Neuroactive steroid solid dispersion, solid dispersion composition, method for preparing same and use thereof, and drug comprising solid dispersion

Abstract

The present invention relates to the field of pharmaceutical technology, and in particular, to a neuroactive steroid solid dispersion, a solid dispersion composition, a method for preparing same and use thereof, and a medicament comprising the solid dispersion. The neuroactive steroid solid dispersion is obtained by melting and extruding a mixture of raw materials. In parts by mass, the mixture of raw materials comprises: 10 to 70 parts of a neuroactive steroid, 30 to 90 parts of a carrier material, and 0 to 60 parts of a plasticizer. The temperature of melting and extruding is < 160 °C. The neuroactive steroid in the neuroactive steroid solid dispersion is present in an amorphous state with a particle size of ≤ 200 nm, and features good oral bioavailability.

Description

Neuroactive steroid solid dispersions, solid dispersion compositions, preparation methods and applications, and drugs containing solid dispersions.

[0001] This application claims priority to Chinese Patent Application No. CN202411388463.X, filed on October 8, 2024, entitled "Neuroactive Steroid Solid Dispersion, Solid Dispersion Composition and Preparation Method and Application, Pharmaceutical Containing Solid Dispersion", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical technology, and in particular to solid dispersions of neuroactive steroids, solid dispersion compositions and their preparation methods and applications, and drugs containing solid dispersions. Background Technology

[0003] Neuroactive steroids (NAS) can affect central nervous system (CNS) function through a variety of mechanisms, including their interaction with GABA. A GABA exerts allosteric regulatory effects through receptor binding. A The receptor is an ionotropic channel receptor gated by γ-aminobutyric acid (GABA) as a ligand. As a major inhibitory neurotransmitter in the central nervous system, GABA can mediate GABA-mediated ionotropic channel receptors. A Receptors thus affect the flow of ions across nerve cell membranes, thereby exerting physiological functions.

[0004] Current extensive research on neuroactive steroid compounds indicates that these compounds can act as GABA. A Allosteric modulators of receptors (PAMs) affect the flow of ions across nerve cell membranes, thereby influencing a wide range of brain circuits crucial for various behavioral states. GABA AReceptor dysregulation is a central factor in a range of neurological disorders, such as postpartum depression, clinical depression, atypical depression, severe depressive disorder, catatonic depression, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder, manic-depressive disorder, mood disorders, anxiety, post-traumatic stress disorder (PTSD), premenstrual anxiety disorder (PMDD), depression due to chronic medical conditions, treatment-resistant depression, suicidal ideation or behavior, premenstrual syndrome, generalized anxiety disorder, and seasonal affective disorder. This includes conditions such as SAD (Self-Affected Adolescence), social anxiety disorder, memory loss, poor stress tolerance, Niemann-Pick II type C disease or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, menstrual epilepsy, childhood epilepsy, epileptiform disorders, essential tremor, NMDA insufficiency, Tourette syndrome, migraine, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19-positive childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease. Currently developed or under development targets for GABA are also included. A Neuroactive steroids targeting receptors include progesterone, pregnanelonone, brinolone, afadolone, seclonone, minaxolone, ganexorone, and alfasalone.

[0005] Postpartum depression (PPD) is a mental syndrome that occurs in women during the puerperium. It is a severe and easily identifiable form of depression that typically begins in late pregnancy or within four weeks postpartum and is a common complication of childbirth. Brexanolone is a novel GABA-containing drug developed by Sage Therapeutics in the United States. A Allosteric regulators of receptors, which can modulate GABA located inside and outside neural synapses. A It modulates receptor function, thereby significantly improving certain symptoms of PPD such as stress and anxiety. Brinolon is an endogenous neuroactive steroid with the chemical name 3α-hydroxy-5α-pregnan-20-one and the molecular formula C. 21 H 34 O2, CAS registry number 516-54-1, has the following structure:

[0006] In March 2019, the U.S. FDA approved brinolone intravenous injection (Zulresso) for the treatment of postpartum papillary dysplasia (PPD). Clinical trial results showed that Zulresso has advantages in treating PPD, including rapid onset of action, long duration of action, good safety profile, and low incidence of adverse reactions. Despite these advantages, Zulresso is administered via invasive intravenous injection, requiring continuous infusion over 60 hours with multiple dose adjustments at different times (0–4h, 4–24h, 24–52h, 52–56h, and 56–60h). This administration regimen must be administered by qualified healthcare professionals in healthcare facilities certified by Risk Assessment and Remission Strategy (REMS), and frequent monitoring is required throughout the injection process, consuming significant healthcare resources, resulting in high costs and impacting accessibility. Furthermore, continuous intravenous infusion for 60 hours already presents poor compliance issues for ordinary patients; for postpartum PPD patients who are typically breastfeeding, this presents an even greater challenge in terms of compliance.

[0007] Therefore, it is essential to develop non-intravenous formulations of brinolone to provide a convenient, readily available, and more compliant dosing regimen for the treatment of PPD. Compared to other formulations, oral administration offers numerous advantages, including convenient administration, non-invasiveness, high patient compliance, low production costs, large drug loading capacity, and relatively slow absorption. This approach holds promise for addressing the issues of excessive sedation and the need for frequent monitoring during brinolone injections.

[0008] However, the development of oral formulations of brinolone faces numerous challenges. For example, brinolone has poor water solubility and poor permeability through the small intestinal mucosa. Brinolon also suffers from a significant pharmacokinetic defect: the parent drug is rapidly distributed or metabolized in the bloodstream (its metabolites are inactive), leading to a rapid decrease in blood drug concentration, which is detrimental to maintaining a certain blood drug concentration and efficacy. If it is directly dispersed in an oil solvent or in water in the presence of a solubilizer to prepare a conventional formulation for oral administration, it suffers from poor absorption and low bioavailability, with oral bioavailability sometimes falling below 5%. Summary of the Invention

[0009] The purpose of this application is to provide solid dispersions of neuroactive steroids, solid dispersion compositions, preparation methods and applications, and pharmaceuticals containing solid dispersions. The neuroactive steroids in the solid dispersions provided in this application have high oral bioavailability.

[0010] To achieve the above-mentioned objectives, this application provides the following technical solution:

[0011] This application provides a method for preparing a solid dispersion of neuroactive steroids, comprising the following steps:

[0012] The raw material mixture is melt-extruded to obtain the neuroactive steroid solid dispersion;

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

[0014] The temperature of the melt extrusion is <160℃;

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

[0016] Preferably, the neuroactive steroid includes one or more of progesterone, pregnanelonone, brinolone, alfadolone, seclonone, minassolone, ganexolone, and alfasalone.

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

[0018] Preferably, the copovidone comprises PVP / VA64; the acrylic resin is Eudragit RL100; the cellulose derivative comprises one or more of hydroxypropyl methylcellulose, ethylcellulose, and methylcellulose; and the starch derivative comprises cross-linked starch and / or carboxymethyl starch.

[0019] Preferably, the plasticizer includes one or more of polyethylene glycol, poloxamer, and Tween.

[0020] Preferably, the polyethylene glycol includes PEG3350; the poloxamer includes poloxamer 188; and the Tween includes Tween 80.

[0021] Preferably, when the carrier material is lauryl polyethylene glycol glyceride, the raw material mixture is a mixture of brinolone and lauryl polyethylene glycol glyceride, the melt extrusion temperature is 60-80°C, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is 120-200 nm.

[0022] Preferably, the mass ratio of brinolone to lauryl polyethylene glycol glyceride is 10:30 to 60.

[0023] Preferably, when the carrier material is a substance other than lauryl polyethylene glycol glyceride, the melt extrusion temperature is 120-150°C, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is 80-200 nm.

[0024] Preferably, the raw material mixture is a mixture of brinolone, polyethylene glycol and copovidone, wherein the mass ratio of brinolone, polyethylene glycol and copovidone is 10:5 to 15:45 to 85; and the melt extrusion temperature is 125 to 145°C.

[0025] Preferably, the raw material mixture is a mixture of brinolone and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the mass ratio of brinolone to polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 10:30-40; and the melt extrusion temperature is 130-135°C.

[0026] Preferably, the raw material mixture is a mixture of brenolol, plasticizer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the mass ratio of brenolol, plasticizer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 10:5 to 15:45 to 60; and the melt extrusion temperature is preferably 120 to 125°C.

[0027] Preferably, the raw material mixture is a mixture of brinolone, polyethylene glycol and cellulose derivative, wherein the mass ratio of brinolone, polyethylene glycol and cellulose derivative is 10:5 to 15:45 to 55; and the melt extrusion temperature is 140 to 145°C.

[0028] Preferably, the raw material mixture is a mixture of brinolone, polyethylene glycol, copovidone, and cellulose derivative, wherein the mass ratio of brinolone, polyethylene glycol, copovidone, and cellulose derivative is 10:5-15:10-40:10-40; and the melt extrusion temperature is 140-145°C.

[0029] Preferably, the raw material mixture is a mixture of brinolone, polyethylene glycol, copovidone, and acrylic resin, wherein the mass ratio of brinolone, polyethylene glycol, copovidone, and acrylic resin is 10:5-15:30-45:5-30; and the melt extrusion temperature is 140-145°C.

[0030] This application provides a neuroactive steroid solid dispersion prepared by the preparation method described in the above technical solution.

[0031] This application provides a solid dispersion composition comprising, by mass parts:

[0032] The above technical solution comprises 10-100 parts of a neuroactive steroid solid dispersion, 0-50 parts of a sustained-release material, 0-10 parts of a disintegrant, 0-90 parts of a diluent, 0-10 parts of a flow aid, and 0-2 parts of a lubricant, wherein the mass fractions of the sustained-release material, disintegrant, diluent, flow aid, and lubricant are all 0.

[0033] Preferably, the sustained-release material includes one or more of acrylic resin, polyoxyethylene, ethyl cellulose, and hydroxypropyl methylcellulose.

[0034] Preferably, the disintegrant comprises one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone.

[0035] Preferably, the diluent includes one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sodium chloride.

[0036] Preferably, the flow aid comprises colloidal silica.

[0037] Preferably, the lubricant comprises magnesium stearate and / or sodium stearate fumarate.

[0038] Preferably, the neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, and the solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion and a gliding agent, wherein the mass ratio of brinol hot melt extruded solid dispersion to gliding agent is 97:1 to 5.

[0039] Preferably, the neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, and the solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion and diluent, wherein the mass ratio of brinol hot melt extruded solid dispersion to diluent is 10:85-95.

[0040] Preferably, the neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, diluent and gliding agent, and the mass ratio of brinol hot melt extruded solid dispersion, diluent and gliding agent is 50-70:25-50:1-10.

[0041] Preferably, the neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, and the solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, diluent, gliding agent and lubricant, and the mass ratio of brinol hot melt extruded solid dispersion, diluent, gliding agent and lubricant is 30:60-70:3-7:0.5-3.

[0042] Preferably, the neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, and the solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, sustained-release material, diluent, flow aid and lubricant, and the mass ratio of brinol hot melt extruded solid dispersion, sustained-release material, diluent, flow aid and lubricant is 30:35~45:20~30:3~7:0.5~3.

[0043] Preferably, the neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, disintegrant, diluent, gliding agent and lubricant. The mass ratio of brinol hot melt extruded solid dispersion, disintegrant, diluent, gliding agent and lubricant is 20-50:5-10:29-72:2-10:1-2.

[0044] Preferably, the neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, and the solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, sustained-release material, diluent, flow aid and lubricant, and the mass ratio of brinol hot melt extruded solid dispersion, sustained-release material, diluent, flow aid and lubricant is 20-60:20-50:17-37:2.5-5:0.5-1.

[0045] This application provides the use of the neuroactive steroid solid dispersion or the solid dispersion composition described in the above-mentioned technical solutions in the preparation of therapeutic drugs for central nervous system disorders.

[0046] Preferably, the central nervous system disorders include postpartum depression, clinical depression, atypical depression, severe depressive disorder, catatonic depression, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder, manic-depressive disorder, mood disorder, anxiety, post-traumatic stress disorder, premenstrual anxiety disorder, depression due to chronic medical conditions, treatment-resistant depression, suicidal ideation or behavior, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder, and social anxiety disorder. Anxiety disorder, memory loss, poor stress tolerance, Niemann-Pick II type C disease or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, menstrual epilepsy, childhood epilepsy, epileptiform disorder, essential tremor, NMDA insufficiency, Tourette syndrome, migraine, sleep disorder, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease.

[0047] Preferably, the therapeutic drug is an oral medication, and the dosage form of the therapeutic drug includes tablets or capsules.

[0048] This application provides a drug containing a solid dispersion, wherein the raw materials for preparation include the neuroactive steroid solid dispersion or the solid dispersion composition described in the above technical solution.

[0049] This application provides a method for preparing a solid dispersion of neuroactive steroids, comprising the following steps: melt extruding a raw material mixture to obtain the solid dispersion of neuroactive steroids; the raw material mixture comprises, by mass parts, 10-70 parts of neuroactive steroids, 30-90 parts of carrier material, and 0-60 parts of plasticizer; the melt extrusion temperature is <160℃; the neuroactive steroids in the solid dispersion exist in an amorphous state, and the particle size of the neuroactive steroids in the solid dispersion is ≤200nm. The solid dispersion of neuroactive steroids provided by this application, in which the neuroactive steroids exist in an amorphous state (i.e., neuroactive steroid drug molecules are dispersed in the solid dispersion in an amorphous state), and wherein the particle size of the neuroactive steroids is ≤200nm, not only improves the water solubility and permeability of neuroactive steroids, but also significantly improves the oral bioavailability of neuroactive steroids in animals.

[0050] Furthermore, the carrier material described in this application includes one or more of the following: copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glycerol, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polylactic acid, polyhydroxyacetic acid, lactic acid-hydroxyacetic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivatives, starch, and starch derivatives. The carrier material described in the above part of this application is a carrier material with sustained-release effect (hereinafter referred to as sustained-release carrier material), such as acrylic resin, polyoxyethylene, ethyl cellulose, hydroxypropyl methylcellulose, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and ethylene-vinyl acetate copolymer. When the sustained-release carrier material is used to prepare a solid dispersion of neuroactive steroids, it has sustained-release characteristics. When the solid dispersion of neuroactive steroids is further used to prepare oral drugs (such as tablets or capsules), the blood drug concentration after oral administration can be more stable, which is conducive to the maintenance of drug efficacy for a longer period of time, and avoids the phenomenon of central nervous system depression in animals caused by excessively high blood drug concentration. Attached Figure Description

[0051] Figure 1 shows the DSC diagram of brinolone active pharmaceutical ingredient;

[0052] Figure 2 shows the DSC diagram of the blank excipient (PEG3350 to PVP / VA64 mass ratio of 1:5);

[0053] Figure 3 shows the DSC diagram of the physical mixture of Brinolon and excipients (Brinolon, PEG3350 and PVP / VA64 in a mass ratio of 1:1:5).

[0054] Figure 4 shows the DSC diagram of the Brinolon hot melt extruded solid dispersion (Formulation 6);

[0055] Figure 5 shows the DSC diagram of the Brinolon hot melt extruded solid dispersion (Formula 7);

[0056] Figure 6 shows the XRD pattern of brinolone active pharmaceutical ingredient;

[0057] Figure 7 shows the XRD pattern of the blank excipient (PEG3350 to PVP / VA64 mass ratio of 1:5);

[0058] Figure 8 shows the XRD pattern of a physical mixture of brinolone and excipients (brinolone, PEG3350 and PVP / VA64 in a mass ratio of 1:1:5).

[0059] Figure 9 shows the XRD pattern of the Brinolon hot melt extruded solid dispersion (Formula 6);

[0060] Figure 10 shows the XRD pattern of the Brinolon hot melt extruded solid dispersion (Formula 7);

[0061] Figure 11 shows the particle size distribution of the Brinolon hot melt extruded solid dispersion (Formula 7) after being dispersed in water;

[0062] Figure 12 shows the particle size distribution of the Brinolon hot melt extruded solid dispersion (Formula 22) after being dispersed in water;

[0063] Figure 13 shows the pharmacokinetic curves of brinolone hot melt extruded solid dispersions (Formula 6, Formula 7), brinolone hot melt extruded solid dispersion compositions (Composition 1, Composition 13), and brinolone active pharmaceutical ingredient administered orally by gavage.

[0064] Figure 14 shows the pharmacokinetic curve of Brinologne administered via tail vein injection (3 mg / kg);

[0065] Figure 15 shows the pharmacokinetic curves of brinolone nanosuspension and brinolone active pharmaceutical ingredient administered orally by gavage. Detailed Implementation

[0066] This application provides a method for preparing a solid dispersion of neuroactive steroids, comprising the following steps:

[0067] The raw material mixture is melt-extruded to obtain the neuroactive steroid solid dispersion;

[0068] The raw material mixture comprises, by weight, 10-70 parts of neuroactive steroids, 30-90 parts of carrier material, and 0-60 parts of plasticizer;

[0069] The temperature of the melt extrusion is <160℃;

[0070] The neuroactive steroid solid dispersion contains neuroactive steroids in an amorphous state, and the particle size of the neuroactive steroids in the neuroactive steroid solid dispersion is ≤200nm.

[0071] This application first describes the raw material mixture required for preparing the aforementioned neuroactive steroid solid dispersion. In this application, the raw material mixture comprises 10 to 70 parts by mass of a neuroactive steroid, specifically 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 parts. In this application, the neuroactive steroid preferably comprises one or more of progesterone, pregnanedolone, brinolone, alfadolone, seclonone, minassolone, ganexolone, and alfasalone; more preferably, progesterone, pregnanedolone, brinolone, alfadolone, seclonone, minassolone, ganexolone, or alfasalone; and even more preferably, brinolone.

[0072] Based on the mass fraction of the neuroactive steroids, the raw material mixture in this application includes 30 to 90 parts of carrier material, specifically 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 parts. In this application, the carrier material preferably includes copovidone (PVP / VA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), lauryl polyethylene glycol glycerol ester (… 44 / 14), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyoxyethylene (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, specifically copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glycerol, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivatives, starch or starch derivatives, and can also be a mixture of copovidone and cellulose derivatives, or a mixture of copovidone and acrylic resin; the copovidone preferably includes PVP / VA64; the acrylic resin is preferably Eudragit. RL100; the cellulose derivative preferably includes one or more of hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and methylcellulose (MC); the starch derivative preferably includes cross-linked starch and / or carboxymethyl starch. The carrier material described in the above part of this application is a carrier material with sustained-release properties (denoted as sustained-release carrier material), such as acrylic resin, polyoxyethylene, ethylcellulose, hydroxypropyl methylcellulose, copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and ethylene-vinyl acetate copolymer. When the sustained-release carrier material is used to prepare a solid dispersion of neuroactive steroids, it has sustained-release characteristics. When the solid dispersion of neuroactive steroids is further used to prepare oral drugs (such as tablets or capsules), the blood drug concentration after oral administration is more stable, which is beneficial for maintaining the drug effect for a longer time and avoids the central nervous system depression in animals caused by excessively high blood drug concentrations.

[0073] Based on the mass fraction of the neuroactive steroids, the raw material mixture in this application includes 0 to 60 parts of plasticizer, specifically 0.1 parts, 0.5 parts, 1 part, 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 this application, 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; and the Tween preferably includes Tween 80.

[0074] This application involves melt extruding a mixture of raw materials to obtain the neuroactive steroid solid dispersion. Preferably, this application selects a suitable method based on the type of carrier material to prepare the neuroactive steroid solid dispersion, which will be described in detail below.

[0075] In this application, when the carrier material is lauryl polyethylene glycol glyceride, the method for preparing the neuroactive steroid solid dispersion preferably includes the following steps:

[0076] The raw material mixture is melt-extruded and then sieved while hot to obtain the neuroactive steroid solid dispersion.

[0077] In this application, lauryl polyethylene glycol glycerol ester in the raw material mixture is preferably present in the form of a molten liquid, which is preferably obtained by heating and melting lauryl polyethylene glycol glycerol ester. The heating and melting temperature is preferably 60-90°C, specifically 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, or 90°C. The brenone is preferably pulverized and sieved sequentially before use, and the mesh size of the sieve used for sieving is preferably 100-200 mesh. When the carrier material is lauryl polyethylene glycol glycerol ester, the raw material mixture is preferably a mixture of brenone and lauryl polyethylene glycol glycerol ester, i.e., without the addition of plasticizers. In this application, the melt extrusion temperature is preferably <160°C, more preferably 60-80°C, specifically 60°C, 65°C, 70°C, 75°C, or 80°C. In the embodiments of this application, the melt extrusion is preferably carried out in a twin-screw hot melt extruder (with the discharge die removed). In this application, the mesh size of the sieve used for hot sieving is preferably 20 to 80 mesh.

[0078] In this application, when preparing a neuroactive steroid solid dispersion using lauryl polyethylene glycol glyceride as a carrier material, the neuroactive steroid solid dispersion obtained after melt extrusion from a twin-screw hot melt extruder is a milky white granular substance, 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, specifically 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm or 200nm.

[0079] In this application, when the carrier material is a substance other than lauryl polyethylene glycol glyceride, the method for preparing the neuroactive steroid solid dispersion preferably includes the following steps:

[0080] The raw material mixture is melt-extruded and then cooled, cut, crushed and sieved in sequence to obtain the neuroactive steroid solid dispersion.

[0081] In this application, each component in the raw material mixture is preferably crushed and sieved sequentially before use. The mesh size 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℃, more preferably 120-150℃, specifically 120℃, 125℃, 130℃, 135℃, 140℃, 145℃, or 150℃. In the embodiments of this application, the melt extrusion is preferably carried out in a twin-screw hot melt extruder. After the melt extrusion, a strip-shaped extrudate is preferably obtained, which is then cooled and sequentially cut, crushed, and sieved. In the embodiments of this application, the cutting equipment is preferably a pelletizer; the mesh size of the sieve used for sieving is preferably 20-80 mesh, specifically 20 mesh, 40 mesh, or 80 mesh.

[0082] In this application, when preparing a neuroactive steroid solid dispersion using a carrier material other than lauryl polyethylene glycol glyceride, the extrudate obtained after melt extrusion from a twin-screw hot melt extruder is in the form of transparent strips. After cutting, crushing, and sieving, a white granular or powdery neuroactive steroid solid dispersion is obtained. The neuroactive steroid exists in an amorphous state. The particle size of the neuroactive steroid in the solid dispersion is ≤200nm, preferably 80-200nm, specifically 80nm, 90nm, 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm, or 200nm.

[0083] In this application, when the neuroactive steroid is brinolone, the prepared neuroactive steroid solid dispersion is a brinolone hot melt extruded solid dispersion; the following describes the brinolone hot melt extruded solid dispersion in this application in detail, taking brinolone as an example.

[0084] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolone, polyethylene glycol, and copovidone, wherein the polyethylene glycol is preferably PEG3350, and the copovidone is preferably PVP / VA64; the mass ratio of brinolone, polyethylene glycol, and copovidone is preferably 10:5 to 15:45 to 85, more preferably 10:10:50 to 80; the melt extrusion temperature is preferably 125 to 145°C, more preferably 130 to 140°C; the extrudate obtained after melt extrusion is transparent strip-shaped, wherein the brinolone exists in an amorphous state, and the particle size of the brinolone in the brinolone hot melt extruded solid dispersion is 80 to 120 nm.

[0085] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolone and Soluplus, and the mass ratio of brinolone to Soluplus is preferably 10:30 to 40; the melt extrusion temperature is preferably 130 to 135°C; the extrudate obtained after melt extrusion is transparent strip in appearance, wherein brinolone exists in an amorphous state, and the particle size of brinolone in the brinolone hot melt extruded solid dispersion is 80 to 120 nm.

[0086] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolone and Soluplus, and the mass ratio of brinolone to Soluplus is preferably 10:45 to 85, more preferably 10:50 to 80; the melt extrusion temperature is preferably 120 to 125°C; the extrudate obtained after melt extrusion is transparent strip in appearance, wherein brinolone exists in an amorphous state, and the particle size of brinolone in the brinolone hot melt extruded solid dispersion is 80 to 120 nm.

[0087] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolone, plasticizer, and Soluplus, wherein the plasticizer is preferably polyethylene glycol or Tween, wherein the polyethylene glycol is preferably PEG3350, and the Tween is preferably Tween 80; the mass ratio of brinolone, plasticizer, and Soluplus is preferably 10:5 to 15:45 to 60, more preferably 10:10:50 to 55; the melt extrusion temperature is preferably 120 to 125°C; the extrudate obtained after melt extrusion is transparent strip in appearance, wherein the brinolone exists in an amorphous state, and the particle size of brinolone in the brinolone hot melt extruded solid dispersion is 80 to 120 nm.

[0088] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolone, polyethylene glycol, and cellulose derivative, wherein the polyethylene glycol is preferably PEG3350, and the cellulose derivative is preferably HPMC; the mass ratio of brinolone, polyethylene glycol, and cellulose derivative is preferably 10:5 to 15:45 to 55, more preferably 10:10:50; the melt extrusion temperature is preferably 140 to 145°C; the extrudate obtained after melt extrusion is transparent strip-shaped, wherein the brinolone exists in an amorphous state, and the particle size of the brinolone in the brinolone hot melt extruded solid dispersion is 80 to 120 nm.

[0089] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolone, polyethylene glycol, copovidone, and cellulose derivative, wherein the polyethylene glycol is preferably PEG3350, the copovidone is preferably PVP / VA64, and the cellulose derivative is preferably HPMC; the mass ratio of brinolone, polyethylene glycol, copovidone, and cellulose derivative is preferably 10:5~15:10~40:10~40, more preferably 10:10:20~25:25~40; the melt extrusion temperature is preferably 140~145℃; the extrudate obtained after melt extrusion is transparent strip-shaped, wherein the brinolone exists in an amorphous state, and the particle size of the brinolone in the brinolone hot melt extruded solid dispersion is 80~120nm.

[0090] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolone, polyethylene glycol, copovidone, and acrylic resin, wherein the polyethylene glycol is preferably PEG3350, the copovidone is preferably PVP / VA64, and the acrylic resin is preferably Eudragit RL100; the mass ratio of brinolone, polyethylene glycol, copovidone, and acrylic resin is preferably 10:5~15:30~45:5~30, more preferably 10:10:25~40:10~25; the melt extrusion temperature is preferably 140~145℃; the extrudate obtained after melt extrusion is transparent strip in appearance, wherein the brinolone exists in an amorphous state, and the particle size of brinolone in the brinolone hot melt extruded solid dispersion is 80~120nm.

[0091] In the embodiments of this application, the raw material mixture is preferably a mixture of brinolon and... A mixture of 44 / 14, wherein the brinolone and The preferred mass ratio of 44 / 14 is 10:30 to 60, and the preferred temperature for melt extrusion is 60 to 80°C. The Brinolon hot melt extruded solid dispersion has a milky white granular appearance, with Brinolon existing in an amorphous state. The particle size of Brinolon in the Brinolon hot melt extruded solid dispersion is 120 to 200 nm.

[0092] This application provides a neuroactive steroid solid dispersion prepared by the preparation method described in the above technical solution.

[0093] This application provides a solid dispersion composition comprising, by mass parts:

[0094] The above technical solution comprises 10-100 parts of a neuroactive steroid solid dispersion, 0-50 parts of a sustained-release material, 0-10 parts of a disintegrant, 0-90 parts of a diluent, 0-10 parts of a flow aid, and 0-2 parts of a lubricant, wherein the mass fractions of the sustained-release material, disintegrant, diluent, flow aid, and lubricant are all 0.

[0095] Based on parts by weight, the solid dispersion composition described in this application comprises 10 to 100 parts of a neuroactive steroid solid dispersion, specifically 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, or 100 parts.

[0096] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of this application comprises 0 to 50 parts of a sustained-release material, specifically 0.1 parts, 0.5 parts, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, or 50 parts. In this application, the sustained-release material preferably comprises 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 this application, 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 can be 0 or not 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 can be 0 or not 0, preferably not 0 (i.e., sustained-release material is added). Adding sustained-release material to the solid dispersion composition of this application (especially when the carrier material used in preparing the neuroactive steroid solid dispersion does not include a sustained-release carrier material), and further utilizing the solid dispersion composition to prepare oral drugs (such as tablets or capsules), can result in a more stable blood drug concentration after oral administration, which is beneficial for maintaining the drug effect for a longer period of time and avoids central nervous system depression in animals caused by excessively high blood drug concentrations.

[0097] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of this application includes 0 to 10 parts of disintegrant, specifically 0.1 parts, 0.5 parts, 1 part, 3 parts, 5 parts, 8 parts, or 10 parts. In this application, the disintegrant preferably includes one or more of low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl starch (CMS-Na), and crospovidone (PVPP), more preferably low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, or crospovidone.

[0098] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of this application includes 0 to 90 parts of diluent, specifically 0.1 parts, 0.5 parts, 1 part, 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 this application, 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.

[0099] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of this application includes 0 to 10 parts of a flow aid, specifically 0.1 parts, 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, or 10 parts. In this application, the flow aid preferably includes colloidal silica.

[0100] Based on the mass fraction of the neuroactive steroid solid dispersion, the solid dispersion composition of this application includes 0 to 2 parts of lubricant, specifically 0.1 parts, 0.3 parts, 0.5 parts, 0.8 parts, 1 part, 1.3 parts, 1.5 parts, 1.8 parts, or 2 parts. In this application, the lubricant preferably includes magnesium stearate and / or sodium stearate fumarate, more preferably magnesium stearate.

[0101] In this application, when the neuroactive steroid is brinolone, the prepared neuroactive steroid solid dispersion is a brinolone hot melt extruded solid dispersion; the following describes in detail the solid dispersion composition prepared based on the brinolone hot melt extruded solid dispersion in this application, taking brinolone as an example.

[0102] In the embodiments of this application, the solid dispersion composition is preferably a mixture of a brinolon hot melt extruded solid dispersion and a flow aid, wherein the flow aid is preferably colloidal silica; the mass ratio of the brinolon hot melt extruded solid dispersion to the flow aid is preferably 97:1 to 5, more preferably 97:3.

[0103] In the embodiments of this application, the solid dispersion composition is preferably a mixture of a brinolone hot melt extruded solid dispersion and a diluent, wherein the diluent is preferably lactose; the mass ratio of the brinolone hot melt extruded solid dispersion to the diluent is preferably 10:85 to 95, more preferably 10:90.

[0104] In the embodiments of this application, the solid dispersion composition is preferably a mixture of a brenolol hot melt extruded solid dispersion, a diluent, and a flow aid. The diluent is preferably lactose or MCC, and the flow aid is preferably colloidal silica. The mass ratio of the brenolol hot melt extruded solid dispersion, the diluent, and the flow aid is preferably 50-70:25-50:1-10, more preferably 50-70:27-45:3-5.

[0105] In the embodiments of this application, the solid dispersion composition is preferably a mixture of a brinolone hot melt extruded solid dispersion, a diluent, a flow aid, and a lubricant. The diluent is preferably MCC, the flow aid is preferably colloidal silica, and the lubricant is preferably magnesium stearate. The mass ratio of the brinolone hot melt extruded solid dispersion, diluent, flow aid, and lubricant is preferably 30:60-70:3-7:0.5-3, and more preferably 30:64:5:1.

[0106] In the embodiments of this application, the solid dispersion composition is preferably a mixture of a brinolone hot melt extruded solid dispersion, a slow-release material, a diluent, a flow aid, and a lubricant. The slow-release material is preferably HPMC, the diluent is preferably anhydrous calcium hydrogen phosphate, the flow aid is preferably colloidal silica, and the lubricant is preferably magnesium stearate. The mass ratio of the brinolone hot melt extruded solid dispersion, the slow-release material, the diluent, the flow aid, and the lubricant is preferably 30:35-45:20-30:3-7:0.5-3, and more preferably 30:40:24:5:1.

[0107] In the embodiments of this application, the solid dispersion composition is preferably a mixture of a brinolone hot melt extruded solid dispersion, a disintegrant, a diluent, a flow aid, 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 flow aid is preferably colloidal silica; and the lubricant is preferably magnesium stearate. The mass ratio of the brinolone hot melt extruded solid dispersion, disintegrant, diluent, flow aid, 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.

[0108] In the embodiments of this application, the solid dispersion composition is preferably a mixture of a brinolone hot melt extruded solid dispersion, a slow-release material, a diluent, a flow aid, and a lubricant. The slow-release material is preferably Eudragit RL100, HPMC, EC, or PEO. The diluent is preferably MCC or anhydrous dicalcium phosphate. The flow aid is preferably colloidal silica. The lubricant is preferably magnesium stearate. The mass ratio of the brinolone hot melt extruded solid dispersion, the slow-release material, the diluent, the flow aid, and the lubricant is preferably 20–60:20–50:17–37:2.5–5:0.5–1, more preferably 20–30:30–50:24–34:2.5–5:0.5–1.

[0109] This application provides the use of the neuroactive steroid solid dispersion or the solid dispersion composition described in the above-mentioned technical solutions in the preparation of therapeutic drugs for central nervous system disorders.

[0110] In this application, the central nervous system disorders preferably include postpartum depression, clinical depression, atypical depression, severe depressive disorder, catatonic depression, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder, manic-depressive disorder, mood disorder, anxiety, post-traumatic stress disorder, premenstrual anxiety disorder, depression due to chronic medical conditions, intractable depression, suicidal ideation or behavior, premenstrual syndrome, generalized anxiety disorder, and seasonal affective disorder. Social anxiety disorder, memory loss, poor stress tolerance, Niemann-Pick II type C disease or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, menstrual epilepsy, childhood epilepsy, epileptiform disorder, essential tremor, NMDA insufficiency, Tourette syndrome, migraine, sleep disorder, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease.

[0111] In this application, the therapeutic drug is preferably an oral drug, and the dosage form of the therapeutic drug preferably includes tablets or capsules.

[0112] In this application, the method for preparing the tablet preferably includes the following steps: mixing a neuroactive steroid solid dispersion with excipients (the excipients being one or more of sustained-release materials, disintegrants, diluents, glidants, and lubricants) and then compressing the mixture to obtain a plain tablet; coating the plain tablet with a gastric-soluble coating premix to obtain the tablet (specifically, a film-coated tablet).

[0113] In this application, the preferred method for preparing the capsule formulation includes the following steps: filling a neuroactive steroid solid dispersion into an empty hard capsule to obtain the capsule formulation; or mixing a neuroactive steroid solid dispersion with excipients (the excipients being one or more of sustained-release materials, disintegrants, diluents, glidants, and lubricants) and then filling the mixture into an empty hard capsule to obtain the capsule formulation. In this application, the empty hard capsule is preferably a gelatin empty hard capsule.

[0114] This application provides a drug containing a solid dispersion, the raw materials of which include the neuroactive steroid solid dispersion or the solid dispersion composition described in the above-mentioned technical solutions. As one embodiment of this application, the drug containing a solid dispersion can specifically be a therapeutic drug for central nervous system disorders as described in the above-mentioned technical solutions.

[0115] The technical solutions of this application will be clearly and completely described below with reference to the embodiments therein. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.

[0116] Examples 1-4 and Comparative Examples 1-8

[0117] Using copovidone (PVP / VA64) as the carrier material and polyethylene glycol (PEG3350) as the plasticizer, a brinolon hot melt extrusion solid dispersion was prepared. The steps are as follows:

[0118] Brinolon, carrier material PVP / VA64 and plasticizer PEG3350 were pulverized separately and passed through a 100-mesh sieve. The sieve-passing material was collected and mixed to obtain a mixture.

[0119] Set the extrusion temperature of the twin-screw hot melt extruder. After the temperature reaches the set value and stabilizes, add the mixture into the twin-screw hot melt extruder through the feed inlet for melt extrusion to obtain strip-shaped extrudate. After cooling, the extrudate is cut by a pelletizer, then crushed by a pulverizer and passed through an 80-mesh sieve. The material passing through the sieve is a powdered Brinolon hot melt extruded solid dispersion.

[0120] Table 1 shows the raw material ratios, melt extrusion temperatures, and extrudate properties for each formulation. As shown in Table 1, when preparing a Brenolone hot-melt extruded solid dispersion using PVP / VA64 as the carrier material, without the addition of a plasticizer, a transparent and uniform strip extrudate could not be obtained at an extrusion temperature of 150℃. However, with the addition of the plasticizer PEG3350, a transparent and uniform strip extrudate could be obtained at an extrusion temperature of 130℃. This indicates that the addition of the plasticizer PEG3350 can significantly reduce the melt temperature of the Brenolone / PVP / VA64 mixture. Comparing formulations 4 and 10, it can be seen that even with an increase in the amount of PVP / VA64, the melt temperature of the Brenolone / PVP / VA64 mixture cannot be significantly reduced without the addition of a plasticizer. Table 1 also shows that extrusion temperature has a significant impact on the properties of the extrudate. As the extrusion temperature increases, the mixture is in a fully molten state, which is beneficial for Brenolone to be in an amorphous state in the solid dispersion; however, the increase in temperature is not conducive to the chemical stability of Brenolone.

[0121] Table 1. Raw material ratios, melt extrusion temperatures, and extrudate properties for formulations 1-12

[0122] *Extrudate refers to a solid dispersion extruded from a twin-screw hot melt extruder without further cutting or pulverizing. All extrudates in this experiment were in strip form, and the "Extrudate Properties" section only describes whether the strip is transparent, translucent, or opaque.

[0123] Test Example 1: Characterization of the properties of the Brinolon hot melt extruded solid dispersion

[0124] In this test example, differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) were used to determine the presence state of brinolone in the brinolone hot-melt extruded solid dispersion. High-performance liquid chromatography (HPLC) was then used to detect related substances to investigate the stability of brinolone during the preparation of the brinolone hot-melt extruded solid dispersion. Details are as follows:

[0125] 1. Differential scanning calorimetry detection

[0126] The brenlon hot-melt extruded solid dispersions prepared from each formulation in Table 1, as well as brenlon active pharmaceutical ingredient, blank excipients (PEG3350 and PVP / VA64 mass ratio of 1:5), and physical mixtures of brenlon and excipients (brinolon, PEG3350 and PVP / VA64 mass ratio of 1:1:5) were used as test samples. The thermal phase transition behavior of the above test samples was investigated using differential scanning calorimetry (DSC) with a thermal analyzer.

[0127] The results showed that the DSC spectrum of brinolone active pharmaceutical ingredient (API) exhibited a sharp endothermic peak near 177℃ (melting point), indicating that brinolone API was in a crystalline state. The blank excipient showed no characteristic endothermic or exothermic peaks, indicating that it existed in an amorphous state. In the DSC spectrum of transparent brinolone hot-melt extruded solid dispersions, the characteristic endothermic peak of brinolone completely disappeared, suggesting that brinolone in these dispersions had completely transformed into an amorphous state. However, in the DSC spectra of physical mixtures of brinolone and blank excipients, as well as opaque and translucent brinolone hot-melt extruded solid dispersions, the characteristic endothermic peak of brinolone (near 177℃) also disappeared or was almost invisible. This may be due to the low proportion of brinolone in the mixture and insufficient DSC detection sensitivity; it may also be due to the thermal phase change behavior of the excipient components affecting the detection of the endothermic peak of brinolone. Representative DSC diagrams are shown in Figures 1 to 5. Specifically, Figure 1 is the DSC diagram of brinolone active pharmaceutical ingredient, Figure 2 is the DSC diagram of blank excipient (PEG3350 and PVP / VA64 mass ratio of 1:5), Figure 3 is the DSC diagram of physical mixture of brinolone and excipient (brinolone, PEG3350 and PVP / VA64 mass ratio of 1:1:5), Figure 4 is the DSC diagram of brinolone hot melt extruded solid dispersion (Formula 6), and Figure 5 is the DSC diagram of brinolone hot melt extruded solid dispersion (Formula 7).

[0128] 2. Powder X-ray diffraction (XRD) detection

[0129] The brenlon hot-melt extruded solid dispersions prepared from each formulation in Table 1, as well as the brenlon active pharmaceutical ingredient, blank excipients (PEG3350 and PVP / VA64 in a mass ratio of 1:5), and physical mixtures of brenlon and blank excipients (brinolon, PEG3350 and PVP / VA64 in a mass ratio of 1:1:5) were used as test samples. The crystallinity of the above test samples was further studied by powder X-ray diffraction.

[0130] The results showed that the XRD patterns of brinolone active pharmaceutical ingredient (API) and the physical mixture of brinolone and blank excipient both had abundant characteristic peaks, and the peak positions in the XRD patterns of the two samples were basically consistent. The XRD pattern of the blank excipient had no characteristic peaks, further proving that brinolone API is in a crystalline state and that the physical mixing of brinolone and blank excipient does not change its crystalline state. The XRD patterns of opaque or translucent brinolone hot-melt extruded solid dispersions (such as the translucent brinolone hot-melt extruded solid dispersion obtained from Formulation 6) still showed obvious characteristic peaks of brinolone API, but the peak intensity was lower than that in the physical mixture of brinolone and blank excipient. This indicates that in these brinolone hot-melt extruded solid dispersions, some brinolone was transformed into an amorphous state, while some remained in a crystalline state. The transparent brenolone hot-melt extruded solid dispersion (such as the brenolone hot-melt extruded solid dispersion prepared by Formulation 7) showed complete disappearance of its characteristic peaks in its XRD pattern, indicating that the brenolone was completely transformed into an amorphous state. The amorphous state of brenolone is expected to significantly improve the oral bioavailability of brenolone. Representative XRD patterns are shown in Figures 6 to 10. Specifically, Figure 6 is the XRD pattern of brenolone active pharmaceutical ingredient, Figure 7 is the XRD pattern of blank excipient (PEG3350 and PVP / VA64 mass ratio of 1:5), Figure 8 is the XRD pattern of the physical mixture of brenolone and excipient (brinolone, PEG3350 and PVP / VA64 mass ratio of 1:1:5), Figure 9 is the XRD pattern of brenolone hot-melt extruded solid dispersion (Formulation 6), and Figure 10 is the XRD pattern of brenolone hot-melt extruded solid dispersion (Formulation 7).

[0131] 3. Particle size detection

[0132] The brenone hot-melt extruded solid dispersions prepared according to each formulation were mixed with water at a mass ratio of 1:1000. Transparent brenone hot-melt extruded solid dispersions dissolved relatively quickly, forming a pale blue, milky, homogeneous liquid. Opaque or translucent brenone hot-melt extruded solid dispersions dissolved more slowly, forming a pale blue, milky, homogeneous liquid, or a milky white, homogeneous liquid. Particle size was measured using a nanolaser particle size analyzer. The results showed that the particle size of the transparent solid dispersions was in the range of 80–200 nm; while the particle size of the opaque or translucent solid dispersions was higher than 500 nm, even reaching over 1000 nm (i.e., 1 μm), and was no longer a nano-dispersion system. Specific test results are shown in Table 2. A representative particle size distribution is shown in Figure 11. Figure 11 shows the particle size distribution of the brinnolon hot-melt extruded solid dispersion (Formula 7) after being dispersed in water. The Z-average particle size is 86.71 nm, and the PDI is 0.255. The nanoscale size is expected to significantly improve the oral bioavailability of brinnolon.

[0133] 4. Related substance testing

[0134] The brenolol hot-melt extruded solid dispersions prepared from each formulation, as well as the brenolol active pharmaceutical ingredient (API), were analyzed for related substances using high-performance liquid chromatography (HPLC). The total impurity content in the brenolol API was 0.019%. The results of the total impurity content in the brenolol hot-melt extruded solid dispersions prepared by each treatment are shown in Table 2. Table 2 shows that the total impurity content in the brenolol hot-melt extruded solid dispersions gradually increases with increasing extrusion temperature. According to the proposed quality standard, the total impurity content in the formulation should not exceed 0.5%. When the extrusion temperature exceeds 150℃, the total impurity content increases significantly; while at an extrusion temperature of 160℃, the total impurity content is 1.067%, far exceeding the 0.5% limit. Therefore, suitable carrier materials and plasticizers should be selected to control the extrusion temperature during the preparation of brenolol solid dispersions below 160℃, preferably at or below 150℃.

[0135] Table 2 Melt extrusion temperature and product specifications for formulations 1-12

[0136] *Extrudate refers to a solid dispersion extruded from a twin-screw hot melt extruder without further cutting or pulverizing. In this experiment, all extrudates were in strip form, and the "Extrudate Properties" section only describes whether the strip is transparent, translucent, or opaque.

[0137] Example 5 and Comparative Examples 9-12

[0138] Using copovidone (PVP / VA64) as the carrier material and poloxamer 188 as the plasticizer, a brinolon hot melt extrusion solid dispersion was prepared, and the steps are as follows:

[0139] Brinolan, carrier material PVP / VA64 and plasticizer poloxamer 188 were pulverized separately and passed through a 120-mesh sieve. The sieve-passing material was collected and mixed to obtain a mixture.

[0140] Set the extrusion temperature of the twin-screw hot melt extruder. After the temperature rises to the set value and stabilizes, add the mixture into the twin-screw hot melt extruder through the feed port for melt extrusion to obtain strip-shaped extrudate. After cooling, the extrudate is cut by a pelletizer, then crushed by a pulverizer and passed through a 20-mesh sieve. The material passing through the sieve is granular Brinolon hot melt extruded solid dispersion.

[0141] Table 3 shows the raw material ratios, melt extrusion temperatures, and product specifications for each formulation. As shown in Table 3, when using PVP / VA64 as the carrier material to prepare a Brenolone hot-melt extruded solid dispersion, even with a PVP / VA64 to Brenolone mass ratio of 8:1 and an extrusion temperature of 150°C, poloxamer 188 as the plasticizer, a transparent strip-shaped extrudate still could not be formed. Compared to the results in the examples above where PEG3350 was used as the plasticizer, this indicates that in the Brenolone and PVP / VA64 mixture system, using PEG3350 as the plasticizer is more effective than using poloxamer 188 in reducing the system's melt temperature.

[0142] Table 3 shows the raw material ratios, melt extrusion temperatures, and product specifications for formulas 13-17.

[0143] *Extrudate refers to a solid dispersion extruded from a twin-screw hot melt extruder without further cutting or pulverizing. In this experiment, all extrudates were in strip form, and the "Extrudate Properties" section only describes whether the strip is transparent, translucent, or opaque.

[0144] Examples 6-10 and Comparative Examples 13-14

[0145] Using polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) as the carrier material, and polyethylene glycol (PEG3350), poloxamer 188, and Tween 80 as plasticizers, a brinolon hot melt extrusion solid dispersion was prepared, with the following steps:

[0146] Brinolan, Soluplus carrier material and plasticizer were pulverized separately and passed through an 80-mesh sieve. The sieve-passing material was collected and mixed to obtain a mixture.

[0147] Set the extrusion temperature of the twin-screw hot melt extruder. After the temperature reaches the set value and stabilizes, add the mixture into the twin-screw hot melt extruder through the feed inlet for melt extrusion to obtain strip-shaped extrudate. After cooling, the extrudate is cut by a pelletizer, then crushed by a pulverizer and passed through an 80-mesh sieve. The material passing through the sieve is a powdered Brinolon hot melt extruded solid dispersion.

[0148] Table 4 shows the raw material ratios, melt extrusion temperatures, and product specifications for each formulation. As shown in Table 4, when using Soluplus as the carrier material to prepare the Brenolone hot-melt extruded solid dispersion, a transparent strip extrudate can be formed at an extrusion temperature of 130℃ when the mass ratio of Soluplus to Brenolone is 3:1 and no plasticizer is added; while when the mass ratio of Soluplus to Brenolone is 5:1 and no plasticizer is added, a transparent strip extrudate can be formed at an extrusion temperature of 120℃. This indicates that increasing the amount of Soluplus can lower the melt temperature of the mixture. Adding plasticizers PEG3350 or Tween 80 to the Brenolone and Soluplus mixture has no significant effect on the properties of the extrudate; however, adding the plasticizer poloxamer 188 has an adverse effect on the properties of the extrudate.

[0149] Table 4. Raw material ratios, melt extrusion temperatures, and product specifications for formulas 18-24

[0150] *Extrudate refers to a solid dispersion extruded from a twin-screw hot melt extruder without further cutting or pulverizing. In this experiment, all extrudates were in strip form, and the "Extrudate Properties" section only describes whether the strip is transparent, translucent, or opaque.

[0151] Figure 12 shows the particle size distribution of the Brinolon hot melt extruded solid dispersion (Formula 22) after being dispersed in water. The Z-average particle size is 99.59 nm and the PDI is 0.222.

[0152] Examples 11-16

[0153] Using water-soluble carrier copovidone (PVP / VA64) and / or hydrophilic carrier hydroxypropyl methylcellulose (HPMC) as carrier materials, and polyethylene glycol (PEG3350) as plasticizer, a brinellon hot melt extrusion solid dispersion was prepared, with the following steps:

[0154] Brinolan, carrier material and plasticizer are pulverized separately and passed through a 120-mesh sieve. The sieve-passing material is then mixed to obtain a mixture.

[0155] The extrusion temperature of the twin-screw hot melt extruder is set to 140℃. After the temperature reaches the set value and stabilizes, the mixture is added into the twin-screw hot melt extruder through the feed inlet for melt extrusion to obtain strip-shaped extrudate. The extrudate is cooled and then cut into pieces by a pelletizer, then crushed by a pulverizer and passed through an 80-mesh sieve. The material passing through the sieve is a powdered Brinolon hot melt extruded solid dispersion.

[0156] Table 5 shows the raw material ratios and product specifications for formulations 25-30. As shown in Table 5, when using PVP / VA64 and HPMC as carrier materials, PEG3350 as plasticizer, and an extrusion temperature of 140℃ to prepare Brenolone hot-melt extruded solid dispersions, various ratios of PVP / VA64 and HPMC as carrier materials can all form transparent, uniform strip-shaped extrudates.

[0157] Table 5. Raw material ratios and product indicators for prescriptions 25-30

[0158] *Extrudate refers to a solid dispersion extruded from a twin-screw hot melt extruder without further cutting or pulverizing. In this experiment, all extrudates were in strip form, and the "Extrudate Properties" section only describes whether the strip is transparent, translucent, or opaque.

[0159] Examples 17-18 and Comparative Examples 15-16

[0160] Using water-soluble carrier copovidone (PVP / VA64) and water-insoluble carrier Eudragit (Eudragit RL100) as carrier materials, and polyethylene glycol (PEG3350) as plasticizer, a brinellon hot melt extrusion solid dispersion was prepared. The steps are as follows:

[0161] Brinolan, carrier material and plasticizer are pulverized separately and passed through a 100-mesh sieve. The sieve-passing material is then mixed to obtain a mixture.

[0162] The extrusion temperature of the twin-screw hot melt extruder is set to 140℃. After the temperature reaches the set value and stabilizes, the mixture is added into the twin-screw hot melt extruder through the feed inlet for melt extrusion to obtain strip-shaped extrudate. The extrudate is cooled and then cut into pieces by a pelletizer, then crushed by a pulverizer and passed through a 40-mesh sieve. The material passing through the sieve is granular Brinolon hot melt extruded solid dispersion.

[0163] Table 6 shows the raw material ratios and product specifications for formulations 31-34. As shown in Table 6, when using PVP / VA64 and Eudragit RL100 as carrier materials, PEG3350 as plasticizer, and an extrusion temperature of 140℃ to prepare the Brinolon hot-melt extruded solid dispersion, a transparent and uniform strip-shaped extrudate can be formed when the mass ratio of Eudragit RL100 to PVP / VA64 is ≤1.

[0164] Table 6. Raw material ratios and product indicators of prescriptions 31-34

[0165] *Extrudate refers to a solid dispersion extruded from a twin-screw hot melt extruder without further cutting or pulverizing. In this experiment, all extrudates were in strip form, and the "Extrudate Properties" section only describes whether the strip is transparent, translucent, or opaque.

[0166] Examples 19-23

[0167] With lauryl polyethylene glycol glyceride ( Using 44 / 14) as the carrier material, a brinolon hot-melt extruded solid dispersion was prepared, and the steps are as follows:

[0168] Brinolon was pulverized and passed through a 200-mesh sieve; the material passing through the sieve was collected to obtain Brinolon powder. The carrier material was then... 44 / 14 is melted at 80°C, and the resulting melt is mixed with the branolone powder to obtain a suspension;

[0169] Set the extrusion temperature of the twin-screw hot melt extruder. After the temperature rises to the set value and stabilizes, add the suspension into the twin-screw hot melt extruder through the feed port for melt extrusion (remove the discharge port mold). Pass the resulting granular extrudate through a 20-mesh sieve while it is still hot. The material passing through the sieve is granular Brinolon hot melt extruded solid dispersion.

[0170] Table 7 shows the raw material ratios, melt extrusion temperatures, and product specifications for formulas 35-39. As can be seen from Table 7, with... When using 44 / 14 as the carrier material and extruding at a temperature of 60–80°C to prepare a Brenolar hot-melt extruded solid dispersion, the resulting solid dispersion extrudate is milky white granules. After dispersing with water, the particle size is in the range of 120–200 nm, which increases with increasing extrusion temperature and... As the 44 / 14 ratio increases, the particle size tends to decrease.

[0171] Table 7. Raw material ratios, melt extrusion temperatures, and product specifications for formulas 35-39

[0172] *Extrudate refers to a solid dispersion extruded from a twin-screw hot melt extruder and not further sieved while still hot. In this experiment, all extrudates were granular, and the "Extrudate Properties" section only describes the granules as milky white.

[0173] Example 24

[0174] A brenolol hot melt extruded solid dispersion (specifically, formulations 7, 22, 25, 27, or 33) is mixed with excipients (specifically, at least one of sustained-release materials, disintegrants, diluents, glidants, and lubricants) to obtain a mixture; the mixture is compressed into tablets to obtain uncoated tablets, and then coated with a gastrointestinal-soluble coating premix to obtain film-coated tablets; or the mixture is filled into gelatin empty hard capsules to obtain capsules.

[0175] The brenolol hot melt extruded solid dispersion (specifically Formula 38) was directly filled into gelatin hollow hard capsules to obtain capsules.

[0176] Table 8 shows the raw material ratios for different dosage forms; in Table 8, API-SD represents Brinolon hot melt extruded solid dispersion, SiO2 represents colloidal silica, dicalcium phosphate represents anhydrous dicalcium phosphate, SSF represents sodium stearate fumarate, and RL100 represents Eudragit RL100.

[0177] Table 8 Raw material ratios (wt%) for different dosage forms

[0178] Test Example 2: Pharmacokinetic Study of Brenolone Hot Melt Extruded Solid Dispersion and Brenolone Hot Melt Extruded Solid Dispersion Composition After Oral Gavage Administration

[0179] To investigate the improvement in oral absorption and bioavailability of the brinol thermally extruded solid dispersion and brinolon thermally extruded solid dispersion compositions in animals, representative brinolon thermally extruded solid dispersions (Formula 6 and Formula 7) and brinolon thermally extruded solid dispersion compositions (Composition 1 and Composition 13) were selected and administered via oral gavage to female SD rats for pharmacokinetic studies. The brinolon active pharmaceutical ingredient (suspended in 0.5 wt% CMC-Na solution, with a brinolon concentration of 5 mg / mL) was used as a control.

[0180] 1. Test drug:

[0181] Solid dispersions (Formulas 6 and 7, both of which are powders obtained by cutting and crushing strip extruders and passing them through an 80-mesh sieve): Take the two powders respectively and disperse them fully in 0.5wt% CMC-Na solution to prepare a suspension with a brinolone concentration of 2.5mg / mL.

[0182] Composition 1 and Composition 13 (both capsules): Take the contents of the two capsules respectively, and disperse them thoroughly with 0.5wt% CMC-Na solution to prepare a suspension with a brinolone concentration of 2.5mg / mL;

[0183] Brinolon raw material: It is fully dispersed in 0.5wt% CMC-Na solution to prepare a suspension with a Brinolon concentration of 5.0 mg / mL.

[0184] 2. Experimental animals:

[0185] Female SD rats, weighing 200–220 g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0186] 3. Test methods:

[0187] Thirty female SD rats were randomly divided into six groups of five each: Brinolone raw material group (50 mg / kg), Formulation 6 group (25 mg / kg), Formulation 7 group (25 mg / kg), Low-dose group of Composition 1 (25 mg / kg), High-dose group of Composition 1 (50 mg / kg), and Composition 13 group (25 mg / kg). All animals were administered the designed doses orally via gavage. Blood samples were collected from the orbital venous plexus at 0 time, and at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h post-administration. After heparin-anticoagulated centrifugation, plasma was separated for analysis.

[0188] Accurately measure 50 μL of plasma sample and add 200 μL of protein precipitant (acetonitrile-isopropanol solution containing 5 ng / mL brinol-d5, wherein the volume ratio of acetonitrile to isopropanol in the acetonitrile-isopropanol solution is 1:1). Vortex mix for 1 min. Transfer all samples to a dephospholipid plate, place a 96-well plate underneath, and place under positive pressure for 5 min (N2 pressure below 0.01 MPa). Collect all filtrate and analyze by LC-MS / MS. Calculate the brinol concentration in each plasma sample using the standard curve method.

[0189] 4. Test Results:

[0190] The results of the detection of brinolone concentration (ng / mL) in plasma samples of each experimental group at different time points are shown in Table 9, where Composition 1-L and Composition 1-H represent the low-dose group and high-dose group of Composition 1, respectively.

[0191] Table 9. Results of Brenollon Concentration (ng / mL) in Plasma Samples from Each Experimental Group at Different Time Points

[0192] Figure 13 shows the pharmacokinetic curves of brinolone hot melt extruded solid dispersions (Formula 6, Formula 7), brinolone hot melt extruded solid dispersion compositions (Composition 1, Composition 13), and brinolone active pharmaceutical ingredient administered orally via gavage.

[0193] The above pharmacokinetic data were statistically analyzed using PhoenixWinNonlin, version 8.3.5 software, and the pharmacokinetic parameters are shown in Table 10.

[0194] Table 10 Pharmacokinetic parameters of each experimental group

[0195] The results above show that, compared with the brenolone active pharmaceutical ingredient, the brenolone hot melt extruded solid dispersions (Formula 6 and Formula 7) and the brenolone hot melt extruded solid dispersion compositions (Composition 1 and Composition 13) in this application significantly improve the oral absorption of the active pharmaceutical ingredient.

[0196] 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 formulation 7 were significantly higher than those of formulation 6 (325.8 ng / mL and 468.7 hr × ng / mL). This indicates that the bioavailability of solid dispersions with transparent extrusions (where brinolone exists entirely in an amorphous state in the solid dispersion) is higher than that of solid dispersions with semi-transparent extrusions (where brinolone exists in a partially amorphous and partially crystalline state in the solid dispersion).

[0197] 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 showed a roughly 2-fold ratio, indicating good dose-relatedness of in vivo absorption.

[0198] The oral bioavailability (AUC / dose) of composition 13 (25 mg / kg) was not significantly different from that of the low-dose group of composition 1 (25 mg / kg). However, composition 13 exhibited sustained-release characteristics, with smaller fluctuations in blood drug concentration, lower Cmax, and higher Cmin within 30 min to 8 h after administration, which is beneficial for maintaining the drug effect in the body for a longer period of time.

[0199] In addition, given that brinolone exhibits significant central nervous system depression at high blood concentrations (during pharmacokinetic studies, the behavior of animals in each group was observed, and it was found that the low-dose group of Composition 1 showed varying degrees of central nervous system depression from 30 minutes to 1 hour after administration, and the high-dose group of Composition 1 showed varying degrees of central nervous system depression from 15 minutes to 2 hours after administration, such as unsteady gait, limb stiffness, convulsions, drowsiness, and sluggish response to external stimuli, with the high-dose group showing more severe central nervous system depression), the blood concentration fluctuation of Composition 13 is smaller (lower Cmax), which helps to reduce or even avoid the occurrence of central nervous system depression (no central nervous system depression was observed during the pharmacokinetic studies of Composition 13).

[0200] Test Example 3: In vivo efficacy test of brinolone hot melt extruded solid dispersion composition in ICR mice.

[0201] To investigate the in vivo efficacy of the Brino hot-melt extruded solid dispersion composition in this application, female ICR mice were used as test animals. A forced swimming test was conducted after a single dose. The immobility time in the last 4 minutes of swimming was used as the evaluation index of antidepressant efficacy. The efficacy was investigated at 1 h, 3 h and 8 h after administration.

[0202] 1. Test drug:

[0203] Composition 1 and Composition 13 (both capsules): Take the contents of the two capsules respectively, and disperse them thoroughly with 0.5wt% CMC-Na solution to prepare a suspension with a concentration of 2.5mg / mL;

[0204] Imipramine: Dissolve in physiological saline to prepare a solution with a concentration of 3.0 mg / mL.

[0205] 2. Experimental animals:

[0206] Female ICR mice, SPF grade, weighing 18–20 g, were purchased from Spiford (Beijing) Biotechnology Co., Ltd.

[0207] 3. Test methods:

[0208] Female ICR mice were randomly divided into 8 groups according to their body weight: a blank control group (administered with physiological saline), a positive control group (administered with imipramine, 30 mg / kg intraperitoneally), a combination 1-1h group (25 mg / kg orally administered by gavage, efficacy tested 1 hour after administration), a combination 1-3h group (25 mg / kg orally administered by gavage, efficacy tested 3 hours after administration), a combination 1-8h group (25 mg / kg orally administered by gavage, efficacy tested 8 hours after administration), a combination 13-1h group (25 mg / kg orally administered by gavage, efficacy tested 1 hour after administration), a combination 13-3h group (25 mg / kg orally administered by gavage, efficacy tested 3 hours after administration), and a combination 13-8h group (25 mg / kg orally administered by gavage, efficacy tested 8 hours after administration), with 10 mice in each group. Forced swimming tests were performed at specified time points (1 hour, 3 hours, and 8 hours) after a single administration, and the immobility time in the last 4 minutes of swimming was recorded.

[0209] 4. Test Results

[0210] Compared with the blank control group, the immobility time of the positive control group (imipramine, 30 mg / kg), the composition 1-3h group, the composition 13-1h group, the composition 13-3h group, and the composition 13-8h group was significantly reduced, with statistically significant differences (p < 0.05, p < 0.05, p < 0.01, P < 0.01, P < 0.05, respectively). There was no statistically significant difference in immobility time between the composition 1-1h group and the composition 1-8h group compared with the control group (p > 0.05). The immobility time in the last 4 minutes and the statistical differences (compared to the control group) of different groups are shown in Table 11.

[0211] Table 11. Statistical differences in immobility time and swimming duration in animals after drug administration in each experimental group.

[0212] The experimental results showed that female ICR mice exhibited significant antidepressant effects 3 hours after administration of Composition 1 and 1, 3 and 8 hours after administration of Composition 13 following a single gavage.

[0213] Specifically, Composition 1 showed no efficacy 1 hour after administration, presumably due to excessively high brinol blood concentration at this time point, resulting in central nervous system depression and affecting the animals' motor behavior in the forced swimming test. This is consistent with the previous results of the oral gavage pharmacokinetic test of Composition 1 in SD rats (peak blood concentration was between 15 min and 1 hour). Composition 1 showed no efficacy 8 hours after administration, presumably because the brinol blood concentration at this time point had fallen below the effective concentration. This is also consistent with the previous results of the oral gavage pharmacokinetic test of Composition 1 in SD rats (blood concentration was 10.5 ng / mL at 8 hours).

[0214] Composition 13 showed significant efficacy at 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 is relatively stable between 1h and 8h, neither too high nor too low. Therefore, it can maintain the drug concentration without producing significant central depression.

[0215] As can be seen from the above experimental results, the brinolone hot-melt extruded solid dispersion composition of this application allows the active pharmaceutical ingredient brinolone to exist in an amorphous state in the solid dispersion and has a nanoscale particle size, which greatly improves the bioavailability of brinolone for oral administration. Moreover, the brinolone hot-melt extruded solid dispersion prepared using a sustained-release carrier has a good sustained-release effect, making the blood drug concentration in vivo more stable, which can maintain the efficacy for a longer period of time and avoid the central nervous system depression caused by excessively high blood drug concentration.

[0216] Comparative Test Example 1

[0217] This test example examines the bioavailability of brinolone aqueous solution and brinolone oil solution. The brinolone aqueous solution is prepared by mixing brinolone, a solubilizer (specifically sulfobutyl ether-β-cyclodextrin), and water, with a solubilizer concentration of 30 wt%. The brinolone oil solution is prepared by mixing brinolone with sesame oil. The specific test steps are as follows:

[0218] 1. Investigational drug:

[0219] Tail vein injection: 0.5 mg / mL brinolone aqueous solution (abbreviated as A) 静脉 );

[0220] Oral administration via gavage: 3 mg / mL brinolone aqueous solution (abbreviated as A) 口服1 ); 3 mg / mL brinolone oil solution (abbreviated as A) 口服2 ).

[0221] 2. Experimental animals:

[0222] Female SD rats, weighing 200–220 g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0223] 3. Test methods:

[0224] Fifteen female SD rats were randomly divided into three groups (A, B, C, D, E, F, G, F, 静脉 A 口服1 A 口服2 ), 5 in each group. A 静脉 Group A was administered drug A via tail vein injection. 静脉 3 mg / kg (approximately 1.2 mL of drug solution). A 口服1 A 口服2 Group A was administered drug A orally via gavage.口服 1 and A 口服2 Each group was administered 25 mg / kg (approximately 1.67 mL of drug solution). Blood samples were collected from the orbital venous plexus at 5 min, 30 min, 1 h, 2 h, 4 h, and 8 h after drug administration in each group. After heparin anticoagulation and centrifugation, the plasma was separated for analysis.

[0225] 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 to mix, centrifuge (14000 rpm, 4℃), and collect the supernatant. Detect the concentration of brinolone in each plasma sample using UPLC-MS / MS and calculate the concentration using the standard curve method.

[0226] 4. Test Results:

[0227] Brinolan aqueous solution administered via tail vein injection (3 mg / kg, i.e., A) 静脉 Table 12 shows the results of brenolol concentration detection in plasma samples at different time points after administration (group A), where "--" indicates not detected; brenolol aqueous solution and brenolol oil solution were administered orally by gavage (25 mg / kg, i.e., A). 口服1 and A 口服2 After group 1, brinolone was not detected in plasma at any time point.

[0228] Table 12 A 静脉 Results of Detection of Brinolan Concentration in Plasma Samples at Different Time Points After Drug Administration

[0229] The DAS software was used to administer brinolone aqueous solution via tail vein injection (3 mg / kg, i.e., A). 静脉 The pharmacokinetic parameters of the drug-time curves (as shown in Figure 14) of the group were statistically analyzed and are shown in Table 13. AUC represents the area under the curve; Tmax represents the time to peak plasma concentration; Cmax represents the peak plasma concentration; MRT is the first moment, representing the average residence time of the drug in vivo; VRT is the second moment, representing the difference in average residence time of the drug in vivo. As shown in Figure 14 and Table 13, after intravenous injection of brinolone aqueous solution, brinolone enters the bloodstream and is rapidly distributed (or metabolized), with its blood concentration decreasing rapidly; Tmax is only 0.083 h. However, the conventional formulation of brinolone (solvent-soluble with cyclodextrin or dissolved in sesame oil) is essentially not absorbed (or absorbed very little, below the method detection limit) after oral gavage administration to rats, therefore, its absolute bioavailability relative to intravenous administration cannot be calculated.

[0230] Table 13 A 静脉 Pharmacokinetic parameters of the group were obtained.

[0231] Comparative Test Example 2

[0232] This test example examines the bioavailability of brinolone nanosuspension. The brinolone nanosuspension uses lecithin as a stabilizer (brinolone to lecithin mass ratio of 1:2), water as the dispersion medium, and is prepared using a high-pressure homogenization method. The brinolone nanosuspension has a nano-scale particle size with uniform distribution, good storage stability, and significantly better solubility and in vitro dissolution than brinolone raw material. The specific test steps are as follows:

[0233] 1. Investigational drug:

[0234] Brinolon nano-suspension (1): Brinolon concentration 5.34 mg / mL, particle size 158 nm, PDI 0.279;

[0235] Brinolon nano-suspension (2): Brinolon concentration 5.17 mg / mL, particle size 45.8 nm, PDI 0.262;

[0236] Brinolon active pharmaceutical ingredient (suspended in 0.5 wt% CMC-Na solution at a concentration of 5 mg / mL) was used as a control.

[0237] 2. Experimental animals and experimental methods: All animals were tested using the "Comparative Test Example 1" method. The oral gavage dose for each group was 25 mg / kg. The only difference was the blood collection time points, which were 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h.

[0238] 3. Test Results:

[0239] Table 14 shows the results of brinolone concentration detection in plasma samples at different time points after oral gavage administration (25 mg / kg) of brinolone nanosuspension (concentrations of 5.34 mg / mL and 5.17 mg / mL, respectively) and brinolone raw material (suspended in 0.5 wt% CMC-Na solution at a concentration of 5 mg / mL), where "--" indicates not detected.

[0240] Table 14 Results of Brenodrolone Concentration Detection in Plasma Samples at Different Time Points After Drug Administration in Each Experimental Group

[0241] Figure 15 shows the pharmacokinetic time-release curves of brinolone nanosuspension and brinolone active pharmaceutical ingredient administered orally via gavage. Due to the limited number of detection points for hematoxylin and eosin concentration in the brinolone nanosuspension, pharmacokinetic statistics could not be performed based on the pharmacokinetic time-release curves of the brinolone nanosuspension administered orally via gavage.

[0242] The results above show that, compared with the raw material of brinolone, although the nano-suspension improved the solubility and in vitro dissolution of brinolone, it did not show any improvement in oral absorption and bioavailability in rats.

[0243] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

A method for preparing a neuroactive steroid solid dispersion includes the following steps: The raw material mixture is melt-extruded to obtain the neuroactive steroid solid dispersion; The raw material mixture comprises, by weight, 10-70 parts of neuroactive steroids, 30-90 parts of carrier material, and 0-60 parts of plasticizer; The temperature of the melt extrusion is <160℃; The neuroactive steroid solid dispersion contains neuroactive steroids in an amorphous state, and the particle size of the neuroactive steroids in the neuroactive steroid solid dispersion is ≤200nm. The production method according to claim 1, wherein The neuroactive steroids include one or more of progesterone, pregnanelonone, brinolone, alfadolone, seclonone, minassolone, ganexolone, and alfasalone. The production method according to claim 1 or 2, characterized in that, The carrier material includes one or more of the following: copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, lauryl polyethylene glycol glycerol, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, ethylene-vinyl acetate copolymer, acrylic resin, cellulose derivatives, starch, and starch derivatives. The production method according to claim 3, characterized in that The copovidone comprises PVP / VA64; the acrylic resin is Eudragit RL100; the cellulose derivative comprises one or more of hydroxypropyl methylcellulose, ethylcellulose, and methylcellulose; and the starch derivative comprises cross-linked starch and / or carboxymethyl starch. The production method according to claim 3, characterized in that The plasticizer includes one or more of polyethylene glycol, poloxamer, and Tween. The production method according to claim 5, characterized in that The polyethylene glycol includes PEG3350; the poloxamer includes poloxamer 188; and the Tween includes Tween 80. The production method according to claim 3, characterized in that When the carrier material is lauryl polyethylene glycol glyceride, the raw material mixture is a mixture of brinolone and lauryl polyethylene glycol glyceride, the melt extrusion temperature is 60-80°C, and the particle size of the neuroactive steroid in the neuroactive steroid solid dispersion is 120-200 nm. The production method according to claim 7, characterized in that The mass ratio of brinolone to lauryl polyethylene glycol glyceride is 10:30 to 60. The production method according to claim 5 or 6, characterized in that When the carrier material is any substance other than lauryl polyethylene glycol glyceride, the melt extrusion temperature is 120–150°C, and the particle size of the neuroactive steroids in the neuroactive steroid solid dispersion is 80–200 nm. The production method according to claim 9, wherein The raw material mixture is a mixture of brinolone, polyethylene glycol and copovidone, wherein the mass ratio of brinolone, polyethylene glycol and copovidone is 10:5 to 15:45 to 85; and the melt extrusion temperature is 125 to 145°C. The production method according to claim 9, wherein The raw material mixture is a mixture of brinolone and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the mass ratio of brinolone to polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 10:30-40; and the melt extrusion temperature is 130-135°C. The production method according to claim 9, wherein The raw material mixture is a mixture of brenolol, plasticizer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the mass ratio of brenolol, plasticizer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 10:5-15:45-60; the melt extrusion temperature is preferably 120-125°C. The production method according to claim 9, wherein The raw material mixture is a mixture of brinolone, polyethylene glycol and cellulose derivative, and the mass ratio of brinolone, polyethylene glycol and cellulose derivative is 10:5 to 15:45 to 55; the melt extrusion temperature is 140 to 145°C. The production method according to claim 9, wherein The raw material mixture is a mixture of brinolone, polyethylene glycol, copovidone, and cellulose derivatives, wherein the mass ratio of brinolone, polyethylene glycol, copovidone, and cellulose derivatives is 10:5-15:10-40:10-40; and the melt extrusion temperature is 140-145°C. The production method according to claim 9, wherein The raw material mixture is a mixture of brinolone, polyethylene glycol, copovidone, and acrylic resin, wherein the mass ratio of brinolone, polyethylene glycol, copovidone, and acrylic resin is 10:5-15:30-45:5-30; and the melt extrusion temperature is 140-145°C. The neuroactive steroid solid dispersion prepared by the preparation method according to any one of claims 1 to 15. A solid dispersion composition, comprising, by weight parts: The neuroactive steroid solid dispersion of claim 16 comprises 10-100 parts, a sustained-release material of 0-50 parts, a disintegrant of 0-10 parts, a diluent of 0-90 parts, a flow aid of 0-10 parts, and a lubricant of 0-2 parts, wherein the mass fractions of the sustained-release material, disintegrant, diluent, flow aid, and lubricant are all 0. The solid dispersion composition according to claim 17, characterized in that, The sustained-release material includes one or more of acrylic resin, polyoxyethylene, ethyl cellulose, and hydroxypropyl methylcellulose. The solid dispersion composition according to claim 17, characterized in that, The disintegrant includes one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and crospovidone. The solid dispersion composition according to claim 17, characterized in that, The diluent includes one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sodium chloride. The solid dispersion composition according to claim 17, characterized in that, The flow aid includes colloidal silica. The solid dispersion composition according to claim 17, characterized in that, The lubricant includes magnesium stearate and / or sodium stearate fumarate. The solid dispersion composition according to claim 17 or 21, characterized in that, The neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion and a gliding agent, and the mass ratio of brinol hot melt extruded solid dispersion to gliding agent is 97:1 to 5. The solid dispersion composition according to claim 17 or 20, characterized in that, The neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion and diluent, and the mass ratio of brinol hot melt extruded solid dispersion to diluent is 10:85-95. The solid dispersion composition according to claim 17, 20 or 21, characterized in that, The neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, diluent and gliding agent, and the mass ratio of brinol hot melt extruded solid dispersion, diluent and gliding agent is 50-70:25-50:1-10. The solid dispersion composition according to claim 17, 20, 21 or 22, characterized in that, The neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, diluent, gliding agent and lubricant. The mass ratio of brinol hot melt extruded solid dispersion, diluent, gliding agent and lubricant is 30:60~70:3~7:0.5~3. The solid dispersion composition according to claim 17, 18, 20, 21 or 22, characterized in that, The neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, sustained-release material, diluent, gliding agent and lubricant. The mass ratio of brinol hot melt extruded solid dispersion, sustained-release material, diluent, gliding agent and lubricant is 30:35~45:20~30:3~7:0.5~3. The solid dispersion composition according to claim 17, 19, 20, 21 or 22, characterized in that, The neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, disintegrant, diluent, gliding agent and lubricant. The mass ratio of brinol hot melt extruded solid dispersion, disintegrant, diluent, gliding agent and lubricant is 20-50:5-10:29-72:2-10:1-2. The solid dispersion composition according to any one of claims 17 to 22, characterized in that, The neuroactive steroid solid dispersion is a brinol hot melt extruded solid dispersion, which is a solid dispersion obtained by melt extrusion of brinol, a neuroactive steroid. The solid dispersion composition is a mixture of brinol hot melt extruded solid dispersion, sustained-release material, diluent, flow aid and lubricant. The mass ratio of brinol hot melt extruded solid dispersion, sustained-release material, diluent, flow aid and lubricant is 20-60:20-50:17-37:2.5-5:0.5-1. The use of the neuroactive steroid solid dispersion of claim 16 or the solid dispersion composition of any one of claims 17 to 29 in the preparation of a therapeutic medicament for central nervous system disorders. The use according to claim 30, characterized in that The central nervous system disorders mentioned include postpartum depression, clinical depression, atypical depression, severe depressive disorder, catatonic depression, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder, manic-depressive disorder, mood disorders, anxiety, post-traumatic stress disorder, premenstrual anxiety disorder, depression due to chronic medical conditions, treatment-resistant depression, suicidal ideation or behavior, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder, and social anxiety. Symptoms, memory loss, poor stress tolerance, Niemann-Pick II type C disease or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, menstrual epilepsy, childhood epilepsy, epileptiform disorder, essential tremor, NMDA insufficiency, Tourette syndrome, migraine, sleep disorder, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease. The use according to claim 30 or 31, characterized in that The therapeutic drug is an oral medication, and the dosage form of the therapeutic drug includes tablets or capsules. A drug containing a solid dispersion, wherein the raw materials for preparation include the neuroactive steroid solid dispersion of claim 16 or the solid dispersion composition of any one of claims 17 to 29.

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