liquid chromatography (HPLC) was used to detect related substances to examine the stability of brenolon in the preparation of brenolon hot-melt extruded solid dispersion. The details are as follows:

[0109] 1. Differential scanning calorimetry

[0110] The brenolon hot melt extrusion solid dispersions prepared from the prescriptions in Table 1, as well as the brenolon API, blank excipients (the mass ratio of PEG3350 to PVP / VA64 was 1:5), and the physical mixture of brenolon and excipients (the mass ratio of brenolon, PEG3350 to PVP / VA64 was 1:1:5) were taken as the samples to be tested. The thermal phase change behavior of the above samples to be tested was investigated by differential scanning calorimetry using a thermal analyzer.

[0111] The results showed that: there was a sharp endothermic peak near 177°C (melting point) in the DSC graph of the brenosolone API, indicating that the brenosolone API was in a crystalline state; the blank excipient had no characteristic endothermic and exothermic peaks, indicating that the blank excipient existed in an amorphous state; the characteristic endothermic peak of brenosolone in the DSC graph of the transparent brenosolone hot-melt extruded solid dispersion completely disappeared, and it was speculated that the brenosolone therein was completely transformed into an amorphous state. However, the characteristic endothermic peak of brenosolone (near 177°C) in the DSC graph of the physical mixture of brenosolone and the blank excipient, as well as the opaque and translucent brenosolone hot-melt extruded solid dispersion, also disappeared or was almost invisible. This may be due to the low proportion of brenosolone in the mixed system and the insufficient sensitivity of DSC detection; it may also be due to the thermal phase change behavior of the excipient component affecting the detection of the endothermic peak of brenosolone. Representative DSC graphs are shown in Figure 1~Figure 5 , specifically, Figure 1 This is the DSC diagram of the raw material of brenolon. Figure 2 This is the DSC graph of the blank excipient (the mass ratio of PEG3350 to PVP / VA64 is 1:5). Figure 3 This is the DSC graph of the physical mixture of brenolon and excipients (the mass ratio of brenolon, PEG3350 and PVP / VA64 is 1:1:5). Figure 4This is the DSC graph of the hot melt extruded solid dispersion of Brenolone (Formulation 6). Figure 5 This is the DSC graph of the hot melt extruded solid dispersion of brenoside (Formulation 7).

[0112] 2. Powder X-ray diffraction (XRD) detection

[0113] The brenolon hot melt extrusion solid dispersions prepared from the prescriptions in Table 1, as well as the brenolon API, blank excipients (the mass ratio of PEG3350 to PVP / VA64 is 1:5), and the physical mixture of brenolon and blank excipients (the mass ratio of brenolon, PEG3350 to PVP / VA64 is 1:1:5) were taken as the samples to be tested. The crystal state of the above samples to be tested was further studied by powder X-ray diffraction.

[0114] The results show that the XRD patterns of the brenosolone API and the physical mixture of brenosolone and blank excipients all have abundant characteristic peaks, and the peak positions in the XRD patterns of the two samples to be tested are basically consistent. There is no characteristic peak in the XRD pattern of the blank excipient, which further proves that the brenosolone API is in a crystalline state, and the physical mixing of brenosolone and blank excipients does not change its crystalline state; the brenosolone hot-melt extruded solid dispersion with opaque or translucent appearance (such as the translucent brenosolone hot-melt extruded solid dispersion prepared by Prescription 6) still has obvious characteristic peaks of the brenosolone API in its XRD pattern, but the peak intensity is lower than that in the physical mixture of brenosolone and blank excipients, indicating that part of the brenosolone in these brenosolone hot-melt extruded solid dispersions has been transformed into an amorphous state, and part of it still exists in a crystalline state. The characteristic peaks in the XRD graph of the transparent brenosone hot melt extruded solid dispersion (such as the brenosone hot melt extruded solid dispersion prepared by prescription 7) completely disappeared, indicating that the brenosone therein has completely transformed into an amorphous state. The amorphous brenosone is expected to significantly improve the oral bioavailability of brenosone. The representative XRD graph is shown in Figure 6~Figure 10 , specifically, Figure 6 This is the XRD diagram of the raw material of brenolon. Figure 7 This is the XRD pattern of the blank excipient (the mass ratio of PEG3350 to PVP / VA64 is 1:5). Figure 8 This is the XRD pattern of the physical mixture of brenolon and excipients (the mass ratio of brenolon, PEG3350 and PVP / VA64 is 1:1:5). Fig. 9 This is the XRD pattern of the hot melt extruded solid dispersion of Brenolone (Formulation 6). Fig.10 This is the XRD pattern of the hot melt extruded solid dispersion of brenoside (Formulation 7).

[0115] 3. Particle size detection

[0116] The brenolide hot-melt extruded solid dispersions prepared from each prescription were mixed with water at a mass ratio of 1:1000. The brenolide hot-melt extruded solid dispersions with a transparent appearance can be dissolved quickly to form a uniform liquid with a light blue opalescent luster; while the brenolide hot-melt extruded solid dispersions with an opaque or translucent appearance dissolve more slowly to form a uniform liquid with a light blue opalescent luster, or a milky white uniform liquid. The particle size was measured using a nano-laser particle size analyzer, and the results showed that the particle size of the solid dispersions with a transparent appearance was in the range of 80~200nm; while the particle size of the solid dispersions with an opaque or translucent appearance was higher than 500nm, and even as high as 1000nm (i.e., 1μm) or more, and was no longer a nano-dispersion system. The specific test results are shown in Table 2. The representative particle size distribution diagram is shown in Fig.11 , Fig.11 This is the particle size distribution diagram of brenolon hot melt extruded solid dispersion (formulation 7) after water dispersion, Z-average particle size = 86.71nm, PDI = 0.255. Nano-scale size is expected to significantly improve the oral bioavailability of brenolon.

[0117] 4. Related substance testing

[0118] The brenolon hot melt extruded solid dispersions and brenolon APIs prepared by each prescription were taken and tested for brenolon related substances by high performance liquid chromatography (HPLC). The total impurity content in the brenolon API was 0.019%, and the total impurity content in the brenolon hot melt extruded solid dispersions prepared by each treatment was shown in Table 2. As shown in Table 2, with the increase of extrusion temperature, the related substances (total impurity content) in the prepared brenolon hot melt extruded solid dispersions also gradually increased. According to the proposed quality standard, the total impurity content in the preparation should not be higher than 0.5%. When the extrusion temperature is higher than 150°C, the total impurity content increases significantly; and when the extrusion temperature is 160°C, the total impurity content is 1.067%, far exceeding the limit of 0.5%. Therefore, suitable carrier materials and plasticizers should be selected to control the extrusion temperature below 160°C during the preparation of brenolon solid dispersions, preferably at or below 150°C.

[0119] Table 2 Melt extrusion temperature and product indexes of prescriptions 1 to 12

[0120]

[0121] * Extrudate refers to the solid dispersion extruded from a twin-screw hot melt extruder without further cutting or crushing. In this test, the extrudates are all in the form of strips, and the column "Extrudate Properties" only describes whether the strips are transparent, translucent or opaque.

[0122] Example 5 and Comparative Examples 9-12

[0123] Using copolyvidone (PVP / VA64) as a carrier material and poloxamer 188 as a plasticizer, brenolon hot melt extrusion solid dispersion was prepared in the following steps:

[0124] The brenoside, carrier material PVP / VA64 and plasticizer poloxamer 188 were crushed separately and passed through a 120-mesh sieve, and the sieve residues were mixed to obtain a mixed material;

[0125] The extrusion temperature of the twin-screw hot melt extruder is set. After the temperature reaches the set value and stabilizes, the mixed material is added into the twin-screw hot melt extruder from the feed port for melt extrusion 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 brenolon hot-melt extruded solid dispersion.

[0126] Table 3 shows the raw material ratio, melt extrusion temperature and product index of each prescription. It can be seen from Table 3 that when PVP / VA64 is used as the carrier material to prepare the brinolone hot melt extrusion solid dispersion, when poloxamer 188 is used as the plasticizer, the mass ratio of PVP / VA64 to brinolone is 8:1 and the extrusion temperature is 150°C, it is still impossible to form a transparent strip extrudate. Compared with the results of using PEG3350 as a plasticizer in the above embodiment, it shows that in the mixed system of brinolone and PVP / VA64, the effect of using PEG3350 as a plasticizer to reduce the melting temperature of the system is better than using poloxamer 188 as a plasticizer.

[0127] Table 3 Raw material ratio, melt extrusion temperature and product index of prescriptions 13~17

[0128]

[0129] * Extrudate refers to the solid dispersion extruded from a twin-screw hot melt extruder without further cutting or crushing. In this test, the extrudates are all in the form of strips, and the column "Extrudate Properties" only describes whether the strips are transparent, translucent or opaque.

[0130] Examples 6-10 and Comparative Examples 13-14

[0131] Using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) as carrier material, polyethylene glycol (PEG3350), poloxamer 188 and Tween 80 as plasticizers, respectively, brenolon hot melt extrusion solid dispersion was prepared in the following steps:

[0132] The brenolon, carrier material Soluplus and plasticizer are crushed separately and passed through an 80-mesh sieve, and the sieve residues are mixed to obtain a mixed material;

[0133] The extrusion temperature of the twin-screw hot melt extruder is set. After the temperature reaches the set value and stabilizes, the mixed material is added into the twin-screw hot melt extruder from the feed port for melt extrusion to obtain a strip-shaped extrudate. The extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer and passed through an 80-mesh sieve. The sieved material is a powdered brenolon hot-melt extruded solid dispersion.

[0134] Table 4 shows the raw material ratio, melt extrusion temperature and product index of each prescription. As shown in Table 4, when Soluplus is used as the carrier material to prepare the brenolon hot melt extrusion solid dispersion, when the mass ratio of Soluplus to brenolon is 3:1 and no plasticizer is added, a transparent strip extrudate can be formed at an extrusion temperature of 130°C; and when the mass ratio of Soluplus to brenolon is 5:1 and no plasticizer is added, a transparent strip extrudate can be formed at an extrusion temperature of 120°C. It can be seen that the increase in the amount of Soluplus can reduce the melting temperature of the mixed system. Adding plasticizers PEG3350 or Tween 80 to the mixed system of brenolon and Soluplus has no obvious effect on the properties of the extrudate; when the plasticizer poloxamer 188 is added, it has an adverse effect on the properties of the extrudate.

[0135] Table 4 Raw material ratio, melt extrusion temperature and product index of prescription 18~24

[0136]

[0137] * Extrudate refers to the solid dispersion extruded from a twin-screw hot melt extruder without further cutting or crushing. In this test, the extrudates are all in the form of strips, and the column "Extrudate Properties" only describes whether the strips are transparent, translucent or opaque.

[0138] Fig.12 This is the particle size distribution diagram of the hot-melt extruded solid dispersion of brenolon (prescription 22) after dispersion with water, Z-average particle size = 99.59nm, PDI = 0.222.

[0139] Embodiments 11 to 16

[0140] Using water-soluble carrier copolyvidone (PVP / VA64) and / or hydrophilic carrier hydroxypropyl methylcellulose (HPMC) as carrier materials and polyethylene glycol (PEG3350) as plasticizer, the hot melt extrusion solid dispersion of brenolide was prepared in the following steps:

[0141] The brenolon, carrier material and plasticizer are crushed separately and passed through a 120-mesh sieve, and the sieve residues are mixed to obtain a mixed material;

[0142] The extrusion temperature of the twin-screw hot-melt extruder is set to 140°C. After the temperature reaches the set value and stabilizes, the mixed material is added into the twin-screw hot-melt extruder from the feed port for melt extrusion to obtain a strip-shaped extrudate. The extrudate is cooled and cut with a pelletizer, and then crushed with a pulverizer and passed through an 80-mesh sieve. The sieved material is a powdered brenolon hot-melt extruded solid dispersion.

[0143] Table 5 shows the raw material ratio and product index of prescriptions 25 to 30. As shown in Table 5, when PVP / VA64 and HPMC are used as carrier materials, PEG3350 is used as a plasticizer, and the extrusion temperature is 140°C to prepare the brenolon hot melt extrusion solid dispersion, the two carrier materials PVP / VA64 and HPMC are mixed in various proportions to form transparent, uniform strip extrudates.

[0144] Table 5 Raw material ratio and product index of prescription 25~30

[0145]

[0146] * Extrudate refers to the solid dispersion extruded from a twin-screw hot melt extruder without further cutting or crushing. In this test, the extrudates are all in the form of strips, and the column "Extrudate Properties" only describes whether the strips are transparent, translucent or opaque.

[0147] Examples 17-18 and Comparative Examples 15-16

[0148] Using water-soluble carrier copolyvidone (PVP / VA64) and water-insoluble carrier Eudragit RL100 as carrier materials, and polyethylene glycol (PEG3350) as plasticizer, the hot melt extrusion solid dispersion of brenolide was prepared in the following steps:

[0149] The brenolon, carrier material and plasticizer are crushed separately and passed through a 100-mesh sieve, and the sieve residues are mixed to obtain a mixed material;

[0150] The extrusion temperature of the twin-screw hot-melt extruder is set to 140°C. After the temperature reaches the set value and stabilizes, the mixed material is added into the twin-screw hot-melt extruder from the feed port for melt extrusion 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 brenolon hot-melt extruded solid dispersion.

[0151] Table 6 shows the raw material ratios and product indicators of prescriptions 31 to 34. As shown in Table 6, when PVP / VA64 and EudragitRL100 are used as carrier materials, PEG3350 is used as a plasticizer, and the extrusion temperature is 140°C to prepare the brenolon hot melt extrusion solid dispersion, when the mass ratio of Eudragit RL100 to PVP / VA64 is ≤1, a transparent, uniform strip extrudate can be formed.

[0152] Table 6 Raw material ratios and product indicators of prescriptions 31 to 34

[0153]

[0154] * Extrudate refers to the solid dispersion extruded from a twin-screw hot melt extruder without further cutting or crushing. In this test, the extrudates are all in the form of strips, and the column "Extrudate Properties" only describes whether the strips are transparent, translucent or opaque.

[0155] Embodiments 19 to 23

[0156] Using lauryl macrogol glyceride (Gelucire® 44 / 14) as the carrier material, the hot melt extrusion solid dispersion of brenolon was prepared as follows:

[0157] The brenospermum extract was crushed and passed through a 200-mesh sieve, and the brenospermum extract under the sieve was taken to obtain brenospermum extract powder; the carrier material Gelucire® 44 / 14 was melted at 80° C., and the obtained melt was mixed with the brenospermum extract powder to obtain a suspension;

[0158] The extrusion temperature of the twin-screw hot melt extruder is set. After the temperature reaches the set value and stabilizes, the suspension is added into the twin-screw hot melt extruder from the feed port for melt extrusion (the discharge port mold is removed). The obtained granular extrudate is passed through a 20-mesh sieve while hot. The sieved material is a granular brenolon hot-melt extruded solid dispersion.

[0159] Table 7 shows the raw material ratio, melt extrusion temperature and product index of prescriptions 35 to 39. As shown in Table 7, when Gelucire® 44 / 14 is used as the carrier material and the extrusion temperature is 60 to 80°C to prepare the brenolon hot melt extrusion solid dispersion, the obtained solid dispersion extrudate is milky white particles, and the particle size is in the range of 120 to 200 nm after dispersion with water. With the increase of extrusion temperature and Gelucire® 44 / 14 ratio, the particle size tends to decrease.

[0160] Table 7 Raw material ratio, melt extrusion temperature and product index of prescriptions 35~39

[0161]

[0162] * Extrudate refers to the solid dispersion extruded from a twin-screw hot melt extruder without further sieving while hot. In this test, the extrudates are all granular, and the column "Extrudate Properties" only states that the granules are milky white granules.

[0163] Embodiment 24

[0164] The hot-melt extruded solid dispersion of brenolide (specifically, Prescription 7, Prescription 22, Prescription 25, Prescription 27 or Prescription 33) is mixed with excipients (specifically including at least one of a sustained-release material, a disintegrant, a diluent, a glidant and a lubricant) to obtain a mixed material; the mixed material is tableted to obtain plain tablets, and then the plain tablets are film-coated with a gastric-soluble coating premix to obtain film-coated tablets; or the mixed material is loaded into a gelatin hollow hard capsule to obtain a capsule.

[0165] The hot melt extruded solid dispersion of brenoside (specifically, prescription 38) is directly loaded into a hollow hard gelatin capsule to obtain a capsule.

[0166] Table 8 shows the raw material ratios of different dosage forms; in Table 8, API-SD represents brendolone hot melt extruded solid dispersion, SiO2 represents colloidal silicon dioxide, calcium hydrogen phosphate represents anhydrous calcium hydrogen phosphate, SSF represents sodium fumarate, and RL100 represents Eudragit RL100.

[0167] Table 8 Raw material ratios of different dosage forms (wt%)

[0168]

[0169] Test Example 2 Pharmacokinetics of oral administration of brenolan hot-melt extruded solid dispersion and brenolan hot-melt extruded solid dispersion composition

[0170] In order to investigate the oral absorption and bioavailability improvement of the breno hot-melt extruded solid dispersion and the brenolon hot-melt extruded solid dispersion composition of the present invention in animals, representative brenolon hot-melt extruded solid dispersions (Formulation 6 and Formulation 7) and brenolon hot-melt extruded solid dispersion compositions (Composition 1 and Composition 13) were selected to conduct a pharmacokinetic test of oral gavage in female SD rats, and the brenolon bulk drug (suspended in 0.5wt% CMC-Na solution, brenolon concentration of 5mg / mL) was used as a control.

[0171] 1. Experimental drugs:

[0172] Solid dispersion (Formulation 6 and Formulation 7, both of which are powders obtained by cutting and crushing the strip extrudates and then passing through an 80-mesh sieve): Take the two powders separately, fully disperse them in 0.5wt% CMC-Na solution, and prepare a suspension with a concentration of 2.5mg / mL of brexanolone.

[0173] Composition 1 and Composition 13 (both capsules): take the contents of the two capsules respectively, fully disperse them with 0.5wt% CMC-Na solution to prepare a suspension with a brexanolone concentration of 2.5mg / mL;

[0174] Brenolone API: fully dispersed with 0.5wt% CMC-Na solution to prepare a suspension with a Brenolone concentration of 5.0mg / mL.

[0175] 2. Experimental animals:

[0176] SD female rats, weighing 200-220 g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0177] 3. Test methods:

[0178] Thirty SD female rats were randomly divided into 6 groups, 5 rats in each group, as the raw material drug group of brucenolide (50 mg / kg), the prescription group 6 (25 mg / kg), the prescription group 7 (25 mg / kg), the low-dose group of composition 1 (25 mg / kg), the high-dose group of composition 1 (50 mg / kg), and the composition group 13 (25 mg / kg). The animals in each group were orally gavaged according to the designed dose, and blood was collected from the orbital venous plexus at 0 time, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h after administration. After the blood was anticoagulated with heparin and centrifuged, the plasma was separated for testing.

[0179] Accurately measure 50 μL of plasma sample, add 200 μL of protein precipitant (acetonitrile-isopropanol solution containing 5 ng / mL brenolide-d5, 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 brenolide concentration in each plasma sample using the standard curve method.

[0180] 4. Test results:

[0181] The test results of brexanolone concentration (ng / mL) in plasma samples of each test group at different times are shown in Table 9, wherein Composition 1-L and Composition 1-H represent the low-dose group of Composition 1 and the high-dose group of Composition 1, respectively.

[0182] Table 9 Detection results of brexanolone concentration (ng / mL) in plasma samples of each experimental group at different times

[0183]

[0184] Fig.13 These are the drug-time curves of brenolon hot-melt extruded solid dispersions (Formulation 6, Formulation 7), brenolon hot-melt extruded solid dispersion compositions (Composition 1, Composition 13) and brenolon raw materials for oral gavage administration.

[0185] Phoenix WinNonlin, version 8.3.5 software was used to perform statistics on the above drug-time curve data, and the pharmacokinetic parameter results are shown in Table 10.

[0186] Table 10 Pharmacokinetic parameters of each test group

[0187]

[0188] From the above results, it can be seen that compared with the brenosone raw material, the brenosone hot-melt extruded solid dispersion (Formulation 6, Formulation 7) and the brenosone hot-melt extruded solid dispersion composition (Composition 1 and Composition 13) in the present invention significantly improved the oral absorption of the raw material.

[0189] Specifically, at the same dose (25 mg / kg), the in vivo exposure Cmax (496.2 ng / mL) and AUC (678.6 hr×ng / mL) of prescription 7 were significantly higher than those of prescription 6 (325.8 ng / mL) and AUC (468.7 hr×ng / mL), indicating that the bioavailability of the solid dispersion with a transparent extrudate appearance (brenolone exists completely in an amorphous state in the solid dispersion) is higher than the bioavailability of the solid dispersion with a translucent extrudate appearance (brenolone exists in a partially amorphous and partially crystalline state in the solid dispersion).

[0190] The in vivo exposure Cmax and AUC of the low-dose group (25 mg / kg) and high-dose group (50 mg / kg) of Composition 1 were roughly 2-fold proportional, indicating that the in vivo absorption had a good dose correlation.

[0191] The oral bioavailability (AUC / dose) of Composition 13 (25 mg / kg) was not much different from that of the low-dose group of Composition 1 (25 mg / kg), but Composition 13 exhibited a sustained-release characteristic. Within 30 minutes to 8 hours after administration, its blood drug concentration fluctuated less, Cmax was lower, and Cmin was higher, which was beneficial for maintaining the drug efficacy in the body for a longer period of time.

[0192] In addition, given that brenoside will show obvious central nervous system inhibition when the blood concentration is too high (when conducting pharmacokinetic tests, the behavioral performance of each group of animals was observed, and it can be seen that the low-dose group of Composition 1 showed varying degrees of central nervous system inhibition in the 30-min to 1-h period, and the high-dose group of Composition 1 showed central nervous system inhibition in the 15-min to 2-h period after administration, such as unstable gait, limb stiffness, convulsions, drowsiness, slow response to the outside world, etc., and the central nervous system inhibition in the high-dose group was more serious), the blood concentration of Composition 13 fluctuates less (Cmax is lower), which is beneficial to reduce or even avoid the occurrence of central nervous system inhibition (no central nervous system inhibition was observed during the pharmacokinetic test of Composition 13).

[0193] Test Example 3 In vivo efficacy test of brexanolone hot melt extruded solid dispersion composition in ICR mice

[0194] In order to investigate the in vivo efficacy of the Brenol hot-melt extruded solid dispersion composition of the present invention, female ICR mice were used as test animals, and a forced swimming test was performed after a single dose of the drug. The immobility time after 4 minutes of swimming was used as an evaluation index for the antidepressant efficacy, and the efficacy was investigated 1h, 3h, and 8h after administration, respectively.

[0195] 1. Experimental drugs:

[0196] Composition 1 and composition 13 (both capsules): take the contents of the two capsules respectively, fully disperse them with 0.5wt% CMC-Na solution to prepare a suspension with a concentration of 2.5mg / mL;

[0197] Imipramine: Dissolve in saline to prepare a solution with a concentration of 3.0 mg / mL.

[0198] 2. Experimental animals:

[0199] Female ICR mice, SPF grade, weighing 18-20 g, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.

[0200] 3. Test methods:

[0201] Female ICR mice were randomly divided into 8 groups according to body weight, namely, blank control group (administered with normal saline), positive control group (imipramine, 30 mg / kg intraperitoneal injection), composition 1-1h group (25 mg / kg, oral gavage, test efficacy 1h after administration), composition 1-3h group (25 mg / kg, oral gavage, test efficacy 3h after administration), composition 1-8h group (25 mg / kg, oral gavage, test efficacy 8h after administration), composition 13-1h group (25 mg / kg, oral gavage, test efficacy 1h after administration), composition 13-3h group (25 mg / kg, oral gavage, test efficacy 3h after administration), composition 13-8h group (25 mg / kg, oral gavage, test efficacy 8h after administration), 10 mice in each group. Forced swimming test was performed at the specified time (1h, 3h, 8h) of the corresponding group after a single administration, and the immobility time after swimming for the last 4 minutes was recorded.

[0202] 4. Test results

[0203] Compared with the blank control group, the immobility time of the positive control group (imipramine, 30 mg / kg), the combination 1-3h group, the combination 13-1h group, the combination 13-3h group, and the combination 13-8h group was significantly reduced, with statistical differences (p < 0.05, p < 0.05, p < 0.01, P < 0.01, P < 0.05, respectively). There was no significant statistical difference in the immobility time of the combination 1-1h group and the combination 1-8h group compared with the control group (p> 0.05). The immobility time of the last 4 minutes of different groups and the statistical differences (compared with the control group) are shown in Table 11.

[0204] Table 11 Immobility time of animals in swimming for the last 4 minutes after drug administration and statistical differences in each test group

[0205]

[0206] The test results showed that after a single oral administration to female ICR mice, composition 1 showed obvious antidepressant effects 3 hours after administration and composition 13 showed obvious antidepressant effects 1 hour, 3 hours and 8 hours after administration.

[0207] Specifically, composition 1 had no effect 1 hour after administration, which was presumably because the blood concentration of brinosone was too high at this time point, resulting in a central inhibitory effect, which affected the animal's behavior in the forced swimming test, which was consistent with the results of the oral gavage pharmacokinetic test of composition 1 in SD rats (15min to 1h was the high point of blood concentration). Composition 1 had no effect 8 hours after administration, which was presumably because the blood concentration of brinosone was lower than the effective concentration at this time point, which was also consistent with the results of the oral gavage pharmacokinetic test of composition 1 in SD rats (blood concentration was 10.5ng / mL at 8h).

[0208] Composition 13 had significant pharmacological effects 1h, 3h, and 8h after administration. It is speculated that this is because the preparation has a sustained-release characteristic after oral administration, and the blood drug concentration between 1h and 8h is relatively stable, neither too high nor too low, so the drug effect concentration can be maintained without causing obvious central nervous system inhibition.

[0209] It can be seen from the above test results that the brenosone hot-melt extruded solid dispersion composition of the present invention enables the raw material brenosone to exist in an amorphous state in the solid dispersion and has a nanometer-scale particle size, which greatly improves the bioavailability of brenosone for oral administration; moreover, the brenosone hot-melt extruded solid dispersion prepared by using a sustained-release carrier has a good sustained-release effect, which makes the blood drug concentration in the body more stable, which can not only maintain the efficacy for a longer time, but also avoid the central nervous system inhibition phenomenon due to excessively high blood drug concentration.

[0210] Comparative test example 1

[0211] This test example tests the bioavailability of a brinolone aqueous solution preparation and a brinolone oil solution preparation, wherein the brinolone aqueous solution preparation is obtained by mixing brinolone, a solubilizer (specifically sulfobutyl ether-β-cyclodextrin) and water, and the concentration of the solubilizer in the brinolone aqueous solution preparation is 30wt%; the brinolone oil solution preparation is obtained by mixing brinolone and sesame oil. The specific test steps are as follows:

[0212] 1. Experimental drugs:

[0213] Tail vein injection: 0.5 mg / mL brexanolone aqueous solution (abbreviated as A 静脉 );

[0214] Oral gavage: 3 mg / mL brexanolone aqueous solution (abbreviated as A 口服1 ); 3mg / mL bruceanolone oil solution (abbreviated as A 口服2 ).

[0215] 2. Experimental animals:

[0216] SD female rats, weighing 200-220 g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0217] 3. Test methods:

[0218] Fifteen female SD rats were randomly divided into three groups (A 静脉 , A 口服1 , A 口服2 ), 5 in each group. 静脉 Group A was injected into the tail vein 静脉 3mg / kg (about 1.2mL of liquid medicine). 口服1 , A口服2 The two groups were given drug A orally orally. 口服1 and A 口服2 Each 25mg / kg (about 1.67mL of drug solution). Blood was collected from the orbital venous plexus at 5min, 30min, 1h, 2h, 4h, and 8h after administration. The blood was anticoagulated with heparin and centrifuged to separate the plasma for testing.

[0219] Accurately measure 100 μL of plasma sample, 10 μL of internal standard solution (100 ng / mL testosterone D-3 solution) and 310 μL of acetonitrile, vortex mix, centrifuge (14000 rpm, 4°C), take the supernatant, and use UPLC-MS / MS to detect. Use the standard curve method to calculate the concentration of brexanolone in each plasma sample.

[0220] 4. Test results:

[0221] Injection of brexanolone aqueous solution into the tail vein (3 mg / kg, i.e. A 静脉 The results of the detection of brucenaolone concentration in plasma samples at different times after administration of the group) are shown in Table 12, where "--" represents undetectable; brucenaolone aqueous solution and brucenaolone oil solution were administered orally by gavage (25 mg / kg, i.e., A 口服1 and A 口服2 After the treatment with 1 mg / kg Bruynolone (group A), no brexanolone was detected in plasma at any time point.

[0222] Table 12 A 静脉 Results of brexanolone concentrations in plasma samples of different groups at different times after administration

[0223]

[0224] DAS software was used to perform tail vein injection of brexanolone aqueous solution (3 mg / kg, i.e. A 静脉 The drug-time curve of the group Fig.14 The data were statistically analyzed, and the pharmacokinetic parameters are shown in Table 13; AUC represents the area under the drug-time curve; Tmax represents the time when the drug reaches the peak concentration in plasma; Cmax represents the peak concentration of the drug in plasma; MRT is the first-order moment, representing the average residence time of the drug in the body; VRT is the second-order moment, representing the difference in the average residence time of the drug in the body. Fig.14 As shown in Table 13, after the tail vein injection of brucenolide aqueous solution, brucenolide enters the blood and is rapidly distributed (or metabolized), and its blood concentration decreases rapidly, with Tmax being only 0.083h. However, after oral gavage administration of brucenolide to rats, the common preparation (solubilized with cyclodextrin to make an aqueous solution, or dissolved with sesame oil to make an oil solution) is basically not absorbed (or absorbed very little, below the detection limit of the method), so it is impossible to calculate its absolute bioavailability relative to intravenous administration.

[0225] Table 13 A 静脉 Pharmacokinetic parameters of the two groups

[0226]

[0227] Comparative test example 2

[0228] This test example tests the bioavailability of brenosuspension, which uses lecithin as a stabilizer (the mass ratio of brenosuspension to lecithin is 1:2), water as a dispersion medium, and is prepared by high-pressure homogenization. The particle size of the brenosuspension is at the nanometer level, the particle size distribution is uniform, the storage stability is good, and the solubility and in vitro dissolution are significantly better than the brenosuspension API. The specific test steps are as follows:

[0229] 1. Experimental drugs:

[0230] Brenolone nanosuspension (1): Brenolone concentration 5.34 mg / mL, particle size 158 nm, PDI 0.279;

[0231] Brenolone nanosuspension (2): Brenolone concentration 5.17 mg / mL, particle size 45.8 nm, PDI 0.262;

[0232] The brexanolone raw material (suspended in 0.5wt% CMC-Na solution, with a concentration of 5mg / mL) was used as a control.

[0233] 2. Experimental animals and experimental methods: The method of "Comparative Test Example 1" was adopted. The oral gavage dose for each group was also 25 mg / kg. Only the blood collection time points were different, which were 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours respectively.

[0234] 3. Test results:

[0235] After oral gavage administration (25 mg / kg) of brenosuspension (concentrations of 5.34 mg / mL and 5.17 mg / mL, respectively) of brenosulone nanosuspension (concentrations of 5.34 mg / mL and 5.17 mg / mL, respectively) and brenosulone API (suspended in 0.5 wt % CMC-Na solution, concentration of 5 mg / mL), the detection results of brenosulone concentrations in plasma samples at different times are shown in Table 14, where “--” represents not detected.

[0236] Table 14 Detection results of brexanolone concentration in plasma samples at different times after administration in each test group

[0237]

[0238] The concentration-time curves of oral administration of brenolan nanosuspension and brenolan raw material are shown in Fig.15Since there were too few points at which the blood drug concentration of brenolan nanosuspension was detected, it was impossible to perform pharmacokinetic-related statistics based on the drug-time curve of oral gavage administration of brenolan nanosuspension.

[0239] From the above results, it can be seen that compared with the brexanolone raw material, although the nanosuspension improved the solubility and in vitro dissolution of brexanolone, it did not show improvement in oral absorption and bioavailability in rats.

[0240] 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 neuroactive steroid solid dispersion, comprising the following steps: Melting and extruding the raw material mixture to obtain the neuroactive steroid solid dispersion; The raw material mixture comprises, by weight, 10 to 70 parts of neuroactive steroid, 30 to 90 parts of carrier material, and 0 to 60 parts of plasticizer; The neuroactive steroid in the neuroactive steroid solid dispersion is in an amorphous state; The neuroactive steroid is brexanolone; The carrier material is selected from one or more of copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl macrogol glyceride, acrylic resin and hypromellose; The plasticizer is selected from one or more of polyethylene glycol, poloxamer and Tween; When the carrier material is lauryl macrogol glyceride, the raw material mixture is a mixture of brenolon and lauryl macrogol glyceride, the temperature of the melt extrusion is 60-80° C., and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is 120-200 nm; When the carrier material is a substance other than lauryl macrogol glyceride, the temperature of the melt extrusion is 120-150° C., and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is 80-200 nm.

2. The preparation method according to claim 1, characterized in that: The copovidone is PVP / VA64; the polyethylene glycol is PEG3350; the poloxamer is poloxamer 188; and the Tween is Tween 80.

3. A neuroactive steroid solid dispersion prepared by the preparation method according to any one of claims 1 to 2.

4. A solid dispersion composition, calculated by weight: Includes the following components: 10 to 100 parts of the neuroactive steroid solid dispersion according to claim 3, 0 to 50 parts of a sustained-release material, 0 to 10 parts of a disintegrant, 0 to 90 parts of a diluent, 0 to 10 parts of a glidant, and 0 to 2 parts of a lubricant, wherein the mass fractions of the sustained-release material, disintegrant, diluent, glidant, and lubricant are not 0 at the same time.

5. The solid dispersion composition according to claim 4, characterized in that The sustained-release material is one or more of acrylic resin, polyoxyethylene, ethyl cellulose and hypromellose; The disintegrant is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone; The diluent is one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and sodium chloride; The glidant is colloidal silicon dioxide; The lubricant is magnesium stearate and / or sodium fumarate.

6. Use of the neuroactive steroid solid dispersion according to claim 3 or the solid dispersion composition according to claim 4 or 5 in the preparation of a therapeutic drug for central nervous system disorder-related diseases.

7. The use according to claim 6, characterized in that: The central nervous system disorder-related conditions include postpartum depression, atypical depression, catatonic depression, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, depression caused by chronic medical conditions, refractory depression, suicidal ideation or suicidal behavior, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder, social anxiety disorder, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, TSC-related epilepsy, menstrual epilepsy, essential tremor, NMDA hypofunction, Tourette syndrome, migraine, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female pediatric epilepsy, sexual dysfunction, Parkinson's disease or Alzheimer's disease.

8. The use according to claim 6, characterized in that: The central nervous system disorder-related conditions include clinical depression, epilepsy or cognitive impairment.

9. The use according to claim 6, characterized in that: The central nervous system disorder-related conditions include childhood epilepsy.

10. The use according to any one of claims 6 to 9, characterized in that: The therapeutic drug is an oral drug, and the dosage form of the therapeutic drug is tablets or capsules.

11. A medicine containing a solid dispersion, wherein the preparation raw materials include the neuroactive steroid solid dispersion according to claim 3 or the solid dispersion composition according to claim 4 or 5.

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