Neuroactive steroid self-microemulsion composition as well as preparation method and application thereof

Abstract

The invention discloses a neuroactive steroid self-microemulsifying composition as well as a preparation method and application thereof. The neuroactive steroid self-microemulsifying composition is prepared from 1-10 parts of neuroactive steroid; 100 to 1000 parts of an oil phase; 100 to 1500 parts of an emulsifier; wherein the oil phase is selected from any one or a combination of more of medium chain triglyceride, isopropyl myristate, isopropyl palmitate, ethyl oleate and caprylic capric triglyceride; the emulsifier is selected from any one or a combination of more of the following components: polyoxyethylene castor oil EL, polyoxyethylene hydrogenated castor oil RH, polyoxyethylene hydrogenated castor oil PEG-40, lecithin, DSPE-5000 phospholipid, Tween 80, poloxamer F127 and poloxamer F68. The neuroactive steroid self-microemulsifying composition provided by the invention has the characteristics of stability, uniform particle size and high bioavailability.

Description

Technical Field

[0001] The present invention generally relates to the pharmaceutical field. More specifically, the present invention relates to a neuroactive steroid self-microemulsifying composition and a preparation method and application thereof. Background Art

[0002] Neuroactive steroids (NAS) are compounds of natural and synthetic origin that affect central nervous system (CNS) function through a variety of mechanisms, including interactions with GABA A Receptor binding exerts allosteric regulation. GABA A The receptor is an ionotropic channel receptor gated by GABA (γ-aminobutyric acid). As the main inhibitory neurotransmitter in the central nervous system, GABA (γ-aminobutyric acid) can mediate GABA A The receptors affect the flow of ions inside and outside the nerve cell membrane and exert physiological effects. Extensive research on neuroactive steroid compounds has shown that these compounds can act as GABA A Positive allosteric modulators (PAMs) of the receptor affect the flow of ions in and out of the nerve cell membrane, thereby influencing a wide range of brain circuits that are critical for a variety of behavioral states. A Receptor dysregulation is a core factor in a range of neurological disorders, such as postpartum or postpartum depression, clinical depression, atypical depression, major depressive disorder, catatonic depression, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder, manic-depressive disorder, mood disorders, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), depression due to a chronic medical condition, refractory depression, suicidal tendencies, suicidal ideation or behavior, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), and urticaria. AD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, menstrual epilepsy, pediatric epilepsy, epileptiform disorders, essential tremor, NMDA hypofunction, Tourette syndrome, migraine, status epilepticus, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female pediatric epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease, etc. Currently developed and / or under development for GABA A Receptor-mediated neuroactive steroids include progesterone, pregnanolone, brexanolone, alfalone, sepnanolone, minaxolone, ganaxolone, and alfaxalone.

[0003] Postpartum depression (PPD) is a psychiatric syndrome that occurs in women during the postpartum period. It is an obvious and easily identifiable severe depression that usually begins in late pregnancy or within 4 weeks after delivery. It is the leading cause of maternal suicide after childbirth and a common complication of childbirth in women.

[0004] Brenolone is a new type of GABA developed by Sage Therapeutics in the United States. A Allosteric modulators of GABA receptors that regulate GABA activity both inside and outside of synapses A receptor function, thereby significantly improving certain symptoms of PPD such as mental stress and anxiety.

[0005] Brexanolone is an endogenous neuroactive steroid, its chemical name is 3α-hydroxy-5α-pregnan-20-one, its English name is (brexanolone, 3α-Hydroxy-5α-pregnan-20-one), and its molecular formula is: C 21 H 34 O2, CAS registration number: 516-54-1, structural formula:

[0006]

[0007] In March 2019, the U.S. FDA approved Zulresso, an intravenous injection of brexanolone, for the treatment of PPD. Clinical trial results show that Zulresso has the advantages of rapid onset, long duration of action, good safety, and low incidence of adverse reactions in the treatment of PPD. Although Zulresso has many advantages, its administration route is invasive intravenous injection, which requires continuous injection for 60 hours, and the dosage is adjusted multiple times at different times (0-4h, 4-24h, 24-52h, 52-56h, and 56-60h, respectively). This dosing regimen needs to be implemented by qualified medical staff in medical institutions that have passed the Risk Evaluation and Mitigation Strategy (REMS) certification, and frequent monitoring is required during the entire injection process, which will occupy more medical resources, have high costs, and will also affect availability. In addition, continuous intravenous infusion for 60 hours still has the problem of poor compliance for ordinary patients, and for PPD patients who are usually in the lactation period after childbirth, it will bring great challenges in compliance.

[0008] Therefore, it is necessary to develop non-intravenous formulations of brexanolone in order to provide a convenient and more compliant dosing regimen for the treatment of PPD. Compared with other dosage forms, oral preparations have many advantages such as convenient administration, non-invasiveness, high patient compliance, low production cost, large drug loading, and relatively slow absorption after oral administration. It is expected to solve the problem of excessive sedation during brexanolone injection and the need for frequent monitoring during medication.

[0009] However, the development of oral preparations of brinolone faces many difficulties, such as poor water solubility of brinolone and poor permeability through the small intestinal epithelial mucosa. brinolone also has a very important pharmacokinetic defect, that is, the prototype drug will be rapidly distributed or metabolized (its metabolites are inactive) after entering the blood, resulting in a rapid decrease in blood drug concentration, which is not conducive to maintaining a certain blood drug concentration and efficacy. If it is made into a common preparation for oral administration, it has the defects of poor absorption and low bioavailability, and the oral bioavailability is even less than 5%. Other preparations of neuroactive steroids also have similar defects as brinolone. Summary of the invention

[0010] In order to solve the above problems, the present invention provides a neuroactive steroid self-microemulsifying composition, comprising: 1-10 parts of neuroactive steroid; 100-1000 parts of oil phase; 100-1500 parts of emulsifier; wherein the oil phase is selected from any one or more of the following combinations: medium chain triglycerides, isopropyl myristate, isopropyl palmitate, ethyl oleate and caprylic decanoate; the emulsifier is selected from any one or more of the following combinations: polyoxyethylene castor oil EL, polyoxyethylene hydrogenated castor oil RH, polyoxyethylene hydrogenated castor oil PEG-40, lecithin, DSPE-5000 phospholipids, Tween 80, poloxamer F127, poloxamer F68.

[0011] According to one embodiment of the present invention, the neuroactive steroid is selected from the group consisting of progesterone, pregnanolone, brexanolone, alfalone, sepnanolone, minaxolone, ganaxolone, and alfaxalone.

[0012] According to one embodiment of the present invention, the neuroactive steroid is brexanolone.

[0013] According to one embodiment of the present invention, the neuroactive steroid self-microemulsifying composition comprises: 5-10 parts of neuroactive steroid; 100-1000 parts of oil phase; and 100-1500 parts of emulsifier.

[0014] According to one embodiment of the present invention, the neuroactive steroid self-microemulsifying composition comprises: 5-10 parts of neuroactive steroid; 400-1000 parts of oil phase; and 600-1500 parts of emulsifier.

[0015] According to one embodiment of the present invention, the neuroactive steroid self-microemulsifying composition comprises: 1 part of neuroactive steroid; 20-80 parts of oil phase; and 34-54 parts of emulsifier.

[0016] According to one embodiment of the present invention, the neuroactive steroid self-microemulsifying composition comprises: 1-10 parts of neuroactive steroid; 100-1000 parts of oil phase; 100-1000 parts of Tween 80; and 50-500 parts of lecithin.

[0017] According to one embodiment of the present invention, the neuroactive steroid self-microemulsifying composition comprises: 1-10 parts of neuroactive steroid; 100-1000 parts of oil phase; 50-500 parts of polyoxyethylene castor oil EL; 50-500 parts of polyoxyethylene hydrogenated castor oil RH; and 10-100 parts of lecithin.

[0018] According to one embodiment of the present invention, the neuroactive steroid self-microemulsifying composition comprises: 1-10 parts of neuroactive steroid; 100-1000 parts of oil phase; 50-500 parts of polyoxyethylene castor oil EL; 50-500 parts of polyoxyethylene hydrogenated castor oil PEG-40; and 10-100 parts of lecithin.

[0019] According to one embodiment of the present invention, the neuroactive steroid self-microemulsifying composition further comprises: 100-1000 parts of an emulsifier; the emulsifier is selected from any one or more of the following combinations: ethanol, ethylene glycol, 1,2-propylene glycol, glycerol, n-butanol, PEG400.

[0020] According to another aspect of the present invention, there is provided a method for preparing the above-mentioned neuroactive steroid self-microemulsifying composition, comprising: adding a co-emulsifier to a prescribed amount of an oil phase and an emulsifier, and stirring and mixing them uniformly at room temperature to obtain an intermediate product; and mixing a prescribed amount of a neuroactive steroid with the intermediate product, and stirring until they are completely dissolved to obtain a neuroactive steroid self-microemulsifying composition.

[0021] According to another aspect of the present invention, there is provided a method for preparing the above-mentioned neuroactive steroid self-microemulsifying composition, comprising: stirring a prescribed amount of an oil phase and an emulsifier at room temperature to uniformly mix them to obtain a first intermediate product; dissolving a prescribed amount of a neuroactive steroid in a prescribed amount of an emulsifier to completely dissolve the neuroactive steroid, and then mixing the first intermediate product with the first intermediate product and stirring until the second intermediate product is completely dissolved to obtain a second intermediate product; and evaporating the second intermediate product to remove the emulsifier to obtain a neuroactive steroid self-microemulsifying composition.

[0022] According to another aspect of the present invention, the use of any of the above-mentioned neuroactive steroid self-microemulsifying compositions in the preparation of a medicament for a disorder related to a central nervous system disorder, wherein the disorder related to the central nervous system disorder includes: postpartum or postpartum depression, clinical depression, atypical depression, severe depressive disorder, tension-type depression, dysthymia, double depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder, manic-depressive disorder, mood disorder, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), depression caused by chronic medical conditions, refractory depression, suicidal tendencies, suicidal ideation or suicidal behavior, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, catamenial epilepsy, pediatric epilepsy, epileptiform disorders, essential tremor, NMDA hypofunction, Tourette syndrome, migraine, status epilepticus, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female pediatric epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease, etc.

[0023] According to another aspect of the present invention, the present invention provides a self-microemulsifying composition of brinolone, comprising: 1-10 parts of brinolone; 100-1000 parts of oil phase; 100-1500 parts of emulsifier; wherein the oil phase is selected from any one or more of the following combinations: medium chain triglycerides (MCT), isopropyl myristate, isopropyl palmitate, ethyl oleate and caprylic decanoic acid glyceride; the emulsifier is selected from any one or more of the following combinations: polyoxyethylene castor oil EL, polyoxyethylene hydrogenated castor oil RH, polyoxyethylene hydrogenated castor oil PEG-40, lecithin, DSPE-5000 phospholipids, Tween 80, poloxamer F127, poloxamer F68.

[0024] According to one embodiment of the present invention, the brexanolone self-microemulsifying composition comprises: 5-10 parts of brexanolone; 100-1000 parts of oil phase; and 100-1500 parts of emulsifier.

[0025] According to one embodiment of the present invention, the brexanolone self-microemulsifying composition comprises: 5-10 parts of brexanolone; 400-1000 parts of oil phase; and 600-1500 parts of emulsifier.

[0026] According to one embodiment of the present invention, the brexanolone self-microemulsifying composition comprises: 1 part of brexanolone; 20-80 parts of oil phase; and 34-54 parts of emulsifier.

[0027] According to one embodiment of the present invention, the brexanolone self-microemulsifying composition comprises: 1-10 parts of brexanolone; 100-1000 parts of oil phase; 100-1000 parts of Tween 80; and 50-500 parts of lecithin.

[0028] According to one embodiment of the present invention, the brinolone self-microemulsifying composition includes: 1-10 parts of brinolone; 100-1000 parts of oil phase; 50-500 parts of polyoxyethylene castor oil EL; 50-500 parts of polyoxyethylene hydrogenated castor oil RH; and 10-100 parts of lecithin.

[0029] According to one embodiment of the present invention, the brinolone self-microemulsifying composition includes: 1-10 parts of brinolone; 100-1000 parts of oil phase; 50-500 parts of polyoxyethylene castor oil EL; 50-500 parts of polyoxyethylene hydrogenated castor oil PEG-40; and 10-100 parts of lecithin.

[0030] According to one embodiment of the present invention, the brexanolone self-microemulsifying composition further comprises: 100-1000 parts of an emulsifier; the emulsifier is selected from any one or more of the following combinations: ethanol, ethylene glycol, 1,2-propylene glycol, glycerol, n-butanol, PEG400.

[0031] According to another aspect of the present invention, there is provided a method for preparing the brinolone self-microemulsifying composition described in any one of the above items, comprising: stirring and mixing the prescribed amount of oil phase, emulsifier, and co-emulsifier at room temperature to obtain an intermediate product; mixing the prescribed amount of brinolone with the intermediate product, stirring until completely dissolved, to obtain a liquid self-microemulsifying composition.

[0032] According to another aspect of the present invention, there is provided a method for preparing the brinolone self-microemulsifying composition described in any of the above items, comprising: stirring a prescribed amount of an oil phase and an emulsifier at room temperature to uniformly mix them to obtain a first intermediate product; dissolving a prescribed amount of brinolone in a prescribed amount of an emulsifier to completely dissolve it, and then mixing it with the first intermediate product and stirring until it is completely dissolved to obtain a second intermediate product; evaporating the second intermediate product to remove the emulsifier to obtain a liquid brinolone self-microemulsifying composition.

[0033] According to another aspect of the present invention, any of the above-mentioned brexanolone self-microemulsifying compositions is used to prepare a drug for treating postpartum depression.

[0034] The brinolone self-microemulsifying composition provided above has the characteristics of stability, uniform particle size and high bioavailability. Further, in some embodiments, by limiting the components of the brinolone self-microemulsifying composition, the brinolone self-microemulsifying composition forms a semisolid microemulsion gel after adding water, and continues to add water to form a microemulsion, which has the effect of sustained release and improved drug absorption characteristics. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] By reading the following detailed description with reference to the accompanying drawings, the above and other objects, features and advantages of the exemplary embodiments of the present invention will become readily understood. In the accompanying drawings, several embodiments of the present invention are shown in an exemplary and non-limiting manner, and the same or corresponding reference numerals represent the same or corresponding parts, wherein:

[0036] Figure 1 The drug-time curve of Brenolone (3 mg / kg) injected into the caudal vein is shown;

[0037] Figure 2 The drug-time curves of the oral administration of the brexanolone nanosuspension and the brexanolone API are shown;

[0038] Figure 3 The drug-time curve of the brexanolone self-microemulsification composition and the brexanolone raw material drug for oral gavage administration is shown;

[0039] Figure 4 The drug-time curve of the sustained-release self-microemulsion composition of brexanolone and the oral gavage administration of brexanolone raw material is shown;

[0040] Figure 5 The drug-time curves of three batches of sustained-release self-microemulsion compositions of brexanolone and brexanolone raw materials for oral gavage administration are shown. DETAILED DESCRIPTION

[0041] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0042] It should be understood that the terms "include" and "comprising" used in the description and claims of the present invention indicate the presence of described features, integers, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or combinations thereof.

[0043] It should also be understood that the terms used in the present specification are only for the purpose of describing specific embodiments and are not intended to limit the present invention. As used in the present specification and claims, the singular forms of "a", "an" and "the" are intended to include the plural forms unless the context clearly indicates otherwise. It should also be further understood that the term "and / or" used in the present specification and claims refers to any combination of one or more of the associated listed items and all possible combinations, and includes these combinations.

[0044] The specific embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0045] The invention provides a neuroactive steroid self-microemulsifying composition, comprising: 1-10 parts of neuroactive steroid; 100-1000 parts of oil phase; 100-1500 parts of emulsifier; wherein the oil phase is selected from any one or more combinations of the following: medium chain triglyceride, isopropyl myristate, isopropyl palmitate, ethyl oleate and caprylic decanoate; and the emulsifier is selected from any one or more combinations of the following: polyoxyethylene castor oil EL, polyoxyethylene hydrogenated castor oil RH, polyoxyethylene hydrogenated castor oil PEG-40, lecithin, DSPE-5000 phospholipid, Tween 80, poloxamer F127 and poloxamer F68.

[0046] Representatives of neuroactive steroids: progesterone, pregnanolone, brexanolone, alfalone, sepnanolone, minaxolone, ganaxolone, alfaxalone and other progesterone analogs.

[0047] The advantages of the present invention are described below using Brenolone as an example.

[0048] The present invention provides a self-microemulsifying composition of brinosone, comprising 1-10 parts by weight of brinosone, 100-1000 parts by weight of oil phase, and 100-1500 parts by weight of emulsifier. The oil phase is selected from any one or more of the following combinations: medium chain triglyceride (MCT), isopropyl myristate, isopropyl palmitate, ethyl oleate, and caprylic decanoate; the emulsifier is selected from any one or more of the following combinations: polyoxyethylene castor oil EL, polyoxyethylene hydrogenated castor oil RH, polyoxyethylene hydrogenated castor oil PEG-40, lecithin, DSPE-5000 phospholipids, Tween 80, poloxamer F127, and poloxamer F68.

[0049] Medium-chain triglycerides, also known as medium-chain fatty acid triglycerides (MCT), are composed of 1 molecule of glycerol and 3 molecules of medium-chain fatty acids. They are triglycerides composed of saturated medium-chain fatty acids with a carbon chain length of 6-12.

[0050] Among the oil phases selected in the present invention: medium chain triglycerides, isopropyl myristate, isopropyl palmitate, ethyl oleate and caprylic decanoate, have similar solubility to brexanolone.

[0051] Among the emulsifiers of the present invention, polyoxyethylene castor oil EL, polyoxyethylene hydrogenated castor oil RH, polyoxyethylene hydrogenated castor oil PEG-40, and Tween 80 have similar solubility to brinolone. Lecithin, DSPE-5000 phospholipids, poloxamer F127, and poloxamer F68 can increase the solubility of brinolone in water or promote absorption.

[0052] Table 1 shows the solubility data of the raw material brexanolone in the oil phase and the emulsifier.

[0053] Table 1.

[0054]

[0055]

[0056] The solubility determination method in Table 1 is as follows: take 10 g of each of the oil phase and emulsifier in Table 1, add excess brenolide thereto respectively, vortex mix, oscillate in a water bath at 37°C for 72 h, take the supernatant after centrifugation, determine the brenolide content therein by HPLC, and calculate the solubility of brenolide in each excipient.

[0057] As can be seen from Table 1, except for the low solubility of soybean oil to brinolone (3.99 mg / g), the solubility of other oils to brinolone is similar to that of medium-chain triglycerides (MCT). Polyoxyethylene castor oil EL and Tween-80 have the highest solubility to brinolone, and the two values ​​are close; polyoxyethylene hydrogenated castor oil PEG-40 has the second highest solubility to brinolone, and polyoxyethylene hydrogenated castor oil RH has the lowest solubility to brinolone. The present invention preferably uses Tween-80 and polyoxyethylene castor oil EL as the main emulsifiers, and uses them together with other emulsifiers as mixed emulsifiers.

[0058] According to one embodiment of the present invention, a brexanolone self-microemulsifying composition is provided, comprising 5-10 parts of brexanolone, 100-1000 parts of oil phase, and 100-1500 parts of emulsifier, which increases the drug loading capacity of the composition and can form a microemulsion system with a stable particle size after adding water, and the particle size range is between 162nm-171nm.

[0059] According to one embodiment of the present invention, a brexanolone self-microemulsifying composition is provided, comprising 5-10 parts of brexanolone, 400-1000 parts of oil phase, and 600-1500 parts of emulsifier. Under the premise of increasing the drug loading amount, the lower limits of the oil phase and the emulsifier are increased, so that the dissolution and dispersion effects of the oil phase and the emulsifier on brexanolone can be fully exerted, and the emulsification effect can be fully exerted.

[0060] The present invention prepares a self-microemulsifying composition of brinosine by selecting the oil phase, the type of emulsifier and the ratio, and the self-microemulsifying composition is in liquid state. According to one embodiment of the present invention, a suitable amount of water can be added to the self-microemulsifying composition of brinosine, with or without a proppant, and a white or off-white powder or cake containing brinosine can be obtained by evaporation, drying, spray drying or freeze drying; or by a carrier adsorption method, a suitable solid carrier material (such as polyacrylic acid resin, microcrystalline cellulose, mesoporous silica, magnesium aluminum silicate, hydroxypropyl methylcellulose, dextrin, maltodextrin, gelatin, polyethylene glycol-4000, polyethylene glycol-6000, mannitol, lactose, dextran, etc.) is added to the self-microemulsifying composition of brinosine to obtain a solid powder containing brinosine. The solid powder or cake containing brinosine obtained above can also be further prepared into dosage forms such as granules, capsules or tablets with or without other excipients. The brexanolone self-microemulsifying composition of the present invention has the characteristics of stability, uniform particle size and high bioavailability.

[0061] According to one embodiment of the present invention, a self-microemulsifying composition of brucenolide is provided, comprising 1 part of brucenolide, 20-80 parts of oil phase, and 34-54 parts of emulsifier. When the components of the self-microemulsifying composition of brucenolide of this embodiment are controlled within the above range, the self-microemulsifying composition can spontaneously form a semisolid microemulsion gel under the condition of adding a very small amount of water (simulating contact with liquid in the gastrointestinal tract), giving full play to the sustained-release properties of the gel matrix, so that the drug brucenolide contained therein is slowly released, prolonging the maintenance time of blood drug concentration, and the gel can be further diluted with water and converted into a microemulsion, which can give play to the inherent properties of microemulsions to improve drug absorption, improve the permeability of drugs through the small intestinal mucosa, and improve bioavailability.

[0062] According to one embodiment of the present invention, the composition of the present invention is prepared for oral administration. The pharmaceutical composition is prepared by combining one or more medicaments and a pharmaceutically acceptable carrier. Some such carriers enable the pharmaceutical composition to be formulated into tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, etc. for oral ingestion by subjects. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; starch or cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). In some embodiments, this mixture is optionally ground and an auxiliary agent is optionally added. In some embodiments, a pharmaceutical composition is formed to obtain a tablet or a dragee core. In some embodiments, a disintegrant (e.g., cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate) is added. In some embodiments, the dragee core has a coating. In some such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablet or dragee coating.

[0063] According to one embodiment of the present invention, the pharmaceutical composition for oral administration is a push-fit capsule made of gelatin. Some such push-fit capsules include one or more medicaments of the present invention mixed with one or more fillers (e.g. lactose), adhesives (e.g. starch) and / or lubricants (e.g. talc or magnesium stearate) and optional stabilizers. In certain embodiments, the composition for oral administration is a soft sealed capsule made of gelatin and a plasticizer such as glycerol or sorbitol. In some soft capsules, one or more medicaments of the present invention are dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. The composition for oral administration can be in bulk liquid solution or bulk powder form.

[0064] Typically, the composition is presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules, etc. in the case of solid compositions.

[0065] When preparing the self-microemulsifying composition of the present invention, a combination of one or more of the co-emulsifiers ethanol, ethylene glycol, 1,2-propylene glycol, glycerol, n-butanol, and PEG400 may be used.

[0066] Example 1

[0067] With MCT as the oil phase and Tween-80 as the emulsifier, brexanolone self-microemulsifying compositions were prepared in different proportions and their properties were tested.

[0068] Preparation method: Weigh the prescribed amount of oil phase and emulsifier respectively, and measure 25 ml of ethanol as an emulsifier, stir at room temperature to mix the three evenly, then add the prescribed amount of brexanolone, stir thoroughly to completely dissolve the brexanolone, and obtain a slightly viscous transparent liquid, that is, a liquid self-microemulsifying composition.

[0069] The components in Example 1 are shown in Table 2.

[0070] Table 2.

[0071]

[0072] Property test: Add a proper amount of water to the liquid self-microemulsifying composition prepared from Prescriptions 1 to 3 and stir to form a translucent milky liquid with a light blue opalescent luster.

[0073] A small amount of water is added dropwise to the liquid self-microemulsifying composition prepared from Prescriptions 4 to 7 and stirred to obtain a microemulsion gel, which is a transparent semisolid gel with light blue opalescence. Water is continued to be added and stirred. When the water is added to 5-10 times the volume of the self-microemulsifying composition, the gel slowly disappears to form a translucent milky liquid with light blue opalescence.

[0074] Example 2

[0075] With MCT as the oil phase, Tween-80 and lecithin as emulsifiers, brenolon self-microemulsifying compositions were prepared in different proportions, and the properties, particle size and PDI were tested.

[0076] Preparation method: Weigh the prescribed amount of oil phase and emulsifier respectively, stir and mix them evenly at room temperature to form a mixture of oil phase and emulsifier; then measure 2.5 ml of ethanol as an auxiliary emulsifier, add the prescribed amount of brexanolone to the ethanol, stir well to completely dissolve the brexanolone, and prepare an ethanol solution of brexanolone; then add the above mixture of oil phase and emulsifier to the ethanol solution of brexanolone, stir evenly, and obtain a slightly viscous transparent liquid, that is, a liquid self-microemulsifying composition.

[0077] The components in Example 2 are shown in Table 3.

[0078] Table 3

[0079]

[0080] Properties, particle size and PDI test: 15 ml of water was added to the liquid self-microemulsifying compositions prepared from Prescriptions 8 to 10 respectively and stirred to form a bryocaron microemulsion system, which was a translucent milky liquid with a light blue opalescence. Among them, the bryocaron microemulsion system formed by Prescription 8 had a particle size of 165 nm, a PDI of 0.253, and remained stable after being placed for one week; the bryocaron microemulsion system formed by Prescription 9 had a particle size of 169 nm, a PDI of 0.265, and remained stable after being placed for one week; the bryocaron microemulsion system formed by Prescription 10 had a particle size of 163 nm, a PDI of 0.247, and remained stable after being placed for one week.

[0081] Example 3

[0082] With MCT as the oil phase, polyoxyethylene castor oil EL (hereinafter referred to as EL), polyoxyethylene hydrogenated castor oil RH or PEG-40 (hereinafter referred to as RH or PEG-40), lecithin as a mixed emulsifier, and ethanol as an auxiliary emulsifier, brexanolone self-microemulsifying compositions were prepared in different proportions, and the properties, particle size and PDI were tested.

[0083] Preparation method: Weigh the prescribed amount of oil phase and emulsifier respectively, stir and mix them evenly at room temperature to obtain a mixture of oil phase and emulsifier; then measure ethanol, add the prescribed amount of brexanolone to the ethanol, stir thoroughly to completely dissolve brexanolone, and obtain an ethanol solution of brexanolone; then add the above mixture of oil phase and emulsifier to the ethanol solution of brexanolone, stir evenly, and remove ethanol by rotary evaporation to obtain the product. Among them, the amount of ethanol used in prescription 11 and prescription 13 is 7.5g, and the amount of ethanol used in prescription 12, prescription 14 to prescription 21 is 20ml.

[0084] The components in Example 3 are shown in Table 4.

[0085] Table 4.

[0086] Brenolone (mg) MCT(g) EL(g) PEG-40 / RH(g) Lecithin(g) Prescription 11 500 10 10 10(PEG-40) 2 Prescription 12 500 20 10 10(PEG-40) 2 Prescription Thirteen 500 40 10 10(RH) 2 Prescription 14 500 20 5 5(RH) 2.5 Prescription 15 500 20 10 5(PEG-40) 2 Prescription 16 500 20 10 15(RH) 2 Prescription 17 500 20 5 10(PEG-40) 2 Prescription 18 500 20 15 10(RH) 2 Prescription 19 500 20 0 5(RH) 2.5 Prescription 20 500 20 5 5(PEG-40) 5 Prescription 21 500 20 5 5(RH) 5

[0087] Property test: Add an appropriate amount of water (2-4 drops) to the products formed by Prescription 11 to Prescription 13, Prescription 15 to Prescription 18 and stir to obtain a microemulsion gel, which is a transparent semisolid gel with a light blue opalescence. When stirring is continued and water is added to 5-10 times the volume of the product, the gel slowly disappears to form a translucent milky liquid with a light blue opalescence.

[0088] Add an appropriate amount of water to the product formed in Prescription 14 and stir to obtain a milky white emulsion system.

[0089] The product system formed by the nineteenth prescription was uneven and lamellar. The product system formed by the twentyth prescription was uniform, and after adding water, a microemulsion system with light blue opalescence was formed, with a particle size of 186nm and a PDI of 0.281. The product system formed by the twenty-first prescription was uniform, and after adding water, a microemulsion system with light blue opalescence was formed, with a particle size of 191nm and a PDI of 0.273.

[0090] Since the self-microemulsifying compositions of Prescriptions 11 to 13, Prescriptions 15 to 18 in this embodiment, and Prescriptions 4 to 7 in Example 1 can first form a microemulsion gel after adding a small amount of water, and are further diluted with water to form a microemulsion, they show certain slow release characteristics in the pharmacokinetic test of oral gavage administration in rats, so these self-microemulsifying compositions are also called brexanolone sustained-release self-microemulsifying compositions.

[0091] Example 4

[0092] With MCT as the oil phase, Tween-80 and lecithin as emulsifiers, brexanolone self-microemulsifying compositions were prepared in different proportions, and the properties, particle size and PDI were tested.

[0093] Preparation method: Weigh the prescribed amount of oil phase and emulsifier respectively, stir and mix them evenly at room temperature to obtain a mixture of oil phase and emulsifier; then measure 2-2.5 ml of ethanol as an emulsifier, add the prescribed amount of brexanolone to the ethanol, stir thoroughly to completely dissolve it, then add the above mixture of oil phase and emulsifier, stir evenly to obtain the product. The amount of ethanol used in Prescription 22 to Prescription 24 is 2.5 ml, and the amount of ethanol used in Prescription 25 to Prescription 27 is 2 ml.

[0094] The components in Example 4 are shown in Table 5.

[0095] Table 5.

[0096]

[0097] Property test: 15 ml of water was added dropwise to the products formed by Prescriptions 22 to 24 and stirred. Prescription 22 formed a brexanolone microemulsion with a particle size of 162 nm and a PDI of 0.231, which remained stable after being placed for one week; Prescription 23 formed a brexanolone microemulsion with a particle size of 168 nm and a PDI of 0.284, which remained stable after being placed for one week; Prescription 24 formed a brexanolone microemulsion with a particle size of 171 nm and a PDI of 0.302, but it was unstable after being placed, and the PDI was greater than 0.4 after being placed for one week.

[0098] 15 ml of water was added to the products formed by Prescription 25 to Prescription 27 respectively and stirred. Prescription 25 formed a brenolon microemulsion with a particle size of 185 nm and a PDI of 0.275, which remained stable after being placed for one week; Prescription 26 formed a brenolon microemulsion with a particle size of 197 nm and a PDI of 0.324, which separated into layers after being placed for one week; the product formed by Prescription 27 could not form a uniform microemulsion system when water was added.

[0099] When Tween-80 and phospholipids are used as mixed emulsifiers, Tween-80 plays an important role in forming a stable microemulsion system.

[0100] In the present invention, the compositions formed by prescriptions 4 to 7, prescriptions 11 to 13, prescriptions 15 to 18, etc. can first form a transparent semisolid microemulsion gel with light blue opalescence under the condition of adding water (or contacting with gastrointestinal fluid), and form a microemulsion when further diluted, which can not only improve the permeability of the drug through the small intestinal mucosa and improve the bioavailability, but also delay the release of the drug and prolong the maintenance time of the blood drug concentration. The preparation method of the composition of the present invention is simple and can be operated at room temperature; the composition that can form a gel does not introduce highly toxic solvents such as DMF or DMSO during the preparation process.

[0101] Pharmacokinetic test 1:

[0102] The absolute bioavailability of brexanolone after oral gavage administration relative to intravenous administration in different common formulations.

[0103] Trial Drugs:

[0104] Tail vein injection: 0.5 mg / ml brexanolone aqueous solution (solubilized with sulfobutyl ether-β-cyclodextrin, referred to as A 静脉 );

[0105] Oral gavage: 3 mg / ml brexanolone aqueous solution (solubilized with sulfobutyl ether-β-cyclodextrin, referred to as: A 口服1 ); 3mg / ml bruceanolone oil solution (with sesame oil as solvent, referred to as: A 口服2 ).

[0106] Experimental Animals:

[0107] SD female rats, weighing 200-220 g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0108] Test method:

[0109] Fifteen female SD rats were randomly divided into three groups (A 静脉 , A 口服1 , A 口服2 ), 5 in each group. 静脉Group A was injected into the tail vein 静脉 3mg / kg (about 1.2ml of liquid medicine). 口服1 , A 口服2 The two groups were given drug A orally orally. 口服1 and A 口服2 Each group was given 25 mg / kg (about 1.67 ml of liquid medicine). Blood was collected from the orbital venous plexus at 5 min, 30 min, 1 h, 2 h, 4 h, and 8 h after administration. The blood was anticoagulated with heparin and centrifuged to separate the plasma for testing.

[0110] Accurately measure 100 μl of plasma sample, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 310 μl of acetonitrile, vortex mix, centrifuge (14000 rpm, 4°C), and take the supernatant. UPLC-MS / MS is used for detection, and the concentration of brexanolone in each plasma sample is calculated using the standard curve method.

[0111] Test results:

[0112] After caudal vein injection of brenosone (3 mg / kg) and oral gavage administration of two different preparations (cyclodextrin solubilized aqueous solution, sesame oil solution) (25 mg / kg), the concentrations of brenosone in plasma samples at different times were as follows:

[0113] Table 6 shows A 静脉 Group results, "--" means not detected, A 口服1 and A 口服2 After administration of the two groups, no brexanolone was detected in the plasma at any time point:

[0114] Table 6.

[0115]

[0116]

[0117] Figure 1 The drug-time curve of brenoside injection (3 mg / kg) via tail vein is shown.

[0118] DAS software was used for statistics, and Table 7 shows the statistical moment parameter results.

[0119] Table 7.

[0120] parameter Parameter Value AUC 0-4 (ug / L*h) 359.483 AUC 0-∞(ug / L*h) 361.719 AUMC 0-4 97.347 AUMC 0-∞ 109.664 MRT 0-4(h) 0.271 MRT 0-∞(h) 0.303 VRT 0-4(h^2) 0.252 VRT 0-∞(h^2) 0.417 MAT(h) － Tmax(h) 0.083 Cmax(ug / L) 927.173

[0121] By the above Figure 1As shown in the results of Table 7, after entering the blood, brinosone is rapidly distributed (or metabolized), and its blood concentration decreases rapidly, with Tmax being only 0.083h. After oral administration of brinosone to rats, the common preparation of brinosone (solubilized with cyclodextrin to make an aqueous solution, or dissolved with sesame oil to make an oil solution) is basically not absorbed (or absorbed very little, below the detection limit of the method), so it is impossible to calculate its absolute bioavailability relative to intravenous administration.

[0122] The above AUC represents the area under the drug-time curve; Tmax represents the time when the drug reaches peak concentration in plasma; Cmax represents the peak concentration of the drug in plasma; MRT is the first-order moment, representing the average residence time of the drug in the body; VRT is the second-order moment, representing the difference in the average residence time of the drug in the body.

[0123] Pharmacokinetic study 2:

[0124] Pharmacokinetic study of brexanolone nanosuspension administered orally or intragastrically

[0125] Using lecithin as a stabilizer, the high-pressure homogenization method was used to prepare brenosolone nanosuspension. The prepared brenosolone nanosuspension had a particle size at the nanometer level, a uniform particle size distribution, good storage stability, and solubility and in vitro dissolution were significantly better than those of the brenosolone raw material.

[0126] Trial Drugs:

[0127] Brenolone nanosuspension (1): Brenolone concentration 5.34 mg / ml, particle size 158 nm, PDI 0.279;

[0128] Brenolone nanosuspension (2): Brenolone concentration 5.17 mg / ml, particle size 45.8 nm, PDI 0.262;

[0129] The raw material of brexanolone (suspended in 0.5% CMC-Na solution, with a concentration of 5 mg / ml) was used as a control.

[0130] Experimental animals and experimental methods: The "pharmacokinetic test 1" method was adopted, and the oral gavage dose for each group was also 25 mg / kg. Only the blood collection time points were different, which were 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours respectively.

[0131] Test results:

[0132] After oral administration (25 mg / kg) of brucenaolone nanosuspension (concentrations of 5.34 mg / ml and 5.17 mg / ml, respectively) and brucenaolone API (suspended in 0.5% CMC-Na solution, concentration of 5 mg / ml), the results of brucenaolone concentration detection in plasma samples at different times are shown in Table 8 below, "--" represents not detected:

[0133] Table 8.

[0134]

[0135] Figure 2 The drug-time curves of oral gavage administration of brexanolone nanosuspension and brexanolone raw material are shown.

[0136] Since there were too few points at which blood drug concentrations of brexanolone nanosuspension were detected, it was impossible to perform pharmacokinetics-related statistics.

[0137] From the above results, it can be seen that compared with the raw material, although the nanosuspension improved the solubility and in vitro dissolution of brexanolone, it did not show improvement in oral absorption and bioavailability in rats.

[0138] Pharmacokinetic test three:

[0139] Pharmacokinetic test of oral administration of the self-microemulsified composition of brexanolone by intragastric administration

[0140] In order to investigate the oral absorption and bioavailability improvement of the brexanolone self-microemulsification composition of the present invention in animals, a pharmacokinetic test of oral gavage administration of brexanolone self-microemulsification compositions (or microemulsions formed after adding water) of different prescriptions was carried out on SD female rats, and the brexanolone raw material (suspended in 0.5% CMC-Na solution at a concentration of 5 mg / ml) was used as a control.

[0141] Trial Drugs:

[0142] Brenolone self-microemulsion formula 8, formula 9 and formula 10 (all with a concentration of 2.5 mg / ml);

[0143] Brenolone API (suspended in 0.5% CMC-Na solution, concentration of 2.5 mg / ml).

[0144] Experimental animals and experimental methods: The "pharmacokinetic test 1" method was adopted. The oral gavage dose for each group was also 25 mg / kg. The only difference was the blood sampling time points, which were before administration (0 time), and 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration.

[0145] Test results:

[0146] After oral gavage administration (25 mg / kg) of brenolan microemulsion (Formulation 8, Formulation 9 and Formulation 10, all with a concentration of 2.5 mg / ml) and brenolan API (suspended in 0.5% CMC-Na solution, with a concentration of 2.5 mg / ml), the results of brenolan concentration detection in plasma samples at different times are shown in Table 9 below, "--" represents not detected:

[0147] Table 9.

[0148]

[0149] Figure 3 The concentration-time curves of brexanolone self-microemulsion and brexanolone raw material oral gavage are shown.

[0150] The DAS software was used to perform statistics on the above drug-time curve data. The pharmacokinetic parameter results are shown in Table 10. The software system did not give statistical results for prescription nine:

[0151] Table 10.

[0152] sample API Prescription 10 Prescription 8 Tmax(h) 0.5 1.0 0.5 Cmax(mg / L) 0.09 1.73 0.82 AUC(0-t)(mg / L*h) 0.38 2.90 0.72 MRT(0-t)(h) 3.16 1.30 0.96 F(AUC(0-t) / AUC(0-t) API) 1.00 7.61 2.25

[0153] The statistical moment parameters of the best absorption prescription are shown in Table 11:

[0154] Table 11.

[0155]

[0156]

[0157] It can be seen from the above results that compared with the raw material drug of brucenaolone, different prescriptions of the self-microemulsion composition of brucenaolone of the present invention significantly improve the oral absorption of the raw material drug, among which the best absorbed prescription ten has a bioavailability of 7.61 times that of the raw material drug, and its maximum blood drug concentration Cmax is 1.73 / 0.09=19.2 times that of the raw material drug. Compared with the tail vein injection (3 mg / kg), the bioavailability of the prescription ten (25 mg / kg) of the self-microemulsion composition of brucenaolone has a bioavailability of F=(2797.93 / 25) / (359.483 / 3)=93.4%.

[0158] Pharmacokinetic test 4:

[0159] Pharmacokinetic study of oral administration of sustained-release self-microemulsion composition of brexanolone

[0160] Although the above-mentioned brinolone self-microemulsion composition preparation significantly improves oral absorption and greatly improves bioavailability compared with the raw material drug, due to the inherent characteristics of brinolone that is rapidly distributed or metabolized after entering the blood, the blood drug concentration drops rapidly after reaching the peak, and the effective blood drug concentration is maintained for too short a time (the blood drug concentration drops to 33% of the peak value in 2 hours and 3% of the peak value in 4 hours). In addition, the blood drug concentration corresponding to the absorption peak is too high, which is also easy to cause adverse reactions of the central nervous system such as excessive sedation.

[0161] Therefore, on the basis of the above-mentioned self-microemulsification composition preparation significantly improving the oral absorption of brexanolone, the inventors further optimized the prescription and introduced a sustained-release factor to prepare a brexanolone sustained-release self-microemulsification composition.

[0162] In order to investigate whether the sustained-release self-microemulsion composition of brexanolone has the characteristics of improving absorption and delaying release in animals, a pharmacokinetic test of oral gavage administration of the sustained-release self-microemulsion composition of brexanolone in the above Example 3 (concentration of 12 mg / ml) to female SD rats was carried out, and the brexanolone raw material (suspended in 0.5% CMC-Na solution, concentration of 12 mg / ml) was used as a control.

[0163] Trial Drugs:

[0164] Brenolone sustained-release self-microemulsion composition (prescription 12, concentration 12 mg / ml);

[0165] Brenolone API (suspended in 0.5% CMC-Na solution, concentration of 12 mg / ml).

[0166] Experimental animals and experimental methods: All of them adopted the method of "pharmacokinetic test 1", and the oral gavage dose of each group was also 25 mg / kg. Only the blood collection time point and fasting method were different from the above: the blood collection time points were before administration (0 time) and 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, and 12h after administration. Fasting method: divided into 2 groups, 5 animals in each group, one of which fasted for 12h before administration (marked as "prescription 12, fasting"), and the other group had a normal diet (marked as "prescription 12, no fasting").

[0167] Test results:

[0168] After oral gavage (25 mg / kg, administered after fasting for 12 hours) of the fasting group and the non-fasting group of the sustained-release microemulsion of brexanolone (Formula 12, 12 mg / ml), and the raw material of brexanolone (suspended in 0.5% CMC-Na solution, concentration of 12 mg / ml), the detection results of brexanolone concentration in plasma samples at different times are shown in Table 12, wherein the data are the results after deducting the background value at time 0 (so the concentration at time 0 of each group is 0); "--" means not detected.

[0169] Table 12.

[0170]

[0171] Figure 4 The drug-time curve of the sustained-release self-microemulsion composition of brexanolone and the oral gavage administration of brexanolone raw material is shown.

[0172] DAS software was used to perform statistics on the drug-time curve data of the prescription twelve-fasting group, and its statistical moment parameters are shown in Table 13:

[0173] Table 13.

[0174]

[0175] As can be seen from the above results, compared with the raw material of brinolone, the sustained-release self-microemulsion composition of brinolone can still significantly improve oral absorption, and its maximum blood drug concentration Cmax is 292.4 / 14.8=19.7 times that of the raw material. Compared with the above-mentioned brinolone self-microemulsion composition (prescription ten), it shows a "slow-release" effect, and the blood drug concentration is maintained at a level above 30ng / ml within 8h. Compared with the non-fasting group, the fasting group before administration has better absorption.

[0176] Compared with tail vein injection (3 mg / kg), the absolute bioavailability of "Prescription 12, fasting" (25 mg / kg) F = (852.405 / 25) / (359.483 / 3) = 28.4%, which is much lower than the absolute bioavailability (93.4%) of the above-mentioned brexanolone self-microemulsification composition (Prescription 10), but a specific analysis of the blood drug concentration data at each time point shows that: compared with Prescription 10, "Prescription 12, fasting" has a smaller fluctuation in blood drug concentration within 8 hours, a lower blood drug concentration peak, which is beneficial to reducing the risk of adverse reactions; and the effective blood drug concentration (estimated to be around 30 ng / ml according to relevant literature) is maintained for a longer time, which is beneficial to maintaining the efficacy, thereby reducing the frequency of administration. The scheme of administering once every 8 hours has higher clinical feasibility.

[0177] The sustained release mechanism is speculated to be: the sustained-release self-microemulsion composition of brucenolide is a water-free solution system composed of a drug, an oil phase, an emulsifier and an emulsifier. When it comes into contact with a small amount of water (or liquid in the gastrointestinal tract), a phase transition occurs, and a microemulsion gel phase with a bicontinuous structure is spontaneously formed. The macroscopic manifestation is the formation of a semisolid gel, and the gel is light blue opalescent. The formation of the gel phase allows the drug to be slowly released therefrom, thereby allowing the preparation to exhibit certain sustained-release characteristics. As the system is further diluted, the gel phase continues to undergo a phase transition to form a microemulsion, thereby still being able to exert the inherent absorption-improving characteristics of the microemulsion.

[0178] Pharmacokinetic test 5:

[0179] The reproducibility of the pharmacokinetics of the sustained-release self-microemulsion composition of brexanolone of the present invention was investigated.

[0180] Trial Drugs:

[0181] Prescription 12 was appropriately amplified and three batches of samples were prepared continuously, with batch numbers 01, 02 and 03 respectively. Pharmacokinetic tests were carried out according to the method of pharmacokinetic test 4, and brexanolone raw material (suspended in 0.5% CMC-Na solution, concentration of 12 mg / ml) was used as a control.

[0182] 2. Experimental animals and experimental methods: They were consistent with the experiment of prescription 12 in pharmacokinetic experiment 4. All groups were fasted for 12 hours before administration.

[0183] 3. Test results:

[0184] After oral administration (25 mg / kg) of the sustained-release self-microemulsion composition of brucenolide (sustained-release self-microemulsion batch 01, sustained-release self-microemulsion batch 02, sustained-release self-microemulsion batch 03) and the raw material of brucenolide (suspended in 0.5% CMC-Na solution, concentration of 12 mg / ml), the detection results of brucenolide concentration in plasma samples at different times are shown in Table 14. The data in the table are the results after deducting the background value at time 0 (so the concentration at time 0 of each group is 0), and "--" means that it is not detected:

[0185] Table 14.

[0186]

[0187]

[0188] Figure 5 The drug-dose curves of three batches of sustained-release self-microemulsion of brexanolone and oral gavage of brexanolone raw materials are shown.

[0189] It can be seen from the above results that the pharmacokinetic curves of the three batches of brexanolone sustained-release self-microemulsion samples, which were appropriately enlarged and continuously prepared from prescription 12, are different from the pharmacokinetic curve of prescription 12 in "pharmacokinetic test 4", but the overall trend of the curves is consistent, and they are all rapidly absorbed after administration, and the blood drug concentration peaks around 1 hour, and then the blood drug concentration fluctuates and decreases within a certain range, and the blood drug concentration can still be maintained at a level above 30ng / ml within 8 hours. The brexanolone sustained-release self-microemulsion composition of the present invention has good reproducibility in pharmacokinetic properties.

[0190] Although multiple embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Those skilled in the art may conceive of many changes, modifications, and alternatives without departing from the thought and spirit of the present invention. It should be understood that in the process of practicing the present invention, various alternatives to the embodiments of the present invention described herein may be adopted. The appended claims are intended to define the scope of protection of the present invention, and therefore cover equivalents or alternatives within the scope of these claims.

Claims

1. A neuroactive steroid self-microemulsifying composition, characterized in that: include: 1-10 parts neuroactive steroids; 100-1000 parts of oil phase; 100-1500 parts of emulsifier; in, The oil phase is selected from any one or more of the following combinations: medium chain triglycerides, isopropyl myristate, isopropyl palmitate, ethyl oleate and caprylic decanoate; The emulsifier is selected from any one or more of the following combinations: polyoxyethylene castor oil EL, polyoxyethylene hydrogenated castor oil RH, polyoxyethylene hydrogenated castor oil PEG-40, lecithin, DSPE-5000 lecithin, Tween 80, poloxamer F127, and poloxamer F68.

2. The neuroactive steroid self-microemulsifying composition according to claim 1, characterized in that The neuroactive steroid is selected from the group consisting of progesterone, pregnanolone, brexanolone, alfalone, sepnanolone, minaxolone, ganaxolone, and alfaxalone.

3. The neuroactive steroid self-microemulsifying composition according to claim 1, characterized in that The neuroactive steroid is brexanolone.

4. The neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 3, characterized in that include: 5-10 parts neuroactive steroids; 100-1000 parts of oil phase; 100-1500 parts of emulsifier.

5. The neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 3, characterized in that include: 5-10 parts neuroactive steroids; 400-1000 parts of oil phase; 600-1500 parts of emulsifier.

6. The neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 3, characterized in that include: 1 part neuroactive steroid; 20-80 parts of oil phase; 34-54 parts of emulsifier.

7. The neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 3, characterized in that include: 1-10 parts neuroactive steroids; 100-1000 parts of oil phase; 100-1000 parts Tween 80; 50-500 parts lecithin.

8. The neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 3, characterized in that include: 1-10 parts neuroactive steroids; 100-1000 parts of oil phase; 50-500 parts of polyoxyethylene castor oil EL; 50-500 parts of polyoxyethylene hydrogenated castor oil RH; 10-100 parts lecithin.

9. The neuroactive steroid self-microemulsifying composition according to claim 1, characterized in that: include: 1-10 parts neuroactive steroids; 100-1000 parts of oil phase; 50-500 parts of polyoxyethylene castor oil EL; 50-500 parts of polyoxyethylene hydrogenated castor oil PEG-40; 10-100 parts lecithin.

10. The neuroactive steroid self-microemulsifying composition according to claim 1, characterized in that: Also includes: 100-1000 parts of auxiliary emulsifier; The auxiliary emulsifier is selected from any one or more combinations of the following: ethanol, ethylene glycol, 1,2-propylene glycol, glycerol, n-butanol, and PEG400.

11. The method for preparing the neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 9, characterized in that: include: Add the prescribed amount of oil phase and emulsifier and the auxiliary emulsifier, stir and mix them evenly at room temperature to obtain an intermediate product; The prescribed amount of neuroactive steroid is mixed with the intermediate product and stirred until completely dissolved to obtain a neuroactive steroid self-microemulsifying composition.

12. The method for preparing the neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 9, characterized in that: include, Stir the prescribed amount of oil phase and emulsifier at room temperature to mix them evenly to obtain a first intermediate product; Dissolving a prescribed amount of neuroactive steroid in a prescribed amount of an emulsifier to completely dissolve the steroid, and then mixing the steroid with the first intermediate product and stirring the mixture until the steroid is completely dissolved to obtain a second intermediate product; The second intermediate product is evaporated to remove the auxiliary emulsifier, thereby obtaining a neuroactive steroid self-microemulsifying composition.

13. Use of the neuroactive steroid self-microemulsifying composition according to any one of claims 1 to 10 in the preparation of a medicament for a disease related to a central nervous system disorder, The central nervous system disorder-related conditions include: Postpartum or postpartum depression, clinical depression, atypical depression, major depressive disorder, catatonic depression, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder, manic-depressive disorder, mood disorder, anxiety, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), depression due to a chronic medical condition, refractory depression, suicidal tendencies, suicidal ideation or behavior, premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory Memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, status epilepticus, TSC-related epilepsy, catamenial epilepsy, pediatric epilepsy, epileptiform disorders, essential tremor, NMDA hypofunction, Tourette syndrome, migraine, status epilepticus, sleep disorders, narcolepsy, Huntington's disease, fragile X syndrome, 5α-reductase inhibitor-induced depression, infantile spasms, PCDH19 female pediatric epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease or Alzheimer's disease, etc.

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