Epilepsy treatment methods and compositions

Abstract

Disclosed are methods and compositions for treating CNS disorders in a subject. In one embodiment, the method preferably comprises the steps of identifying a subject having or at risk of having epilepsy, and sequentially administering an AED orally to the subject. The administration preferably comprises a regimen of administering a predetermined amount of the AED at a predetermined frequency for a predetermined period. The subject preferably includes subjects experiencing cluster seizures, WWE, particularly WWE of childbearing age. The composition preferably includes NAS, particularly ENAS. The method preferably results in the prevention of epileptic seizures, or a reduction in frequency or magnitude.

Description

Technical Field

[0001] Cross - Reference to Related Applications This PCT patent application claims the benefit of U.S. Patent Application No. 63 / 348,045, filed on June 2, 2022, which is co - pending and is incorporated herein by reference in its entirety pursuant to PCT Rule 4.10.

[0002] Background of the Invention Various compositions suitable for pharmaceutical use and administration to mammals in need thereof are disclosed in the following U.S. patents and applications: U.S. Patent No. 11,337,987, filed on May 7, 2021 and issued on May 24, 2022; U.S. Application No. 17 / 706,210, filed on March 28, 2022; U.S. Application No. 17 / 723,203, filed on April 18, 2022; U.S. Patent No. 11,478,485, filed on May 10, 2022 and issued on October 25, 2022; and U.S. Application No. 17 / 823,080, filed on August 22, 2022 (hereinafter, "the patents"), all of which are incorporated herein by reference in their entirety.

[0003] Field of the Invention The present disclosure relates to compositions, and more particularly to oral compositions, dosage forms, and regimens, as well as methods of treating subjects having central nervous system disorders, and more particularly methods of treating epilepsy. Thus, the present disclosure is involved in the fields of chemistry, pharmacy, medicine, and other health sciences.

[0004] Neuroactive steroids are a type of endogenous steroid that have a potent and selective effect on GABAA receptors, which consist of synaptic and extrasynaptic sites, in the brain, adrenal glands, and gonads. When a neuroactive steroid activates synaptic GABAA receptors, this activation generates a rapid and short chloride ion current called phasic inhibition. When a neuroactive steroid activates extrasynaptic GABAA receptors, a slow and sustained chloride ion current called tonic inhibition occurs.

[0005] 3α-OH-5β-pregnan-20-one having the chemical structure shown in FIG. 1 is characterized by having a hydrogen with β-orientation at the C5 position of the first carbon ring. 3α-OH-5β-pregnan-20-one has low water solubility and high lipophilicity. The melting point of 3α-OH-5β-pregnan-20-one is ~150 °C. Therefore, the desired therapeutic level of serum concentration after oral administration remains unachieved, probably due to insufficient release or dissolution in the digestive tract.

[0006] Currently, there is no acceptable approach that enables an oral dosage form containing 3α-OH-5β-pregnan-20-one to provide a therapeutically effective level of 3α-OH-5β-pregnan-20-one to patients with CNS disorders or other disorders that require 3α-OH-5β-pregnan-20-one. Synthetic chemical modifications from endogenous neuroactive steroids are often employed to improve oral bioavailability, such as ZURANOLONE, ETX-155 (see: https: / / eliemtx.com / pipeline / ), GANAXOLONE, PRAX-114 (see: https: / / en.wikipedia.org / wiki / List_of_investigational_antidepressants), ALPHAXALONE (see: https: / / en.wikipedia.org / wiki / Alfaxalone), etc., but their unknown safety profiles need to be elucidated or studied for potential therapeutic use.

[0007] Epilepsy is defined by 1) the occurrence of at least two unprovoked seizures at intervals exceeding 24 hours, 2) the occurrence of one unprovoked seizure with a likelihood of further seizures in the next 10 years, and / or 3) being diagnosed with epilepsy syndrome. Epilepsy is a brain disorder that causes seizures, affects physical, mental, and social well-being, and is associated with a mortality rate two to three times higher than that of the general population. Approximately 60 - 65% of epilepsy cases are idiopathic, and about 30% of patients have refractory epilepsy (i.e., epilepsy that cannot be well managed with currently available antiepileptic medications (「ASM」), or drugs also called antiepileptic drugs (AED)). Epilepsy is the most common neurological disorder seen during pregnancy. Epilepsy patients are highly likely to have co-existing other disorders such as depression and anxiety disorders. Epilepsy patients have an increased risk of death due to the direct effects of seizures (such as status epilepticus) and the indirect effects of seizures (such as suicide, traffic accidents, and effects on the cardiovascular system).

[0008] In the United States, it is estimated that approximately 900,000 women of childbearing age (CB) suffer from active epilepsy. Epileptic women of CB age face many additional challenges throughout the various stages of the reproductive cycle, such as the hormonal effects on seizure activity and endocrine function. Since about 30% of epilepsy patients cannot effectively control their epilepsy with available ASM, it is important to consider options for the development of newer pharmacological treatments. The main goal is the management of uncontrolled seizures in women with epilepsy (WWE) of CB age during the pre-pregnancy, pregnancy, and postpartum periods. Therefore, an uncompromised ASM efficacy that achieves the lowest possible monotherapy dose to address concerns about fetal toxicity, with acceptable variability and reduced or zero drug-drug interactions, remains an unmet need. Additionally, seizure control, including the prevention of breakthrough seizures, is very important when planning a pregnancy, as it can also lead to unwanted falls and motor vehicle accidents, potentially impairing driving freedom.

[0009] ASM may induce contraceptive failure, reproductive hormone imbalance, anxiety, and depression. There remains an unmet need for ASMs that do not have the aforementioned drawbacks, have no or low fetal-neonatal toxicity, have no concerns regarding lactation, and have the potential to treat related complications. In the United States, more than 30 molecules are approved as antiepileptic drugs, but there are no antiepileptic drugs specifically approved for WWE of childbearing age. Some ASMs are known to have teratogenic effects on the developing fetus (converging evidence from registry studies indicates that valproic acid has the highest teratogenic risk, followed by carbamazepine and topiramate). Other commonly prescribed ASMs, including older-generation drugs such as phenobarbital and phenytoin, are associated with higher risks compared to lamotrigine, levetiracetam, clonazepam, and gabapentin (Vajda et al., 2014; Voinescu and Pennell, 2015). Furthermore, the risks associated with ASMs are considerably higher in the first trimester of pregnancy. Therefore, WWE of childbearing age need to receive counseling, monitoring, and adjustment to the most appropriate ASM prior to pregnancy. WWE of childbearing age should consult with their physicians about seizure control at least 6 months before pregnancy and, if possible, discontinue ASM therapy or use the lowest effective dose of a single antiepileptic drug, depending on the type of epilepsy and the fetal toxicity of the ASM. Women who are worried about unplanned pregnancy or whose pregnancy confirmation is delayed, whether planned or unplanned, may experience anxiety, depression, non-compliance with ASMs, and / or contraceptive failure. ASMs reduce the effectiveness of oral contraceptives, further complicating this issue.

[0010] There are complex and multi-directional interactions among female hormones, seizures, and ASMs. Most hormones act as neuroactive steroids (NAS), so they can regulate the excitability of the brain. Changes in endogenous or exogenous hormone levels can affect the occurrence of seizures directly or through PK interactions that change the plasma concentration of ASMs (Harden, 2008). The PK interaction between oral contraceptives and ASMs is bidirectional (Johnston and Crawford, 2014). In women taking CYP-P450 enzyme-inducing ASMs, the effectiveness of hormonal contraception may be reduced. Epilepsy is not a medical condition for which contraceptives are contraindicated. Contraceptive failure is probably related to ASMs and may be the cause of unplanned pregnancies in up to 1 in 4 women in WWE (∼12.5% of all WWE pregnancies), compared with 1% in healthy women. Moreover, in particular, gender-specific unmet needs remain. For example, there remains a need for safe and adequately orally bioavailable compositions and methods and treatments containing 3α-OH-5β-pregnan-20-one for women with epilepsy (before pregnancy, during pregnancy, during labor / childbirth, after childbirth, or in the perimenopausal and postmenopausal periods).

[0011] In addition, in the United States, more than 150,000 patients with uncontrolled epilepsy experience seizure clusters. Failure to treat seizure clusters (acute repetitive seizures or ARS, cluster seizures, serial seizures, crescendo seizures, seizure storms, recurrent seizures, periodic seizures, etc.) is very important because it increases the risk of physical injury, neuropathy, and status epilepticus. Despite the impact of seizure clusters, many diagnosed patients may remain untreated because currently available treatment options are inconvenient.

[0012] Current options for treating or preventing ARS are rectal or nasal administration. Rectal administration has issues such as the plasma concentration being potentially affected by drug excretion, shedding, and exudation, social concerns regarding rectal administration in public, difficulty in administering to overweight patients, resistance to administration by patients or caregivers, and the need for the patient to lie on their side. Nasal administration is not as complex as rectal administration, but the patient or caregiver needs to carry a spray device. Additionally, dosage limitations, nasal discomfort, throat irritation, eye tearing, respiratory depression, and drowsiness are also treatment challenges.

[0013] There is still an unmet need for new mechanisms of action, such as the selective enhancement of GABA receptor responses with excellent tolerability. 3α-OH-5β-pregnan-20-one has been shown in a mouse electroshock seizure model to have the potential to be useful in the treatment of epilepsy, a central nervous system disorder, via positive allosteric modulators (PAMs) of the GABAA receptor. However, it is still difficult to obtain effective serum concentrations of 3α-OH-5β-pregnan-20-one. Therefore, there is an unmet need for oral compositions and methods that enable the desirable release of 3α-OH-5β-pregnan-20-one and subsequent effective absorption, allowing for the generation of appropriate serum levels of 3α-OH-5β-pregnan-20-one for treating various central nervous system disorders in subjects in need of 3α-OH-5β-pregnan-20-one for treating CNS disorders. We have surprisingly found oral compositions and methods that can rapidly generate desirable levels of 3α-OH-5β-pregnan-20-one, have bioavailability reaching therapeutic levels, are portable, easy to administer, have a good safety profile, and a long shelf life at ambient temperature. Summary of the Invention

[0014] This disclosure encompasses compositions and oral dosage forms and regimens containing 3α-OH-5β-pregnan-20-one, as well as related methods. The compositions and oral dosage forms can be formulated to include a therapeutically effective amount of 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives. In one aspect, the pharmaceutically acceptable additives of the composition or dosage form can provide an amount of 3α-OH-5β-pregnan-20-one sufficient to treat CNS disorders when orally administered to a subject. In another aspect, the composition or dosage form can include an immediate-release or solubilized or solubilizing form of 3α-OH-5β-pregnan-20-one that can enhance, increase, or maximize the bioavailability (e.g., C max and / or AUC) of 3α-OH-5β-pregnan-20-one when orally administered to a subject. For example, in one aspect, when orally administered to a subject through the compositions and methods of the present invention, the in vitro release, in vivo solubilization, absorption, and / or CNS activity of 3α-OH-5β-pregnan-20-one is increased. In another aspect, the absorption and / or CNS activity of 3α-OH-5β-pregnan-20-one when orally administered to a subject by the compositions and methods of this invention is relatively increased compared to a composition containing an equivalent amount of 3α-OH-5β-pregnan-20-one in its untreated crystalline form or a cyclodextrin solution composition when orally administered to a subject.

[0015] This disclosure encompasses compositions and oral dosage forms and administration regimens containing 3α-OH-5β-pregnan-20-one, as well as related methods. The compositions and oral dosage forms can be formulated to include a therapeutically effective amount of 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives. In one aspect, the pharmaceutically acceptable additives of the composition or dosage form can provide a daily amount of 3α-OH-5β-pregnan-20-one sufficient to treat CNS disorders when orally administered to a subject. In another aspect, the composition or dosage form or method can be C max and / or AUC 0-tEnable the effective rate and extent of oral absorption evaluated thereby, or dose-normalized C max and / or AUC 0-t Enable efficient oral absorption / bioavailability evaluated thereby, or include doses and dosing regimens that can enhance, increase, or maximize the absorption / bioavailability of 3α-OH-5β-pregnan-20-one when orally administered to a subject. For example, in one embodiment, when orally administered to a subject by the compositions and methods of the present invention, the absorption of 3α-OH-5β-pregnan-20-one can be effectively enabled and the associated CNS activity of 3α-OH-5β-pregnan-20-one can be achieved or improved.

[0016] In one embodiment, the composition can be formulated as an oral dosage form having from about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one. The 3α-OH-5β-pregnan-20-one may be processed, and as a result, before being formulated into an oral composition or dosage form, it is in a form that has been crushed, sieved, milled, micronized, or nano-sized, or after being formulated into the composition or dosage form, it is in an amorphous or fully solubilized form. The crystalline form of the processed 3α-OH-5β-pregnan-20-one includes a particle size distribution with a D90 of less than 75 μm, a D90 of less than 20 μm, a D90 of 16 μm, a D90 of 13 μm, a D10 of greater than 1 μm, and at least one D50 of 0.15 μm to 50 μm, 30 μm to 50 μm, 0.3 to 30 μm, and 2 μm to 8 μm.

[0017] In one embodiment, the dosage amount of the composition includes from about 10 mg to about 1200 mg of 3α-OH-5β-pregnan-20-one. In one aspect, the composition can be a solid, liquid, semi-liquid or semi-solid, gel, granule, pellet, powder, syrup, emulsion, dispersion, suspension, capsule, powder, tablet, chewable tablet, cream, ointment, paste, paste-like composition, or beverage.

[0018] In yet another embodiment, a method of treating a CNS disorder in a subject can include orally administering to the subject a therapeutically effective amount of 3α-OH-5β-pregnan-20-one. In one aspect, the therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be an amount of 3α-OH-5β-pregnan-20-one sufficient to treat the CNS disorder. In another aspect, a composition comprising 3α-OH-5β-pregnan-20-one as disclosed herein can be in a form that provides a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one lipophilic additive sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating a CNS disorder in a subject.

Brief Description of the Drawings

[0019] The features and advantages of the various embodiments will become apparent from the following detailed description in conjunction with the accompanying drawings which illustrate by way of example the features of the present disclosure:

[0020]

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[0021] Before the embodiments of the invention are described, it is to be understood that the present disclosure is not limited to the specific structures, process steps, or materials disclosed herein, but extends to their equivalents as would be recognized by one of ordinary skill in the relevant art. Also, it is to be understood that the terms used herein are for the purpose of describing particular examples or embodiments only and are not intended to be limiting.

[0022] Furthermore, the described features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details such as examples of compositions, dosage forms, treatments, etc. are provided to provide a thorough understanding of various embodiments of the present invention. However, one of ordinary skill in the relevant art will recognize that such detailed embodiments do not limit the overall inventive concept disclosed herein, but merely represent typical ones thereof.

[0023] Definition Note that the singular forms "a", "an", and "the" include references to plural forms unless the context clearly dictates otherwise. Thus, for example, a reference to "excipient" includes a reference to one or more such excipients, and a reference to "additive" includes a reference to one or more such additives.

[0024] As used herein, terms such as "treat", "treatment", or "treating" refer to the administration of a therapeutic agent to a subject, whether symptomatic or asymptomatic. In other words, "treat", "treatment", or "treating" can refer to an act of reducing or eliminating a condition (i.e., an appearance of symptoms), or can refer to prophylactic treatment (i.e., administration to a subject in whom symptoms have not yet appeared in order to prevent the occurrence of symptoms). Such prophylactic treatment can also be referred to as disease prevention, preventive action, preventive means, etc.

[0025] As used herein, terms such as "therapeutic agent", "active agent", etc. can be used interchangeably and refer to a drug or substance that has a specific or selected physiological activity that can be measured when administered to a subject in a significant or effective amount. Since many drugs and prodrugs are known to have specific physiological activities, it should be understood that the term "drug" is explicitly included in this definition. These terms are well known in the pharmaceutical and medical arts. Further, when these terms are used, or when a specific active agent is specifically identified by name or category herein, such description is intended to include explicit support for the active agent itself, as well as pharmaceutically acceptable salts, esters, or compounds significantly related thereto, including but not limited to prodrugs, active metabolites, isomers, etc. For example, a description of the active agent 3α-OH-5β-pregnan-20-one also includes explicit support for active metabolites.

[0026] As used herein, the terms "formulation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents and additives or other excipients. Further, the term "dosage form" can include one or more formulations or compositions provided in a manner for administration to a subject. For example, an "oral dosage form" may be suitable for administration to a subject's mouth. A "topical dosage form" may be suitable for administration to a subject's skin, such as by rubbing.

[0027] As used herein, the terms "pharmaceutically acceptable additive" or "additive" are used interchangeably and refer to a pharmaceutically acceptable agent or component that can be combined with an active agent as part of a composition or dosage form. In some embodiments, a pharmaceutically acceptable additive can affect the form or behavior of an active agent. For example, in some embodiments, a pharmaceutically acceptable additive can completely or partially dissolve or solubilize an active agent (e.g., 3α-OH-5β-pregnan-20-one) in a pharmaceutical composition or can enable an amorphous form of the active agent. In other embodiments, a pharmaceutically acceptable additive can be formulated with an active agent (e.g., 3α-OH-5β-pregnan-20-one) in a pharmaceutical composition that includes a crystalline form of the active agent. In one embodiment, the composition is such that 3α-OH-5β-pregnan-20-one comprises at least one form of substantially solubilized, partially solubilized, substantially non-solubilized, substantially crystalline, partially crystalline, substantially amorphous, amorphous, solid, dispersion, and eutectic mixture.

[0028] Furthermore, in some embodiments, the additive can affect or control the properties and performance of the composition or dosage form. For example, in some embodiments, the additive can affect or control the pharmacokinetic (PK) performance or profile (e.g., the release rate and / or extent of release of the active agent) of the composition and / or dosage form. Further, in some embodiments, the additive can affect or control the pharmacodynamic (PD) performance or profile (e.g., reduction of a photodynamic response).

[0029] As used herein, "semi-liquid" or "semi-solid" corresponds to a partially solubilized active agent, and "liquid" corresponds to a fully solubilized active agent at room temperature.

[0030] As used herein, "subject" refers to a mammal that may benefit from administration of the pharmaceutical compositions, dosage forms or regimens, or methods disclosed herein. Examples of subjects include humans and may also include other animals such as horses, pigs, cows, dogs, cats, rabbits, and aquatic mammals. In one specific embodiment, the subject is a human. In another embodiment, the subject is a female. In another embodiment, the subject is a female of childbearing age. In another embodiment, the female has given birth within the past 1 to 12 months. In another embodiment, the subject is a male.

[0031] As used herein, "in need of treatment" and the like refer to a subject having or suspected of having a disease, condition, or disorder, or a subject desiring or being an appropriate candidate for treatment, according to various diagnostic criteria commonly in use. Thus, "in need of treatment" can include the act of identifying a subject in need of treatment.

[0032] As used herein, "identifying a subject in need of treatment" can include obtaining a biological sample from the subject, determining the levels of one or more biomarkers described herein, evaluating a biological sample obtained from the subject, performing image analysis on the subject, evaluating one or more clinical characteristics of the subject (e.g., evaluating symptoms or manifestations), or a combination of these operations.

[0033] As used herein, the terms "disease", "disorder", "condition", "symptom", and "ailment" can be used interchangeably and refer to any abnormality or improper functioning of any part, group, or system of the subject's physiology, regardless of its causality. For example, mental disorders and emotional ailments can be caused by environmental factors, genetic factors, physiological events, past experiences, other influences, or combinations thereof.

[0034] As used herein, an "acute" condition refers to a condition with distinct symptoms that develop rapidly and require urgent or semi-urgent treatment. In contrast, a "chronic" condition typically refers to a condition that has a slow onset, persists, or otherwise progresses over time. Examples of acute conditions include, but are not limited to, asthma attacks, bronchitis, heart attacks, pneumonia, etc. Examples of chronic diseases include, but are not limited to, arthritis, diabetes, hypertension, dyslipidemia, etc.

[0035] The terms "serum level", "serum amount", "serum concentration", "plasma level", "plasma concentration", "blood level", and "blood concentration" can be used interchangeably herein and refer to the total amount of an identified analyte (e.g., an identified metabolite or active agent) including the free fraction, the bioavailable fraction, and the bound fraction in the blood of a subject. For example, "serum 3α-OH-5β-pregnan-20-one" or "serum 3α-OH-5β-pregnan-20-one level" or "serum 3α-OH-5β-pregnan-20-one concentration" or "plasma 3α-OH-5β-pregnan-20-one concentration" or "3α-OH-5β-pregnan-20-one blood 3α-OH-5β-pregnan-20-one concentration" refers to the total 3α-OH-5β-pregnan-20-one concentration which is the sum of the existing 3α-OH-5β-pregnan-20-one fractions including substantially free and bound 3α-OH-5β-pregnan-20-one concentrations. It should be understood that herein such terms provide explicit support for the total analyte or drug level, as well as various applicable fractions including bioavailability, bound fraction, and substantially free fraction. Unless otherwise specified, these values are the "observed" concentrations or amounts that do not adjust or correct for the baseline serum level of the subject. As with any bioanalytical measurement method, for consistency, the method employed to measure the initial serum concentration should be consistent with the method used to monitor and re-measure the serum concentration during the subject's clinical examination and treatment. In this specification, the term "C avg " refers to the average serum concentration level from time 0 to t (e.g., 1-day average serum concentration level, 1-day C avg which is calculated as the ratio of AUC 0-24 / 24 hours), and the term "C max " refers to the maximum serum concentration level after a single dose during that period.

[0036] Measurements based on immunoassays of serum 3α-OH-5β-pregnan-20-one and its isomers are not as accurate as conventional radioimmunoassays (RIA) because RIA is usually not specific for the target analyte. To measure the target analyte, an assay based on a method combining chromatography and mass spectrometry (e.g., LC-MS or GC-MS) is required, and reliable data can be obtained to evaluate the true PK and pharmacodynamic (PD) potential of 3α-OH-5β-pregnan-20-one. Therefore, data and results regarding oral 3α-OH-5β-pregnan-20-one are reliable with respect to NAS levels or the validity of NAS levels for desirable GABAA receptor modulation only when determined by an analytical procedure suitable for the separation step of the individual analyte in terms of specificity and accuracy, such as liquid chromatography (LC), gas chromatography (GC), liquid chromatography-tandem mass spectrometry (LC-MS), or gas chromatography-mass spectrometry (GC-MS).

[0037] In one aspect, PK values (e.g., serum concentration, calculated ratio) of an analyte of interest (e.g., 3α-OH-5β-pregnan-20-one) obtained from the compositions and methods of the present invention are based on LC, LC-MS, GC, or GC-MS measurements.

[0038] As used herein with respect to the physiological level of a given substance, the term "baseline" refers to the level or concentration of a substance, such as the target analyte (e.g., 3α-OH-5β-pregnan-20-one), in a subject prior to administration of the active agent. For example, the baseline level of 3α-OH-5β-pregnan-20-one in a subject would be the 3α-OH-5β-pregnan-20-one serum level of the subject immediately prior to (e.g., just before) the initiation of administration or treatment of 3α-OH-5β-pregnan-20-one.

[0039] The term "oral administration" refers to any administration method by which an active agent can be administered by swallowing, chewing, aspirating, or drinking a composition or dosage form. Oral administration can be intended for enteral delivery of the active agent or transmucosal delivery of the active agent. In some embodiments, the compositions and dosage forms of the present disclosure can be admixed with food or beverage prior to oral ingestion or co-administered with food or meal in other ways.

[0040] As used herein, the terms "release" and "release rate" are used interchangeably to refer to the release or liberation of a substance from a composition or dosage form into the surrounding environment, such as an aqueous medium, in vitro or in vivo, although not limited to drugs. In another aspect, the term "disintegration" is a physical process related to the mechanical breakdown of a tablet into smaller particles / granules and represents, in accordance with <701> Disintegration, USP43, the disruption of interparticle interactions that occur during the formation of a tablet by compression of granulated particles of an active pharmaceutical ingredient (API) and excipients. In another aspect, the term "disintegration" is a physical process related to the opening or rupture of a capsule. As used herein, the term "disintegration time" refers to the amount of time elapsed for disintegration to occur.

[0041] As used herein, the term "dissolution" refers to the solubilization of an active entity from a composition or dosage form into the surrounding environment, such as an aqueous medium, either in vitro or in vivo.

[0042] As used herein, "administration regimen" or "regimen", such as "initial administration regimen" or "starting dose" or "maintenance administration regimen", refers to the method, timing, amount, and duration of administering the dosage of the composition or dosage form of the present disclosure to a subject. For example, an initial dose or starting dose regimen for a subject may be divided administration of a total daily dose of about 10 mg to about 3400 mg, repeated daily for 30 days, while eating, with an interval of at least 4 hours.

[0043] As used herein, "daily dose" refers to the amount of 3α-OH-5β-pregnan-20-one administered to a subject over a 24-hour period. The daily dose can be administered once or multiple times over a 24-hour period. In one embodiment, the daily dose provides 2 or 3 or 4 or 6 or 8 administrations during a 24-hour period. With this in mind, "initial dose" or "initial daily dose" refers to the initial regimen or the dose administered during a period of the dosing regimen.

[0044] As used herein, "effective amount" or "therapeutically effective amount" of a drug refers to a non-toxic but sufficient amount of the drug to obtain a therapeutic effect in the treatment of a medical condition for which the drug is known to be effective. It is understood that various biological factors can affect the ability of a substance to perform its intended role. Thus, an "effective amount" or "therapeutically effective amount" may depend on such biological factors. Further, while the achievement of a therapeutic effect can be measured by a physician or other qualified healthcare professional using evaluation methods known in the art, it is recognized that due to individual differences and responses to treatment, the achievement of a therapeutic effect can be a somewhat subjective determination. The determination of an effective amount is within the scope of ordinary skill in the fields of pharmacy and medicine. For example, see Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis", Monographs in Epidemiology and Biostatistics , Vol. 8 (1986).

[0045] As used herein, "single administration" when referring to administration to a subject, refers to a dosage form being a single dosage form, e.g., a single tablet, capsule, pump, or a single puff of a gel or solution. In contrast, "multiple units" used to describe administration to a subject refers to a dosage that includes two or more dosage forms, e.g., two capsules, three tablets, two to four pumps or nebulizers. It should be noted that the multiple unit dosage forms are generally of the same type of dosage form (i.e., tablets or capsules), but do not have to be of the same dosage form type. Further, tablets may be scored or pre-scored such that half or a quarter of a single tablet may be applicable within the present disclosure. The score and / or pre-score may represent a score that divides the tablet into quarters or halves.

[0046] In the present disclosure, terms such as "comprises," "comprising," "containing," and "having" can have the meanings given to them in United States patent law, can mean "includes," "including," etc., and are generally construed as open-ended terms. The terms "consisting of" or "consists of" are closed terms and include only the specifically recited components, structures, steps, etc. in accordance with United States patent law. "Consisting essentially of" or "consists essentially of" or "essentially consisting" has the meaning generally imparted by United States patent law. In particular, such terms are generally closed terms, with the exception of allowing the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or functions of the item used in connection therewith. For example, trace elements present in a composition but that do not affect the nature or properties of the composition are permitted under the term "consisting essentially of" even if not explicitly listed in the list of items following such term. When using open-ended terms such as "comprising" or "including" in this specification, direct support should be given not only to the expression "consisting essentially of" but also to the expression "consisting of" as if it were explicitly recited, and vice versa is understood to be the case.

[0047] The terms "first", "second", "third", "fourth", etc. in this specification and the claims are used, if at all, to distinguish similar elements and are not necessarily used to describe a particular order or chronological sequence. It should be understood that terms used in this way are interchangeable in appropriate circumstances where the embodiments described herein can operate in an order other than, for example, that shown or otherwise described herein. Similarly, in this specification, when a method is described as being composed of a series of steps, the order of the steps as presented herein is not necessarily the only order in which such steps can be performed, a particular step among the described steps may be omitted, and / or other particular steps not described herein may be added to the method.

[0048] Even if the phrases "in one embodiment" or "in one aspect" appear in this specification, they do not necessarily all refer to the same embodiment or aspect.

[0049] As used herein, comparative terms such as "increased," "decreased," "better," "worse," "higher," "lower," "enhanced," "improved," "maximized," "minimized," etc. refer to a property of an apparatus, component, biological response, biological state, or activity that is measurably different from another apparatus, component, composition, biological response, biological state, or activity, compared to the surrounding or adjacent region, a similar location, a single apparatus or composition or a plurality of comparable apparatuses or compositions, a group or class, a plurality of groups or classes, or the original (e.g., untreated) or baseline state, or known prior art. For example, a composition or dosage form containing 3α-OH-5β-pregnan-20-one "increases" the serum level of 3α-OH-5β-pregnan-20-one or provides elevated 3α-OH-5β-pregnan-20-one compared to the serum level at a previous time point such as a baseline level (e.g., prior to treatment) or compared to a previous treatment at a different dose (e.g., a lower dose). Alternatively, a composition or dosage form that provides an "increased" serum level of 3α-OH-5β-pregnan-20-one may result in such an increase compared to an equivalent amount of 3α-OH-5β-pregnan-20-one in an alternative known composition or dosage form, e.g., one that uses suboptimal additives when orally administered to a subject, or a composition containing crystalline 3α-OH-5β-pregnan-20-one, or a composition consisting essentially of 3α-OH-5β-pregnan-20-one suspended / dissolved in an edible oil such as canola oil, peanut oil, medium-chain triglycerides, or a composition consisting essentially of 3α-OH-5β-pregnan-20-one solubilized / dissolved in a cyclodextrin solution, or a composition consisting essentially of 3α-OH-5β-pregnan-20-one suspended in TWEEN-80.

[0050] As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed means that the object is either completely enclosed or nearly completely enclosed. The exact allowable deviation from absolute completeness may in some cases depend on the particular context. However, generally speaking, it is a state close to completeness such that the overall result is the same as if absolute completeness were achieved. The use of "substantially" is equally applicable when used in a negative sense to mean a complete or near complete lack of an action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free of" particles is either completely lacking in particles or nearly completely lacking in particles to the extent that the same effect as being completely lacking in particles is obtained. In other words, a composition that is "substantially free of" a certain component or element may still actually contain such an item as long as there is no measurable effect.

[0051] As used herein, the term "completely" refers to the complete extent or degree of an action, characteristic, property, state, structure, item, or result.

[0052] As used herein, the term "about" is used to provide flexibility to the endpoints of a numerical range by providing that a given value may be "slightly above" or "slightly below" the endpoint. Unless otherwise specified, the use of the term "about" with a particular numerical or numerical range should be understood to provide support for that numerical term or numerical range without the term "about". For example, for the sake of convenience and brevity, the numerical range of "about 50 angstroms to about 80 angstroms" should also be understood to support the range of "50 angstroms to 80 angstroms". Further, it should be understood that in this specification, even when the term "about" is used, support for the actual numerical value is provided. For example, the description of "about" 30 should be interpreted to provide support not only for values slightly above and slightly below 30, but also for the actual numerical value of 30.

[0053] In this specification, multiple items, structural elements, components, and / or materials may, for the sake of convenience, be presented in a common list. However, these lists should be interpreted such that each member of the list is individually identified as a distinct and unique member. Thus, the individual members of such a list should not be interpreted as being equivalent to other members of the same list based solely on their presentation in a common group, unless otherwise indicated.

[0054] As used herein, the term "GABA" refers to gamma-aminobutyric acid (see the Wikipedia entry for gamma-aminobutyric acid).

[0055] In this specification, concentrations, amounts, levels, and other numerical data may be expressed or presented in a range format. Such a range format is merely used for convenience and brevity, and thus, should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also all individual numerical values or sub-ranges or decimal units that are included within that range as if each numerical value and sub-range were explicitly recited. For example, the numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also the individual values and sub-ranges within the indicated range. Thus, this numerical range includes individual values such as 2, 3, 4 as well as sub-ranges such as 1 to 3, 2 to 4, 3 to 5, in addition to the individual 1, 2, 3, 4, 5. This principle also applies to ranges that recite only one numerical value as the minimum or maximum value. Further, such an interpretation should apply regardless of the breadth of the range or the nature of the characteristics being described.

[0056] References throughout this specification to "one embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrase "in one embodiment" throughout this specification are not necessarily all referring to the same embodiment.

Best Mode for Carrying Out the Invention

[0057] Explanation Next, preferred embodiments of the present invention will be described in detail. Although the embodiments are described specifically, the present disclosure is not limited to such embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the present disclosure.

[0058] The following presents a first overview of the technical embodiments, followed by a more detailed description of specific technical embodiments. This first overview is intended to assist the reader in understanding the technology more rapidly, but is not intended to identify the main or essential features of the technology, nor to limit the scope of the claimed subject matter.

[0059] Some of the neuroregulatory and protective effects of 3α-OH-5β-pregnan-20-one result in anticonvulsant, antidepressant, anxiolytic, and neuroprotective effects in experimental animals, tissues, and cell cultures.

[0060] Several efforts have been made to improve the bioavailability of 3α-OH-5β-pregnan-20-one upon oral administration. However, there has been no composition or method of administration directed to providing a sufficient level of GABA A receptor modulator after oral administration with a greater amount and more rapidly of serum 3α-OH-5β-pregnan-20-one, particularly for therapeutic utility.

[0061] Achieving a desirable serum 3α-OH-5β-pregnan-20-one level or appropriate oral dosage for CNS efficacy remains elusive and difficult for many reasons.

[0062] Accordingly, there remains an unmet need for compositions and methods that enable a higher, faster, more reliable, and appropriate serum level of 3α-OH-5β-pregnan-20-one to be generated in a biocompatible manner for treating various CNS disorders, thereby treating subjects in need of 3α-OH-5β-pregnan-20-one for the treatment of CNS disorders. In some embodiments, we have surprisingly found that the oral compositions and methods of the present invention are effective in generating a desirable level of 3α-OH-5β-pregnan-20-one.

[0063] Throughout this specification, references to "one embodiment", "an embodiment", or similar language mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment", "in an embodiment", and the like throughout this specification are not necessarily all referring to the same embodiment.

[0064] The present invention can be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. Thus, the scope of the present invention is indicated by the appended claims rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

[0065] In one embodiment of the present invention, an oral pharmaceutical composition can include a therapeutically effective amount of 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives that provide an amount of 3α-OH-5β-pregnan-20-one sufficient to treat CNS depressive disorders when orally administered to a subject. In some aspects, the additives can maximize, accelerate, or otherwise improve the absorption of 3α-OH-5β-pregnan-20-one from the composition when administered to the subject. In some aspects, the additives can improve the release rate and / or amount of 3α-OH-5β-pregnan-20-one when administered to the subject. In some aspects, the additives can improve the solubilization of 3α-OH-5β-pregnan-20-one when administered to the subject. In some aspects, due to the additives, components, and the shape and / or size of the dosage form (e.g., tablet or capsule) of the composition, the disintegration rate of the dosage form can be improved, for example, to be 25 minutes or less.

[0066] In some aspects of the present invention, the form of 3α-OH-5β-pregnan-20-one in the composition can improve the release rate and / or amount of 3α-OH-5β-pregnan-20-one when tested in vitro or when administered to a subject. In some aspects, the form of 3α-OH-5β-pregnan-20-one in the composition can improve the solubilization of 3α-OH-5β-pregnan-20-one when administered to a subject.

[0067] When using a sulfobutylether-β-cyclodextrin (SBE-β-CD) oral composition having solubilized or semi-solid 3α-OH-5β-pregnan-20-one, due to limitations in the solubility of 3α-OH-5β-pregnan-20-one in various cyclodextrin solutions containing non-encapsulated SBE-β-CD, it may be difficult to fill an appropriate amount of 3α-OH-5β-pregnan-20-one to deliver an effective serum level of 3α-OH-5β-pregnan-20-one. Furthermore, the large amounts of cyclodextrin required for formulation with 3α-OH-5β-pregnan-20-one may also present safety concerns. In some aspects, the compositions and dosage forms of the present invention allow for filling of a greater amount of 3α-OH-5β-pregnan-20-one compared to non-encapsulated SBE-β-CD or any cyclodextrin solution composition.

[0068] In another aspect, a specific weight percentage of 3α-OH-5β-pregnan-20-one in the composition or dosage form can be solubilized. In one example, about 50% to about 100% of the 3α-OH-5β-pregnan-20-one in the composition can be solubilized. In another example, about 50% to about 65% of the 3α-OH-5β-pregnan-20-one in the composition can be solubilized. In yet another example, about 65% to about 85% of the 3α-OH-5β-pregnan-20-one in the composition can be solubilized. In another example, about 85% to about 100% of the 3α-OH-5β-pregnan-20-one in the composition can be solubilized. In another example, about 85% to about 100% of the 3α-OH-5β-pregnan-20-one in the composition may be solubilized in a plurality of additives that are essentially free of SBE-β-CD.

[0069] In another embodiment, an oral pharmaceutical composition or oral dosage form may contain 3α-OH-5β-pregnan-20-one in a therapeutically effective amount that provides a desirable GABA A receptor binding efficiency when administered to a subject.

[0070] In one embodiment, the 3α-OH-5β-pregnan-20-one composition and oral dosage form can be formulated to provide a therapeutically effective amount or peak level of 3α-OH-5β-pregnan-20-one to treat CNS disorders when orally administered to a subject. For example, in one aspect, the composition and oral dosage form may contain a plurality of pharmaceutically acceptable additives that provide a sufficient amount of serum 3α-OH-5β-pregnan-20-one to treat CNS disorders when orally administered to a subject.

[0071] In one embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of additives, when orally administered to a subject having at least one neuropsychiatric disorder and neurodegenerative disorder, increases the serum level of 3α-OH-5β-pregnan-20-one in the subject, and as a result, at least one neuropsychiatric disorder and neurodegenerative disorder is substantially eliminated, improved, or alleviated.

[0072] In one embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides in the subject a serum level of 3α-OH-5β-pregnan-20-one that is higher than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of an SBE-β-CD solution (cyclodextrin solution administration), and at least one of the serum C max level of 3α-OH-5β-pregnan-20-one and the serum C avg level of 3α-OH-5β-pregnan-20-one.

[0073] In another embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides in the subject a serum level of 3α-OH-5β-pregnan-20-one that is higher than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of a medium-chain triglyceride solution (MCT administration), and at least one of the serum C max level of 3α-OH-5β-pregnan-20-one and the serum C avg level of 3α-OH-5β-pregnan-20-one.

[0074] In yet another embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides in the subject a serum level of 3α-OH-5β-pregnan-20-one that is higher than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of a polysorbate-80 suspension (polysorbate 80 administration), and at least one of the serum C max level of 3α-OH-5β-pregnan-20-one and the serum C avg level of 3α-OH-5β-pregnan-20-one.

[0075] In yet another embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides, in the subject, a serum level of 3α-OH-5β-pregnan-20-one that is higher than the serum level obtained by administration of substantially an equivalent amount of 3α-OH-5β-pregnan-20-one (edible oil administration) in a composition consisting essentially of canola oil or peanut oil. max serum C avg level, at least one of the serum C

[0076] In one embodiment, a 3α-OH-5β-pregnan-20-one composition or oral dosage form or method can be formulated to efficiently provide a predicted serum level of 3α-OH-5β-pregnan-20-one that is therapeutically effective for treating a CNS disorder when orally administered to a subject. In another aspect, 3α-OH-5β-pregnan-20-one can be in a form that maximizes the serum level of 3α-OH-5β-pregnan-20-one when orally administered to a subject. In another aspect, 3α-OH-5β-pregnan-20-one can be in a form that increases the serum level of 3α-OH-5β-pregnan-20-one when orally administered to a subject. In another aspect, the compositions and methods of the present invention increase the serum level of 3α-OH-5β-pregnan-20-one as compared to a composition containing an equal amount of a processed crystalline (micronized) form consisting essentially of 3α-OH-5β-pregnan-20-one suspended in an edible oil when orally administered to a subject.

[0077] In one embodiment, the composition of the present invention can be formulated as an oral dosage form having from about 50 mg to about 600 mg of 3α-OH-5β-pregnan-20-one. In one aspect, the oral dosage form can be a liquid, semi-liquid, semi-solid, powder, emulsion, dispersion, granule, syrup, suspension, capsule, tablet, chewable, or beverage.

[0078] In yet another embodiment, a dosing regimen and method for treating a CNS disorder in a subject are provided and may include orally administering a composition comprising a therapeutically effective amount of 3α-OH-5β-pregnan-20-one.

[0079] In one embodiment, the composition and oral dosage form can include a plurality of pharmaceutically acceptable additives, the additives being α-tocopherol, glyceryl monocaprylate, propylene glycol monolaurate, PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil, poloxamer, and at least one of combinations thereof that provide an appropriate level of 3α-OH-5β-pregnan-20-one in an amount sufficient to treat a CNS disorder when orally administered to a subject.

[0080] The present disclosure encompasses compositions and oral dosage forms and regimens comprising 3α-OH-5β-pregnan-20-one, and related methods. The compositions and oral dosage forms can be formulated to include a therapeutically effective amount of 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives. In one aspect, the pharmaceutically acceptable additives of the composition or dosage form can provide an amount of 3α-OH-5β-pregnan-20-one sufficient to treat a CNS disorder when orally administered to a subject. In another aspect, the composition or dosage form, when orally administered to a subject, has a bioavailability of 3α-OH-5β-pregnan-20-one (e.g., C maxand / or AUC), and may include an immediate-release or soluble or solubilized form of 3α-OH-5β-pregnan-20-one. For example, in one aspect, the in vitro release, in vivo solubilization, absorption and / or CNS activity of 3α-OH-5β-pregnan-20-one when orally administered to a subject by the compositions and methods of the present invention is increased. In another aspect, the absorption and / or CNS activity of 3α-OH-5β-pregnan-20-one when orally administered to a subject by the compositions and methods of the present invention is relatively increased compared to a composition containing an equivalent amount of 3α-OH-5β-pregnan-20-one in its untreated crystalline form or a cyclodextrin solution composition when orally administered to the subject.

[0081] In one embodiment, the composition can be formulated as an oral dosage form having from about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one. The 3α-OH-5β-pregnan-20-one may be processed and as a result, prior to formulation into an oral composition or dosage form, is in a ground, sieved, milled, micronized, or nano-sized form, or after formulation into the composition or dosage form, is in an amorphous or fully solubilized form. The crystalline form of the processed 3α-OH-5β-pregnan-20-one includes a particle size distribution with a D90 of less than 75 μm, a D90 of less than 20 μm, a D90 of 16 μm, a D90 of 13 μm, a D10 of greater than 1 μm, and at least one D50 of 0.15 μm to 50 μm, 30 μm to 50 μm, 0.3 to 30 μm, and 2 μm to 8 μm. Further, the crystalline form of the processed 3α-OH-5β-pregnan-20-one includes a particle size distribution with a D90 of less than 40 μm, a D10 of greater than 1 μm, and at least one D50 of 0.15 μm to 50 μm, 30 μm to 50 μm, 0.3 to 30 μm, and 2 μm to 8 μm.

[0082] In yet another embodiment, a method of treating a CNS disorder in a subject can include orally administering to the subject a therapeutically effective amount of 3α-OH-5β-pregnan-20-one. In one aspect, the therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be an amount of 3α-OH-5β-pregnan-20-one that is sufficient to treat the CNS disorder. In another aspect, a composition comprising 3α-OH-5β-pregnan-20-one disclosed herein may be in a form that provides a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnan-20-one may be combined with a plurality of additives including at least one lipophilic additive sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnan-20-one may be combined with a plurality of additives including at least one lipophilic additive and at least one hydrophilic additive sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating a CNS disorder in a subject.

[0083] In yet another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one lipophilic additive and a surfactant sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating a CNS disorder in a subject.

[0084] In yet another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one lipophilic additive and a surfactant in an amount greater than at least 0.5% sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating a CNS disorder in a subject.

[0085] In yet another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one lipophilic additive and at least one surfactant in an amount greater than 0.5% but not exceeding at least one of 25%, 35%, and 50%, which is sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject.

[0086] As discussed above, when prior art compositions or dosage forms or a plurality of additives or methods utilizing solubilized 3α-OH-5β-pregnan-20-one in a non-encapsulated SBE-β-CD solution, a crystalline 3α-OH-5β-pregnan-20-one suspension in polysorbate 80, solubilized 3α-OH-5β-pregnan-20-one in an edible oil (e.g., medium chain triglycerides or canola oil or peanut oil), or a crystalline 3α-OH-5β-pregnan-20-one suspension in an edible oil are orally administered to a subject, the reported activity of 3α-OH-5β-pregnan-20-one after administration is not expected to result in levels of 3α-OH-5β-pregnan-20-one sufficient to effectively treat CNS disorders at the studied dosages. Further, oral 3α-OH-5β-pregnan-20-one administration with those compositions may result in low 3α-OH-5β-pregnan-20-one levels and inconsistent PD effects. Accordingly, enhanced oral compositions and methods for treating CNS disorders will be needed.

[0087] In one embodiment, the oral pharmaceutical composition of the present invention comprises a therapeutically effective amount of 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives expected to provide a level of 3α-OH-5β-pregnan-20-one in serum sufficient to treat CNS depressive disorders when orally administered to a subject. In some embodiments, the additive can maximize, accelerate, or otherwise potentiate or affect the effective absorption or bioavailability of 3α-OH-5β-pregnan-20-one from the composition when administered to a subject. In some embodiments, the additive can affect the release amount of 3α-OH-5β-pregnan-20-one when administered to a subject or can affect in vitro testing. In some embodiments, the additive can affect the solubilization of 3α-OH-5β-pregnan-20-one when administered to a subject or in an in vitro test. In some embodiments, the additive can affect the release rate and / or release amount of 3α-OH-5β-pregnan-20-one when administered to a subject or in an in vitro test.

[0088] In some embodiments, the form of 3α-OH-5β-pregnan-20-one in the composition can affect the release amount of 3α-OH-5β-pregnan-20-one when administered to a subject or during an in vitro test. In some embodiments, the form of 3α-OH-5β-pregnan-20-one in the composition can affect the solubilization of 3α-OH-5β-pregnan-20-one when administered to a subject or during an in vitro test. In some embodiments, the physical form of 3α-OH-5β-pregnan-20-one in the composition can affect the release rate and / or release amount of 3α-OH-5β-pregnan-20-one when administered to a subject or in an in vitro test.

[0089] When using an oral composition of sulfobutyl ether-β-cyclodextrin (SBE-β-CD) containing solubilized or semi-solid 3α-OH-5β-pregnan-20-one, due to limitations regarding solubility in various cyclodextrin solutions containing SBE-β-CD (for example, the solubility of 3α-OH-5β-pregnan-20-one in a non-encapsulated SBE-β-CD solution of 24% w / v is only ~6 mg / ml), it may be difficult to fill an appropriate amount of 3α-OH-5β-pregnan-20-one to deliver an effective serum level of 3α-OH-5β-pregnan-20-one. The solubilized fraction of 3α-OH-5β-pregnan-20-one began to decrease as observed by precipitation when the 3α-OH-5β-pregnan-20-one concentration exceeded 8 mg / ml. The amount of 3α-OH-5β-pregnan-20-one in the cyclodextrin solution is only made possible by a filling amount of about 0.6% w / w of the composition fill. Furthermore, the high amount of cyclodextrin required to solubilize 3α-OH-5β-pregnan-20-one also presents safety concerns. In some embodiments, the compositions and dosage forms of the present invention may contain a higher 3α-OH-5β-pregnan-20-one filling amount than those formulated in non-encapsulated SBE-β-CD or any cyclodextrin solution composition.

[0090] In some embodiments, the compositions and dosage forms of the invention comprise a 3α-OH-5β-pregnan-20-one loading that, when completely solubilized in the composition, exceeds at least 0.6% w / w or 1% w / w. Figure 2 shows a plot of the rate of 3α-OH-5β-pregnan-20-one release from 1 g of each composition (Formulations I-1 and I-2) disclosed herein compared to conventional compositions (Formulations I-3, I-4, and I-5). As seen in Figure 2, the compositions according to the invention, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, can release more than 30 mg or at least 25% more 3α-OH-5β-pregnan-20-one after 30 minutes compared to compositions consisting essentially of a) a conventional tablet formulation without surfactant (Formulation I-3), b) a formulation of crystalline 3α-OH-5β-pregnan-20-one suspension in canola oil (Formulation I-4), and c) a formulation of crystalline 3α-OH-5β-pregnan-20-one suspension in polysorbate 80 (Formulation I-5).

[0091] In yet another aspect, a composition according to the present invention, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP type II dissolution apparatus, can release more than about 30 mg or at least 50% more of 3α-OH-5β-pregnan-20-one after 30 minutes. In another aspect, a composition according to the present invention, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP type II dissolution apparatus, can release more than about 20 mg or at least 40% more of 3α-OH-5β-pregnan-20-one after 15 minutes. In some aspects, the daily dosage or dosing regimen can affect the absorption of 3α-OH-5β-pregnan-20-one when administered to a subject. In some aspects, the daily dosage or dosing regimen of 3α-OH-5β-pregnan-20-one can affect the absorption of 3β-OH-5α-pregnan-20-one (or an isomer of 3α-OH-5β-pregnan-20-one) when administered to a subject.

[0092] In another aspect, 3α-OH-5β-pregnan-20-one in the composition can be in a form that maximizes, accelerates, or otherwise increases the solubilization level of 3α-OH-5β-pregnan-20-one in the gastrointestinal tract and / or serum of a subject when orally administered to the subject. In one embodiment, 3α-OH-5β-pregnan-20-one in the composition can be in a form that increases the serum level of 3α-OH-5β-pregnan-20-one compared to a composition containing an equivalent amount of 3α-OH-5β-pregnan-20-one in a non-encapsulated SBE-β-CD solution when orally administered to a subject. For example, by orally administering the composition disclosed herein, the serum level of 3α-OH-5β-pregnan-20-one in a subject can be increased by at least about 10% compared to when orally administering a composition containing an equivalent amount of 3α-OH-5β-pregnan-20-one in a non-encapsulated SBE-β-CD solution.

[0093] A therapeutically effective amount of 3α-OH-5β-pregnan-20-one can vary in a composition administered to a subject for treating a CNS disorder. In one example, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be present in the composition or oral dosage form in an amount greater than one or more of 0.0001 wt%, 0.001 wt%, 0.01 wt%, 0.1 wt%, 0.5 wt%, 1.0 wt%, 2.0 wt%, 5.0 wt%, 10.0 wt%, 15.0 wt%, 20.0 wt%, 30.0 wt%, 40 wt%, 50 wt%, or combinations thereof. In another example, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be present in the composition or oral dosage form in an amount from about 0.0001 wt% to about 10 wt%. In another example, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be present in an amount from about 10 wt% to about 20 wt%. In yet another example, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be present in an amount from about 20 wt% to about 30 wt%. In a further example, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be present in an amount from about 30 wt% to about 40 wt%. In yet another example, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be present in an amount from about 40 wt% to about 50 wt%. In another example, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be present in an amount from 10 wt% to about 40 wt% or from 3 wt% to 10 wt%. In one aspect, the compositions and methods of the present invention include 3α-OH-5β-pregnan-20-one in at least one form of substantially solubilized, partially solubilized, substantially non-solubilized, substantially crystalline, partially crystalline, substantially non-crystalline, amorphous, solid, dispersion, and eutectic mixture that provides rapid release (e.g., when at least 40% of the 3α-OH-5β-pregnan-20-one is released after 15 minutes as measured in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate at 75 rpm and 37 °C using a USP Type II dissolution apparatus).

[0094] As used herein, "additive" refers to a pharmaceutical agent that can completely or partially dissolve or solubilize 3α-OH-5β-pregnan-20-one in a pharmaceutical composition. In one aspect, a variety of additives can be used to completely or partially solubilize 3α-OH-5β-pregnan-20-one in a pharmaceutical composition to provide a therapeutically effective level of 3α-OH-5β-pregnan-20-one for improving CNS disorders.

[0095] A therapeutically effective amount of 3α-OH-5β-pregnan-20-one, in combination with a plurality of pharmaceutically acceptable additives, can provide an amount of 3α-OH-5β-pregnan-20-one sufficient to treat CNS depressive disorders when administered to a subject. In some embodiments, a variety of additives can be used to completely or partially solubilize or disperse 3α-OH-5β-pregnan-20-one in a pharmaceutical composition to provide a therapeutically effective level of 3α-OH-5β-pregnan-20-one for treating CNS disorders. Examples of suitable additives can include, but are not limited to, (i) tocopherol (e.g., vitamin E) or its derivatives, (ii) fatty acids or their salts, (iii) glyceryl fatty acid esters, (iv) PEG glycerides of fatty acid esters, (v) polyglycerol fatty acid esters, (vi) triglycerides, (vii) hydrogenated polyoxyl vegetable oils or glycerides, (viii) propylene glycol fatty acid esters, (ix) edible oils, (x) sterols or their derivatives, (xi) omega fatty acids, omega oils such as fish oil, flaxseed oil, algal oil, or combinations thereof.

[0096] Examples of suitable solubilizers can include, but are not limited to, tocopherol or its derivatives, fatty acids or their salts, glyceryl fatty acid esters, PEG glycerides of fatty acid esters, polyglycerol fatty acid esters, triglycerides, hydrogenated polyoxyl vegetable oils or glycerides, propylene glycol fatty acid esters, vegetable oils, and sterols or their derivatives.

[0097] In one aspect, the vitamin E or its derivative may include, but is not limited to, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol acetate, tocopherol linoleate, tocopherol succinate, tocotrienol (α-, β-, γ-, or δ-), tocopheryl sorbate, or TPGS (PEG derivative of α-tocopherol), or a combination thereof.

[0098] In one embodiment, the fatty acid or its salt includes, but is not limited to, octanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, sodium caproate, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate, sodium oleate, sodium stearate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate.

[0099] In another aspect, the glyceryl fatty acid ester may include, but is not limited to, glyceryl monooleate, glyceryl monooleate / linoleate, glyceryl monolaurate, glyceryl ricinoleate, glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate / dioleate, glyceryl palmitate / stearate, glyceryl acetate, glyceryl laurate, glyceryl citrate / lactate / oleate / linoleate, glyceryl caprylate, glyceryl caprylate / caprate, glyceryl dicaprylate / dicaprate, mono / diacetylated monoglyceride, glyceryl monostearate, glyceryl dilaurate, glyceryl dioleate, or a combination thereof.

[0100] In yet another aspect, the PEG glycerides of fatty acid esters can include, but are not limited to, PEG fatty acid monoesters, PEG glycerol fatty acid esters, PEG fatty acid diesters, PEG fatty acid mono / diester mixtures, PEG triglycerides of fatty acid esters, etc., or combinations thereof. The PEG glycerol fatty acid esters can include, but are not limited to, PEG glyceryl laurate, PEG glyceryl laurate, PEG glyceryl caprylate, PEG glyceryl caprate, PEG glyceryl oleate, PEG glyceryl mono / di-fatty acid ester mixtures, etc., or combinations thereof. The PEG fatty acid monoesters can include, but are not limited to, esters of capric acid, caprylic acid, lauric acid, oleic acid, and stearic acid, such as those, or combinations thereof. Examples of PEG fatty acid monoesters can include, but are not limited to, PEG(1-100, 200, 300, 400) monocaprylate, PEG(1-100, 200, 300, 400) monocaprate, PEG(1-100, 200, 300, 400) monolaurate, PEG(1-100, 200, 300, 400) monooleate, PEG(1-100, 200, 300, 400) monopalmitate, PEG(1-100, 200, 300, 400) monostearate, and PEG(1-100, 200, 300, 400) monococoate, etc., or combinations thereof. The PEG fatty acid diesters can include, but are not limited to, PEG(4-32) dicaprylate, PEG(4-32) dicaprate, PEG(4-32) dilaurate, PEG(4-32) dioleate, PEG(4-32) distearate, and PEG(4-32) dipalmitate, etc., or combinations thereof. The PEG fatty acid mono- / di-ester mixtures can include, but are not limited to, PEG caprylate / caprate, PEG mono- / di-caprylate, PEG mono- / di-caprate, PEG mono- / di-laurate, PEG mono- / di-oleate, and PEG mono- / di-stearate, etc., or combinations thereof.The PEG triglycerides of fatty acid esters can include, but are not limited to, lauroyl polyoxyl glycerides, stearoyl polyoxyl glycerides, oleoyl polyoxyl glycerides, linoleoyl polyoxyl glycerides, lauroyl polyoxyl glycerides, caprylocaproyloyl polyoxyl glycerides, and behenoyl polyoxyl glycerides, or combinations thereof.

[0101] In a further aspect, the polyglycerol fatty acid esters can include, but are not limited to, polyglyceryl (2,3,4,6,10) oleate, polyglyceryl (2,3,4,6,10) dioleate, polyglyceryl (2,3,4,6,10) trioleate, polyglyceryl (2,3,4,6,10) laurate, polyglyceryl (2,3,4,6,10) dilaurate, polyglyceryl (2,3,4,6,10) trilaurate, polyglyceryl (2,3,4,6,10) stearate, polyglyceryl (2,3,4,6,10) distearate, polyglyceryl (2,3,4,6,10) tristearate, polyglyceryl (2,3,4,6,10) mono / dioleate, polyglyceryl (3,6,10) caprate, polyglyceryl (3,6,10) dicatepate, polyglyceryl (3,6,10) tricatepate, polyglyceryl (3,6,10) caprylate, polyglyceryl (3,6,10) dicaprylate, polyglyceryl (3,6,10) tricaprylate, polyglyceryl (3,6,10) polystearate, polyglyceryl (3,6,10) polyoleate, polyglyceryl (3,6,10) mono- / di-oleate, polyglyceryl (3,6,10) caprylate, polyglyceryl (3,6,10) polycaprylate, polyglyceryl (3,6,10) caprate, polyglyceryl (3,6,10) polycaprate, and polyglyceryl (3,6,10) caprylate / caprate, or combinations thereof.

[0102] In another aspect, the triglyceride may include, but is not limited to, glyceryl tricaprylate, glyceryl tricaprate, glyceryl caprylate / caprate, glyceryl caprylate / caprate / trisuccinate, glyceryl trioleate, glyceryl tristearate, glyceryl trilaurate, medium-chain natural oils, etc., or combinations thereof.

[0103] In yet another aspect, the hydrogenated polyoxyl vegetable oil or glyceride may include, but is not limited to, castor oil or hydrogenated castor oil, or edible vegetable oils such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil, peppermint oil, coconut oil, sunflower seed oil, almond oil, or combinations thereof. Examples of polyoxyl groups include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol, or combinations thereof.Examples of the PEGylated polyoxyl vegetable oils or glycerides include, but are not limited to, PEG-35 castor oil (Incrocas-35, KOLLIPHOR EL, Cremophor EL), PEG-40 hydrogenated castor oil (KOLLIPHOR RH40, Cremophor RH40), PEG-25 trioleate (TAGATRTO), PEG-60 corn glyceride (CROVOL M70), PEG-60 almond oil (CROVOL A70), PEG-40 palm kernel oil (CROVOL PK70), PEG-50 castor oil (EMALEX C-50), PEG-50 hydrogenated castor oil (EMALEX HC-50), PEG-8 caprylic / capric glyceride (CAPRYLCAPROYL MACROGOL GLYCERIDES), PEG-6 caprylic / capric glyceride (SOFTIGEN 767), PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (LABRAFIL M.2125 CS), PEG-6 almond oil (LABRAFIL M 1966 CS), PEG-6 apricot kernel oil (LABRAFIL M 1944CS), PEG-6 olive oil (LABRAFIL M 1980 CS), PEG-6 peanut oil (LABRAFIL M 1969 CS), PEG-6 hydrogenated palm kernel oil (LABRAFIL M2130 BS), PEG-6 palm kernel oil (LABRAFIL M 2130 CS), PEG-6 triolein (LABRAFIL M 2735 CS), PEG-8 corn oil (LABRAFIL WL 2609 BS), PEG-20 corn glyceride (CROVOL M40), and PEG-20 almond glyceride (CROVOL A40), or combinations thereof.

[0104] In one aspect, the propylene glycol fatty acid ester may include, but is not limited to, propylene glycol monolaurate (propylene glycol monolaurate FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (MYVEROL P-O6), propylene glycol dicaprylate / dicaprate (CAPTEX 200), and propylene glycol dioctanoate (CAPTEX 800), propylene glycol monocaprylate (CAPRYOL 90, NIKKOL Sefsol 218), propylene glycol myristate, propylene glycol monostearate, propylene glycol ricinoleate, propylene glycol isostearate, propylene glycol caprylate / caprate, propylene glycol dioleate, propylene glycol distearate, propylene glycol dilaurate, propylene glycol dicaprylate, propylene glycol dicaprate, etc., or combinations thereof.

[0105] In another aspect, the vegetable oil may include, but is not limited to, corn oil, olive oil, peanut oil, coconut oil, peppermint oil, sunflower seed oil, castor oil, safflower oil, borage oil, cottonseed oil, soybean oil, palm kernel oil, apricot kernel oil, almond oil, omega 3 oil, etc., or combinations thereof.

[0106] In one aspect, the sterol or its derivative may include, but is not limited to, cholesterol, sitosterol, lanosterol, phytosterol, its PEG derivative, etc., or a combination thereof. In various aspects, the sterol or its derivative can be hydrophilic or lipophilic. Examples of hydrophilic sterols include, but are not limited to, lanosterol PEG-24 cholesteryl ether (e.g., SOLULAN C-24, AMERCHOL), PEG-30 soy sterol (e.g., NIKKOL BPS-30, manufactured by Nikko), PEG-25 phytosterol (e.g., NIKKOL BPSH-25, manufactured by Nikko), PEG-30 cholestanol (e.g., NIKKOL DHC, manufactured by Nikko). Examples of lipophilic sterol surfactants include cholesterol, sitosterol, phytosterol (e.g., GENEROL series, manufactured by Henkel), PEG-5 soy sterol (e.g., NIKKOL BPS-S, manufactured by Nikko), PEG-10 soy sterol (e.g., NIKKOL BPS-10, manufactured by Nikko), PEG-20 soy sterol (e.g., NIKKOL BPS-20, manufactured by Nikko), etc., or a combination thereof.

[0107] In one embodiment, the additive can be a substance that can be added to a pharmaceutical formulation to enhance the release, separation, or dispersion of particles, or to enhance the dissolution and further absorption of particles into the body. Examples of additives can include lipophilic additives with an HLB value of 10 or less, or hydrophilic additives with an HLB value exceeding 10.

[0108] In one aspect, the pharmaceutically acceptable additive can include hydrophilic additives, lipophilic additives, or a combination thereof.

[0109] For example, the lipophilic additives include mono-, di-glycerides of fatty acids, alcohols or polyhydric alcohols, and reaction mixtures with various natural oils and / or hardened oils such as PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g., LABRAFIL M 2125 CS), PEG-6 almond oil (e.g., LABRAFIL M 1966 CS), PEG-6 apricot kernel oil (e.g., LABRAFIL M 1944 CS), PEG-6 olive oil (e.g., LABRAFIL M 1980 CS), PEG-6 peanut oil (e.g., LABRAFIL M 1969 CS, etc.), PEG-6 hydrogenated palm kernel oil (e.g., LABRAFIL M 2130 BS), PEG-6 palm kernel oil (e.g., LABRAFIL M 2130 CS), PEG-6 triolein (e.g., e.LABRAFIL M 2735 CS), PEG-8 corn oil (e.g., LABRAFIL WL 2609 BS), PEG-20 corn glyceride (e.g., CROVOL M40), PEG-20 almond glyceride (e.g., CROVOL A40), lipophilic polyoxyethylene-polyoxypropylene block copolymers (e.g., Pluronic L92, L101, L121), propylene glycol monolaurate (e.g., propylene glycol monolaurate FCC), propylene glycol ricinoleate (e.g., Propymuls), propylene glycol monooleate (e.g., MYVEROL P-O6), propylene glycol dicaprylate / dicaprate (e.g., CAPTEX 200) and propylene glycol dioctanoate (e.g., CAPTEX 800) such as propylene glycol monoesters of fatty acids, for example, propylene glycol monocaprylate (e.g., CAPRYOL 90), propylene glycol oleate (e.g., LUTROLOP2000), propylene glycol myristate, propylene glycol monostearate, propylene glycol hydroxystearate, propylene glycol ricinoleate, propylene glycol isostearate, propylene glycol monooleate, propylene glycol dicaprylate / dicaprate, propylene glycol dioctanoate, propylene glycol caprylate caprate, propylene glycol dilaurate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dicaprate, a mixture composed of oleic acid ester of propylene glycol and glycerol (for example, ARLACEL 186), etc., a mixture of propylene glycol ester and glycerol ester, cholesterol, sitosterol, phytosterol, phytosterol fatty acid ester, sterols and sterol derivatives such as PEG-5 soy sterol, PEG-10 soy sterol, PEG-20 soy sterol, glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl monostearate, or a combination thereof, sorbitan monolaurate (for example, ARLACEL 20), sorbitan monopalmitate (for example, Span-40), sorbitan monooleate (for example Span-80), sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate and other sorbitan fatty acid esters, capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidylcholine, bile salts and other fatty acids, and mixtures thereof, but not limited thereto. It is important to note that some lipophilic additives may also function as solubilizing agent components in the composition and oral dosage form. In some cases, the additives for the composition and oral dosage form may be lipophilic surfactants.

[0110] In one embodiment, the pharmaceutically acceptable additive may not contain polysorbate 80. In another embodiment, the pharmaceutically acceptable additive may not contain cyclodextrin. In a further embodiment, the pharmaceutically acceptable additive may not contain edible oil.

[0111] The pharmaceutically acceptable additive can also include hydrophilic additives. In one aspect, the hydrophilic additives can include, but are not limited to, nonionic surfactants, ionic surfactants, zwitterionic surfactants, etc., or combinations thereof. Suitable hydrophilic surfactants include, but are not limited to, alcohol - oil transesterification products, polyoxyethylene hydrogenated vegetable oils, polyoxyethylene vegetable oils, alkyl sulfates, dioctyl sulfosuccinates, polyethylene glycol fatty acid esters, polyethylene glycol fatty acid mono - and di - ester mixtures, polysorbates, polyethylene glycol derivatives of tocopherol, etc., or combinations thereof. Two or more hydrophilic additives from the same class or different classes can be referred to as hydrophilic surfactants unless explicitly specified otherwise. In one aspect, non - limiting examples of hydrophilic surfactants can include PEG - 8 caprylic / capric glyceride, lauroyl macrogol - 32 glyceride, stearoyl macrogol glyceride, PEG - 40 hydrogenated castor oil, PEG - 35 castor oil, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polyethylene glycol fatty acid mono - and di - ester mixtures, polysorbate 80, polysorbate 20, polyethylene glycol 1000 succinate tocopherol, phytosterol, phytosterol fatty acid ester, poloxamer, etc., or combinations thereof. In some cases, the hydrophilic additive for the composition and oral dosage form can be a hydrophilic surfactant.

[0112] Pharmaceutically acceptable additives can be combined with additives in various amounts ranges or, alternatively, can contain additives. For example, lipophilic additives and hydrophilic additives can be present in amounts such that the amount (wt%) of the lipophilic additive is greater than or equal to the amount (wt%) of the hydrophilic additive. In another embodiment, the lipophilic additive and the hydrophilic additive can be present in amounts such that the ratio of the amount (wt%) of the lipophilic additive to the amount (wt%) of the hydrophilic additive is greater than about 2:1. In another embodiment, the lipophilic additive and the hydrophilic additive can be present in amounts such that the ratio of the amount (wt%) of the lipophilic additive to the amount (wt%) of the hydrophilic additive is greater than about 3:1 with respect to the amount (wt%) of the hydrophilic additive. In yet another embodiment, the lipophilic additive and the hydrophilic additive can be present in amounts such that the ratio of the amount (wt%) of the lipophilic additive to the amount (wt%) of the hydrophilic additive is at least greater than about 5:1.

[0113] In one embodiment, the composition and the oral dosage form can include a pharmaceutically acceptable additive that includes at least one of α-tocopherol, glyceryl monocaprylate, glyceryl caprylocaprate, propylene glycol monolaurate, PEG-35 castor oil, PEG-40 hydrogenated castor oil, and combinations thereof, and provides an appropriate level of 3α-OH-5β-pregnan-20-one in an amount sufficient to treat CNS disorders when orally administered to a subject.

[0114] In certain examples, the lipophilic additive can account for about 0.6% w / w to about 95% w / w, about 5% w / w to about 70% w / w, about 10% w / w to about 60% w / w, about 15% w / w to about 55% w / w, about 20% w / w to about 50% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, about 80% w / w, about 85% w / w, about 90% w / w or about 95% w / w of any pharmaceutical composition described herein. In some examples, the hydrophilic additive can account for about 1% w / w to about 50% w / w, about 5% w / w to about 45% w / w, about 10% w / w to about 40% w / w, about 15% w / w to about 35% w / w, about 20% w / w to about 30% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, or about 30% w / w of any pharmaceutical composition described herein.

[0115] In certain examples, the additive may be a surfactant. The surfactant in the present invention may be any compound containing a polar or charged hydrophilic moiety and a nonpolar hydrophobic (lipophilic) moiety, i.e., the surfactant compound must be amphiphilic. In the context of the present invention, the hydrophilic surfactant can be any hydrophilic surfactant suitable for use in a pharmaceutical composition. Such surfactants can be anionic, cationic, zwitterionic or nonionic. Mixtures of hydrophilic surfactants are also within the scope of the present invention. Similarly, the hydrophobic surfactant can be any hydrophobic surfactant suitable for use in a pharmaceutical composition. Mixtures of hydrophobic surfactants are also within the scope of the present invention. Generally, suitable hydrophilic surfactants have an HLB value greater than about 10, and suitable hydrophobic surfactants have an HLB value less than about 10. The selection of specific hydrophobic and hydrophilic surfactants should be made with the specific hydrophobic therapeutic agent used in the composition and the appropriate polarity range for the selected therapeutic agent in mind. With these general principles in mind, a very wide range of surfactants are suitable for use in the present invention.

[0116] In one embodiment, the pharmaceutically acceptable additive may optionally include at least one surfactant. When present, the surfactant may constitute from about 0.5 wt% to about 50 wt% of the oral solid dosage form. In one embodiment, the surfactant may constitute from about 2 wt% to about 50 wt% of the oral solid dosage form. In one embodiment, the surfactant may constitute from about 5 wt% to about 27 wt% of the oral solid dosage form. In one embodiment, the surfactant may be a hydrophilic surfactant. The hydrophilic surfactant may have surface-active properties and may have an HLB value of 10 or more. The hydrophilic surfactant may be an anionic surfactant or a nonionic surfactant. Non-limiting examples of hydrophilic surfactants that may be included in the oral solid dosage form include sodium lauryl sulfate, polysorbate, sodium doxsylate, polyoxyl castor oil, polyoxyl hydrogenated castor oil, poloxamer, lecithin or its derivatives, and at least one or a combination of mixtures thereof.

[0117] Poloxamer represents a polyethylene - polyoxypropylene block copolymer and any type of the following formula: HO(C<2>H<4>O) (C<3>H<6>O) (C<2>H<4>O) It can be H, where "a" and "b" represent the number of polyoxyethylene units and polyoxypropylene units, respectively. The compounds are listed by their generic names together with the corresponding values of "a" and "b". The poloxamer is (C<3>H<6>O) (C<2>H<4>O) It can be represented in the form of H(HLB)), for example, (Poloxamer 105 (a = 11, b = 16(8)); (Poloxamer 108 (a = 46, b = 16(>10)); (Poloxamer 122 (a = 5, b = 21(3)); (Poloxamer 123 (a = 7, b = 21(7)); (Poloxamer 124 (a = 11, b = 21(>7)); (Poloxamer 181 (a = 3, b = 30)); (Poloxamer 182 (a = 8, b = 30(2)); (Poloxamer 183 (a = 10, b = 30)); (Poloxamer 184 (a = 13, b = 30)); (Poloxamer 185 (a = 19, b = 30)); (Poloxamer 188 (a = 75, b = 30(29)); (Poloxamer 212 (a = 8, b = 35)); (Poloxamer 215 (a = 24, b = 35)); (Poloxamer 217 (a = 52, b = 35)); (Poloxamer 231 (a = 16, b = 39)); (Poloxamer 234 (a = 22, b = 39)); (Poloxamer 235 (a = 27, b = 39)); (Poloxamer 237 (a = 62, b = 39(24)); (Poloxamer 238 (a = 97, b = 39)); (Poloxamer 282 (a = 10, b = 47)); (Poloxamer 284 (a = 21, b = 47)); (Poloxamer 288 (a = 122, b = 47(>10)); (Poloxamer 331 (a = 7, b = 54(0.5)); (Poloxamer 333 (a = 20, b = 54)); (Poloxamer 334 (a = 31, b = 54)); (Poloxamer 335 (a = 38, b = 54)); (Poloxamer 338 (a = 128, b = 54)); (Poloxamer 401 (a = 6, b = 67)); (Poloxamer 402 (a = 13, b = 67)); (Poloxamer 403 (a = 21, b = 67)); (Poloxamer 407 (a = 98, b = 67)); and combinations thereof.

[0118] In one embodiment, the oral composition described herein may not contain any regulator that slows the release rate of 3α-OH-5β-pregnan-20-one in an aqueous medium or in vivo.

[0119] In an embodiment, the composition is at least one of non-aqueous, non-liquid, and solid.

[0120] In another embodiment, the composition is a non-aqueous composition filled in a capsule or tablet dosage form.

[0121] In another embodiment, the composition is a non-aqueous liquid composition filled in a capsule dosage form.

[0122] In another embodiment, the oral solid dosage form(s) described herein may not have the synchronous release characteristics of 3α-OH-5β-pregnan-20-one with a solubilizing agent in an aqueous medium such that the dosage form can release more than 90% of 3α-OH-5β-pregnan-20-one within 4 hours after administration or in an in vitro test. Alternatively, the release of the active agent may not be synchronized with the release of the lipophilic additive. For example, the release rate of the active agent may not be of the same degree as the release rate of the additive.

[0123] Other components: Although not necessarily required, the compositions of the present invention can also contain one or more additional components, i.e., functional components. Classes of components that can be present in the composition include solvents, absorbents, acids, adjuvants, anti-caking agents, flow promoters, anti-sticking agents, defoaming agents, anticoagulants, antibacterial agents, antioxidants, anti-inflammatory agents, astringents, preservatives, bases, binders, chelating agents, sequestering agents, coagulants, coating agents, colorants, dyes, pigments, solubilizers, complexing agents, softeners, crystal growth regulators, modifiers, humectants, desiccants, dehydrating agents, diluents, dispersants, emollients, emulsifiers, encapsulating agents, enzymes, fillers, extenders, flavor masking agents, fragrances, gelling agents, hardeners, hardening agents, moisturizers, lubricants, humectants, buffers, pH adjusters, plasticizers, sedatives, mucilages, anti-inflammatory agent retardants, spreading agents, stabilizers, suspending agents, sweeteners, disintegrants, thickeners, viscosity modifiers, surfactants, opacifiers, polymers, preservatives, anti-gelling agents, rheology control agents, ultraviolet absorbers, isotonic agents, viscosity adjusters, but are not limited thereto. The composition may contain one or more components from any particular class and one or more components from different classes. Specific examples of components and their usage levels are known in the art.

[0124] Other components such as co-solvents, when present in effective amounts, can partially solubilize 3α-OH-5β-pregnan-20-one. Examples of suitable co-solvents include, but are not limited to, alcohols and polyols such as ethanol, propanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol, glycerin or its derivatives, glycerol, diglycerol, polyglycerol, pentaerythritol, sorbitol, mannitol, trans-catol, dimethylisosorbide, triacetin, trimethyl citrate, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, etc., or combinations thereof.

[0125] In one aspect, the composition can be formulated as a solution, emulsion, liquid, semi-liquid, suspension, semi-solid, powder, emulsion, dispersion, granule, syrup, suspension agent, capsule, tablet, chewable, or drink, or a combination thereof. In one example, the composition, when diluted 10-fold or 100-fold with an aqueous bile salt containing simulated gastric fluid or intestinal fluid or water (e.g., FeSSIF (for "FaSSIF / FeSSIF / FaSSGF" or the FaSSIF medium well-known in the art, refer to the website of biorelevant.com)), can form a dispersion, emulsion, solution, or micellar solution. In another example, the composition may remain substantially solubilized even when diluted 10-fold or 100-fold with an aqueous bile salt containing simulated gastric fluid or intestinal medium or water. In another example, when the composition is diluted 10-fold or 100-fold with an aqueous bile salt or water containing simulated gastric fluid or intestinal fluid, a dispersion with an average dispersed particle size of less than 300 nm or a UV absorbance of less than 5.0 units when measured at 450 nm can be formed. Figure 3 shows an exemplary comparative dispersibility image of the disclosed oral compositions (Formulations #9 and #10 in Table G) containing 3α-OH-5β-pregnan-20-one diluted 100-fold with simulated intestinal fluid at pH 6.8 according to USP 26, compared with the dispersibility of compositions containing 3α-OH-5β-pregnan-20-one dissolved in medium-chain triglycerides (e.g., MIGLYOL 812, Formulation #7 in Table G) and canola oil (Formulation #8 in Table G). As shown in Figure 3, Formulations #7 and #8 did not disperse or solubilize in the x100 diluted aqueous medium (the oily content on the surface was completely separated from the aqueous medium), while the disclosed compositions of the present invention (Formulations #9 and #10) were well-dispersed. The UV absorbance measured at 450 nm was unmeasurable for Formulations #7 and #8 due to phase separation, while measured values of 1.3 Abs and 3.2 Abs were observed for Formulations #9 and #10, respectively (for Abs, refer to the website "Introduction to the Basics of Atomic Absorption Spectroscopy (AAS)" of agilent.com).

[0126] In one embodiment, the 3α-OH-5β-pregnan-20-one in the composition can include a fully or partially crystalline form, such as a processed, solubilized, amorphous solid, solid solution, solid dispersion, etc., or a combination thereof. In one aspect, the composition of the present invention consists only of the active 3α-OH-5β-pregnan-20-one in the additive. In another aspect, a specific weight percent of the 3α-OH-5β-pregnan-20-one in the composition or dosage form may be in an amorphous form (e.g., amorphous solid, solution, emulsion, liquid, semi-liquid, etc.). In one example, at least about 50% of the 3α-OH-5β-pregnan-20-one in the composition may be in an amorphous state. In another example, at least about 65% of the 3α-OH-5β-pregnan-20-one in the composition may be in an amorphous state. In yet another example, at least about 80% of the 3α-OH-5β-pregnan-20-one in the composition may be in an amorphous state. In another example, at least about 95% of the 3α-OH-5β-pregnan-20-one in the composition may be in an amorphous state.

[0127] In one embodiment, the oral composition invented herein may be a crystalline solid form of 3α-OH-5β-pregnan-20-one substantially treated with at least one surfactant.

[0128] As used herein, the term "processed" can apply to either the crystalline form of the active agent or the amorphous form of the active agent. Further, as used herein, when applied to the crystalline form of the active agent, the term "processed" means that the active agent has been subjected to a process as exemplified by being processed into at least one form of the active agent of grinding, sieving, pulverizing, micronizing, and nano-sizing, and when applied to the amorphous form of the active agent, the term "processed" is exemplified by the active agent being processed into at least one form of the active agent of amorphous and completely solubilized. As used herein, the term "unprocessed" is defined as the raw ("as is") active agent or unprocessed active agent, for example, as defined as non-micronized or non-ground. This process of reducing the particle size of the active agent helps to improve the release rate, dissolution rate, and bioavailability of the active agent. In one example, the crude powder of 3α-OH-5β-pregnan-20-one used in the composition of the present invention is subjected to a process such as grinding, sieving, pulverizing, micronizing, nano-sizing, amorphization, or complete solubilization before being formulated into the composition. Further, for example, the "micronizing" process can provide a particle size distribution of 3α-OH-5β-pregnan-20-one ranging from D50 =~ 6 μm and D90 =~ 20 μm. Further, for example, the "nano-sizing" process can provide a particle size distribution of 3α-OH-5β-pregnan-20-one ranging from D50 =~ 150 nm and D90 =~ 300 nm. D10, D50, and D90 are defined as follows: D10 = 10% of the particle population in the composition has a size below the specified value. D50 = 50% of the particle population in the composition has a size below the specified value. D90 = 90% of the particle population in the composition has a size below the specified value.

[0129] In one embodiment, the particle size distribution of the processed crystal form of 3α-OH-5β-pregnan-20-one in the present invention may range from D90 = about 250 nm to about 250 μm. In one aspect, the particle size distribution of the processed 3α-OH-5β-pregnan-20-one crystal form in the present invention may be less than D90 = about 250 μm, for example, D90 = about 250 nm, D90 = about 300 nm, D90 = about 350 nm, D90 = about 400 nm, D90 = about 500 nm, D90 = about 750 nm, D90 = about 1 μm, D90 = about 2 μm, D90 = about 5 μm, D90 = about 10 μm, D90 = about 15 μm, D90 = about 20 μm, D90 = about 30 μm, D90 = about 40 μm, D90 = about 50 μm, D90 = about 75 μm, D90 = about 100 μm, D90 = about 150 μm, D90 = about 200 μm, D90 = about 250 μm, and any one of the D90 sizes between the above values. In another embodiment, the particle size distribution of the processed crystal form of 3α-OH-5β-pregnan-20-one in the present invention may be less than D90 = about 75 μm.

[0130] In one embodiment, the particle size distribution of the processed crystal form of 3α-OH-5β-pregnan-20-one in the present invention may range from D50 = about 150 nm to about 100 μm. In one aspect, the particle size distribution of the processed 3α-OH-5β-pregnan-20-one crystal form in the present invention may be less than D50 = about 100 μm, for example, D50 = about 100 nm, D50 = about 150 nm, D50 = about 200 nm, D50 = about 250 nm, D50 = about 300 nm, D50 = about 350 nm, D50 = about 400 nm, D50 = about 500 nm, D50 = about 750 nm, D50 = about 1 μm, D50 = about 2 μm, D50 = about 5 μm, D50 = about 10 μm, D50 = about 15 μm, D50 = about 20 μm, D590 = about 30 μm, D50 = about 40 μm, D50 = about 50 μm, D50 = about 75 μm, D50 = about 100 μm, and any one of the D50 sizes between the above values. In another embodiment, the particle size distribution of the processed crystal form of 3α-OH-5β-pregnan-20-one in the present invention may be any size between D50 = about 150 nm and about 50 μm.

[0131] In one embodiment, the particle size distribution of the processed crystal form of 3α-OH-5β-pregnan-20-one in the present invention may range from D10 = about 50 nm to about 50 μm. In one aspect, the particle size distribution of the processed 3α-OH-5β-pregnan-20-one crystal form in the present invention may be less than D10 = about 50 μm. For example, D10 = about 50 nm, D10 = about 100 nm, D10 = about 150 nm, D10 = about 200 nm, D10 = about 250 nm, D10 = about 300 nm, D10 = about 350 nm, D10 = about 400 nm, D10 = about 500 nm, D10 = about 750 nm, D10 = about 1 μm, D10 = about 2 μm, D10 = about 5 μm, D10 = about 10 μm, D10 = about 15 μm, D10 = about 20 μm, D10 = about 25 μm, D10 = about 40 μm, D10 = about 50 μm, and any one of the D10 sizes between the above values. In another embodiment, the particle size distribution of the processed crystal form of 3α-OH-5β-pregnan-20-one in the present invention may be greater than D10 = about 1 μm.

[0132] In another aspect, a specific weight percentage of 3α-OH-5β-pregnan-20-one in a composition or dosage form may be solubilized. In one example, about 50% to about 100% of the 3α-OH-5β-pregnan-20-one in the composition may be solubilized. In another example, about 50% to about 65% of the 3α-OH-5β-pregnan-20-one in the composition may be solubilized. In yet another example, about 65% to about 85% of the 3α-OH-5β-pregnan-20-one in the composition may be solubilized. In another example, about 85% to about 100% of the 3α-OH-5β-pregnan-20-one in the composition may be solubilized. In another example, about 85% to about 100% of the 3α-OH-5β-pregnan-20-one in the composition may be solubilized in a plurality of additives essentially free of SBE-β-CD.

[0133] In another embodiment, the oral pharmaceutical composition or oral dosage form may contain 3α-OH-5β-pregnan-20-one in an amount that provides a desirable GABAA receptor binding efficiency at a therapeutically effective amount capable of treating CNS disorders when administered to a subject. For example, in one embodiment, the composition or oral dosage form may contain a plurality of pharmaceutically acceptable additives that maximize or facilitate the absorption of 3α-OH-5β-pregnan-20-one when administered to a subject.

[0134] In one aspect, the composition can be formulated as an oral dosage form having from about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one. In another aspect, the composition can be formulated as an oral dosage form having from about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one, and when orally administered to a subject, measured using a mass spectrometry method combining liquid chromatography or gas chromatography (e.g., LC-MS, LC-MSMS, or GC-MS), it has a 3α-OH-5β-pregnan-20-one C -1 exceeding about 4.25 ng / mL max a 3α-OH-5β-pregnan-20-one AUC exceeding about 22.9 ng·h / mL -1 a 3α-OH-5β-pregnan-20-one C of about 1 hour or less 0-t or a 3α-OH-5β-pregnan-20-one T of about 2.5 hours or more max and provides at least one of the above. max

[0135] The oral pharmaceutical composition containing 3α-OH-5β-pregnan-20-one can be administered as an oral dosage form such as a solid, liquid, or partially or fully solubilized oral dosage form, which is conventionally intended to substantially release and deliver 3α-OH-5β-pregnan-20-one in the digestive tract across the oral cavity and / or buccal cavity.

[0136] In certain embodiments, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one can be administered as a solid dosage form known in the art. Examples of solid dosage forms can include, but are not limited to, two-piece hard gelatin capsules, soft gelatin capsules, beads, beadlets, granules, spheroids, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets, and combinations thereof.

[0137] In certain embodiments, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one can be administered as a liquid (e.g., solution, suspension, beverage, etc.) or in a form partially or completely dissolved in a gelatin or non-gelatin capsule known in the art. The gelatin capsule can be a soft gelatin capsule, a hard gelatin capsule, or other capsules. The hard gelatin capsule can typically be a two-piece standard gelatin capsule comprising a first bottom and a second upper capsule portion. The soft gelatin capsule can be a two-piece capsule with the two parts sealed together or a one-piece substantially sealed capsule.

[0138] In certain embodiments, the pharmaceutical composition can be administered to a subject in need of 3α-OH-5β-pregnan-20-one for CNS disorders. In certain embodiments, the amount of 3α-OH-5β-pregnan-20-one administered ranges from about 50 mg to about 750 mg, from about 150 mg to about 450 mg, from about 225 mg to about 450 mg, or from about 300 mg to about 450 mg. In certain specific embodiments, the active ingredient is 3α-OH-5β-pregnan-20-one.

[0139] In other embodiments, 3α-OH-5β-pregnan-20-one can be administered to a subject (e.g., male and female) in need of the oral pharmaceutical composition of the present disclosure to ingest a therapeutically effective amount of 3α-OH-5β-pregnan-20-one from the oral composition. In one embodiment, the 3α-OH-5β-pregnan-20-one in the oral composition ranges from about 50 mg to about 450 mg, and about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or any amount within the range of the recited values.

[0140] In one embodiment, the amount of 3α-OH-5β-pregnan-20-one in the oral pharmaceutical composition invented herein may range from about 0.6 wt% to about 50 wt% of the composition. In further embodiments, a subject in need thereof may be administered an oral pharmaceutical composition having from about 0.6%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 22%, about 24%, about 25%, about 26%, about 28%, about 30%, about 35%, about 40%, about 45%, about 50%, or any percentage within the range of the recited values of the weight percentage of 3α-OH-5β-pregnan-20-one.

[0141] In certain embodiments, the oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one in the present disclosure can be administered once a day within any of the ranges of the above-mentioned amounts until the disease or condition is alleviated or substantially eliminated. In other embodiments, the oral pharmaceutical composition in the present disclosure can be administered twice a day within any of the ranges of the above-mentioned amounts until the disease or condition is alleviated or substantially eliminated. In further embodiments, the oral pharmaceutical composition in the present disclosure can be administered equal to or more than three times a day within any of the ranges of the above-mentioned amounts until the disease or condition is alleviated or substantially eliminated.

[0142] The compositions disclosed herein can have various amounts of daily dosages. In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be orally administered from once to twelve times a day. In one example, the daily dosage of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include from about 50 mg to about 1350 mg. In another example, the daily dosage of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include from about 200 mg to about 900 mg. In a further example, the daily dosage of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include from about 10 mg to about 450 mg. In yet another aspect, the dosage of 3α-OH-5β-pregnan-20-one can be administered in a dosage form comprising 1 to 4 capsules or 1 / 2 to 4 tablets.

[0143] In one embodiment, the daily dose of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include at least one of about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, or any amount within the range of the recited values.

[0144] In other aspects, 3α-OH-5β-pregnan-20-one can be administered to a subject (e.g., male and female) to provide a therapeutically effective level of 3α-OH-5β-pregnan-20-one. In one example, 3α-OH-5β-pregnan-20-one in an oral composition can have a total daily dose in the range of about 50 mg to about 1400 mg, such as about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1350 mg, about 1400 mg, or any amount within the range of about 50 mg to about 1400 mg.

[0145] In one aspect, the number of dosage units of 3α-OH-5β-pregnan-20-one per dose (e.g., capsules, tablets, etc.) can range from 1 / 2 unit to 4 units, such as 1 / 2, 1, 2, 3, or 4 units.

[0146] To achieve the therapeutic target level of 3α-OH-5β-pregnan-20-one per single dose, in some aspects, a subject can be administered from 50 mg to 450 mg of 3α-OH-5β-pregnan-20-one, such as about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 400 mg, about 450 mg, or any amount within the range of about 50 mg to about 450 mg.

[0147] In one aspect, the amount of 3α-OH-5β-pregnan-20-one can be orally administered once a day at any regular dose until the CNS disease or condition is reduced or substantially eliminated. In one aspect, the oral composition can be administered either in the morning, afternoon, evening, or before bedtime. In another aspect, the oral composition can be administered at bedtime or about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour before bedtime.

[0148] In other aspects, the oral pharmaceutical composition and / or oral dosage form can be administered twice a day in any of the above amounts until the disease or condition is reduced or substantially eliminated. The oral composition can be administered in the morning and evening, or at 12-hour intervals. In a further aspect, the oral pharmaceutical composition or oral dosage form can be administered more than three times a day in any of the above amounts until the disease or condition is reduced or substantially removed. In one aspect, the oral composition or dosage form can be administered every 8 hours, every 6 hours, every 4 hours, every 3 hours, every 2 hours, or every 1 hour.

[0149] In one aspect, 3α-OH-5β-pregnan-20-one in the composition of the present invention can be orally administered to a subject according to a dosing regimen for a predetermined period of about 1 day to about 3 months. In another aspect, the oral pharmaceutical composition can be administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, 14 days, 16 days, 18 days, 20 days, 21 days, 22 days, 24 days, 26 days, 28 days, or 30 days until the disease or condition is alleviated or substantially eliminated. In one aspect, the oral pharmaceutical composition can be administered for 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks until the disease or condition is alleviated or substantially eliminated. In another aspect, the oral medicine can be administered for 1 month, 2 months, or 3 months until the disease or condition is alleviated or substantially eliminated.

[0150] In one aspect, the oral pharmaceutical composition or dosage form can be administered regardless of the presence or absence of titration. In one aspect, the oral pharmaceutical composition can be titrated by increasing the dose by 25%, 33%, 50%, 100%, 150%, 200%, 300%, 400%, or 500% over the initial (pre-titration) dose. In another aspect, the oral pharmaceutical composition can be titrated down to 75%, 50%, or 25% of the initial (pre-titration) dose. In certain aspects, the oral pharmaceutical composition can be administered at a fixed or constant dose as the initial dose.

[0151] In one aspect, the oral pharmaceutical composition or dosage form can be titrated up to subsequent 3α-OH-5β-pregnan-20-one doses based on the pharmacokinetic or pharmacodynamic response of the subject to the initial dose. In one example, the composition or oral dosage form is orally administered at an initial 3α-OH-5β-pregnan-20-one dose of about 50 mg to about 1400 mg and can be titrated up to a maintenance 3α-OH-5β-pregnan-20-one dose of about 25% to about 400% of the initial dose. In one example, the 3α-OH-5β-pregnan-20-one dose is increased or decreased by about 0.25-fold to about 4-fold the initial 3α-OH-5β-pregnan-20-one dose to reach the 3α-OH-5β-pregnan-20-one maintenance dose.

[0152] In another aspect, the oral pharmaceutical composition or dosage form can be administered regardless of the presence of food such as a meal, a snack, an appetizer, or a beverage. In one example, administration without food may be during a fasting period of the subject. The food can include various forms of food having no fat and no calories, no fat and low calories, no fat and medium calories, no fat and high calories, low fat and low calories, low fat and medium calories, low fat and high calories, medium fat and low calories, medium fat and medium calories, medium fat and high calories, high fat and low calories, high fat and medium calories, and high fat and high calories. In one aspect, administration with food can be any of administration with no high-fat foods, administration with a diet having at least about 5% calories from fat, administration with a diet having less than about 20% calories from fat, administration with a diet having about 20% to about 35% calories from fat, and administration with a diet having about 35% to about 60% calories from fat. The amounts of fat and calories are classified by the regulations of foods based on the Federal Food, Drug, and Cosmetic Act and its amendments.

[0153] In one embodiment, the composition can be formulated as an oral dosage form. The oral dosage form can be selected from the group consisting of a liquid, a semi-liquid, a semi-solid, a powder, an emulsion, a dispersant, a granule, a syrup, a suspension, a capsule, a tablet, a chewing agent, a drink, or a combination thereof. In one aspect, the composition can be formulated as an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one. In another aspect, the composition can be formulated as an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one, and when orally administered to a subject, when measured using a mass spectrometry method combining a liquid chromatograph or a gas chromatograph (e.g., LC-MS, LC-MS-MS, or GC-MS), regardless of food intake, 3α-OH-5β-pregnan-20-one C exceeding about 4.25 ng / ml max is provided.

[0154] An oral pharmaceutical composition containing 3α-OH-5β-pregnan-20-one can be administered in an oral dosage form, such as a solid, liquid, or partially or fully solubilized oral dosage form intended to substantially release and deliver 3α-OH-5β-pregnan-20-one into the gastrointestinal tract beyond the oral cavity and / or buccal cavity.

[0155] In one embodiment, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one provides a serum level of 3α-OH-5β-pregnan-20-one (e.g., average serum level: C avg or peak serum level C max ) sufficient to treat a CNS disorder. In another embodiment, the therapeutically effective amount of 3α-OH-5β-pregnan-20-one in the composition can be in a form that provides a therapeutically effective serum level of 3α-OH-5β-pregnan-20-one after oral administration for treating a CNS disorder in a subject. In a further embodiment, 3α-OH-5β-pregnan-20-one in the compositions disclosed herein can be in a form treated with a plurality of additives including at least one surfactant that provides a therapeutically effective level of 3α-OH-5β-pregnan-20-one effective to treat a CNS disorder in a subject. In yet another embodiment, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives sufficient to provide a therapeutically effective serum level of 3α-OH-5β-pregnan-20-one after its oral administration for treating a CNS disorder in a subject.

[0156] In yet another embodiment, the dosage regimens and methods for treating CNS disorders in females in the present invention include lactating females, females under 5 years old, females aged 5 to 18 years, non-pregnant females of childbearing age (e.g., females aged 15 to 45 years), pregnant females, females who have given birth within at least one of within 1 month, within 6 months, and within 12 months, females in the perimenopausal period (e.g., females aged 45 to 50 years), or postmenopausal females.

[0157] In certain embodiments, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one can be administered as a solid dosage form known in the art. Examples of solid dosage forms include, but are not limited to, two-piece hard gelatin capsules, soft gelatin capsules, beads, beadlets, granules, spheroids, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets, and combinations thereof.

[0158] In certain embodiments, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one can be administered as a liquid (e.g., solution, suspension, beverage, etc.) or in a partially or fully solubilized form in a gelatin capsule or non-gelatin capsule known in the art. The gelatin capsule may be a soft gelatin capsule, a hard gelatin capsule, or other capsules. The hard gelatin capsule may typically be a two-piece standard gelatin capsule comprising a first bottom and a second top capsule portion. The soft gelatin capsule may be a two-piece capsule in which the two parts are sealed together, or a one-piece substantially sealed capsule.

[0159] In certain embodiments, the pharmaceutical composition can be administered to a subject in need of 3α-OH-5β-pregnan-20-one for a CNS disorder. In certain embodiments, the amount of 3α-OH-5β-pregnan-20-one administered ranges from about 150 mg to about 775 mg, from about 225 mg to about 1350 mg, from about 50 mg to about 450 mg, or from about 225 mg to about 400 mg. In certain specific embodiments, the active ingredient is 3α-OH-5β-pregnan-20-one.

[0160] In other embodiments, 3α-OH-5β-pregnan-20-one can be administered to a subject (e.g., male and female) in need of the oral pharmaceutical composition of the present disclosure to ingest a therapeutically effective amount of 3α-OH-5β-pregnan-20-one from the oral composition. In one embodiment, the 3α-OH-5β-pregnan-20-one in the oral composition ranges from about 50 mg to about 600 mg, and about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, or any amount within the range of the recited values.

[0161] To achieve the desired therapeutic level of 3α-OH-5β-pregnan-20-one per administration, in certain embodiments, the oral pharmaceutical composition of the invention containing about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1350 mg, about 1400 mg, or any amount within the range of the recited values can be administered to a human in need thereof.

[0162] In one embodiment, the amount of 3α-OH-5β-pregnan-20-one in the oral pharmaceutical composition invented herein may range from about 0.6% to about 50% by weight of the composition. In a further embodiment, an oral pharmaceutical composition containing 3α-OH-5β-pregnan-20-one in an amount of about 0.6%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 22%, about 24%, about 25%, about 26%, about 28%, about 30%, about 35%, about 40%, about 45%, about 50%, or any percentage amount within the range of the recited values can be administered to a subject in need thereof.

[0163] In certain embodiments, the oral pharmaceutical composition containing 3α-OH-5β-pregnan-20-one in the present disclosure can be administered once a day within any of the ranges of the above-described amounts until the disease or condition is alleviated or substantially eliminated. In other embodiments, the oral pharmaceutical composition in the present disclosure can be administered twice a day within any of the ranges of the above-described amounts until the disease or condition is alleviated or substantially eliminated. In a further embodiment, the oral pharmaceutical composition in the present disclosure can be administered equal to or more than three times a day within any of the ranges of the above-described amounts until the disease or condition is alleviated or substantially eliminated.

[0164] The compositions disclosed herein can have a variable daily dosage. In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can be administered orally from 1 to 12 times per day. In one example, the daily dosage of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include from about 150 mg to about 750 mg. In another example, the daily dosage of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include from about 200 mg to about 1400 mg. In a further example, the daily dosage of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include from about 50 mg to about 500 mg. In a further example, the daily dosage of 3α-OH-5β-pregnan-20-one can be a fixed dosage of from about 50 mg to about 500 mg. In a further example, the daily dosage of 3α-OH-5β-pregnan-20-one can be a fixed dosage of from about 50 mg to about 1400 mg. In a further example, the daily dosage of 3α-OH-5β-pregnan-20-one can be a fixed dosage of from about 225 mg to about 900 mg. In a further example, the daily dosage of 3α-OH-5β-pregnan-20-one can be a fixed dosage of from about 225 mg to about 450 mg. In yet another aspect, the dosage of 3α-OH-5β-pregnan-20-one can be administered in a dosage form that includes 1 to 4 capsules, 1 / 2 to 4 tablets, or any combination thereof.

[0165] In one embodiment, the daily dose of a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can include at least one of about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1350 mg, about 1400 mg, or any amount within the range of the recited values.

[0166] In other aspects, 3α-OH-5β-pregnan-20-one can be administered to a subject (e.g., male and female) to provide a therapeutically effective level of 3α-OH-5β-pregnan-20-one. In one example, 3α-OH-5β-pregnan-20-one in an oral composition can have a total daily dosage in the range of about 50 mg to about 1400 mg, for example, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1350 mg, about 1400 mg, or any amount within the range of about 50 mg to about 1400 mg.

[0167] In one aspect, the number of dosage units of 3α-OH-5β-pregnan-20-one per dose (e.g., capsules, tablets, etc.) can be in the range of 1 / 2 to 4 units, such as 1 / 2, 1, 2, 3, or 4 units.

[0168] To achieve the therapeutic target level of 3α-OH-5β-pregnan-20-one per single dose, in some aspects, an amount of 3α-OH-5β-pregnan-20-one from 50 mg to 450 mg can be administered to a subject, for example, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 400 mg, about 450 mg, or any amount within the range of about 50 mg to about 450 mg.

[0169] In one aspect, the amount of 3α-OH-5β-pregnan-20-one can be orally administered once a day at any regular dose until the CNS disease or condition is reduced or substantially eliminated. In one aspect, the oral composition can be administered either in the morning, afternoon, evening, or before bedtime. In another aspect, the oral composition can be administered at bedtime, or about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour before bedtime.

[0170] In other aspects, the oral pharmaceutical composition and / or oral dosage form can be administered twice a day at any of the above amounts until the disease or condition is reduced or substantially eliminated. The oral composition can be administered in the morning and evening, or at 12-hour intervals. In a further aspect, the oral pharmaceutical composition or oral dosage form can be administered more than three times a day at any of the above amounts until the disease or condition is reduced or substantially removed. In one aspect, the oral composition or dosage form can be administered every 8 hours, every 6 hours, every 4 hours, every 3 hours, every 2 hours, or every 1 hour.

[0171] In one aspect, 3α-OH-5β-pregnan-20-one in the composition of the present invention can be orally administered to a subject according to a dosing regimen for a predetermined period of about 1 day to about 3 months. In another aspect, the oral pharmaceutical composition can be administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, 14 days, 16 days, 18 days, 20 days, 21 days, 22 days, 24 days, 26 days, 28 days, or 30 days until the disease or condition is alleviated or substantially disappears. In one aspect, the oral pharmaceutical composition can be administered for 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks until the disease or condition is alleviated or substantially disappears. In another aspect, the oral medicine can be administered for 1 month, 2 months, or 3 months until the disease or condition is alleviated or substantially disappears.

[0172] In one aspect, the oral pharmaceutical composition or dosage form can be administered regardless of the presence or absence of titration. In one aspect, the oral pharmaceutical composition can be titrated 25%, 33%, 50%, 100%, 150%, 200%, 300%, 400%, or 500% more than the initial (pre-titration) dose. In another aspect, the oral pharmaceutical composition can have its titration reduced to 75%, 50%, or 25% of the initial (pre-titration) dose. In certain aspects, the oral pharmaceutical composition can be administered with a fixed dose or a constant dose as the initial dose.

[0173] In one aspect, the oral pharmaceutical composition or dosage form can be titrated up to subsequent 3α-OH-5β-pregnan-20-one doses based on the pharmacokinetic or pharmacodynamic response of the subject to the initial dose. In one example, the composition or oral dosage form is orally administered with an initial 3α-OH-5β-pregnan-20-one dose of about 50 mg to about 1400 mg and can be titrated up to a maintenance 3α-OH-5β-pregnan-20-one dose of about 25% to about 400% of the initial dose. In one example, the 3α-OH-5β-pregnan-20-one dose increases or decreases by about 0.25-fold to about 4-fold the initial 3α-OH-5β-pregnan-20-one dose to reach the 3α-OH-5β-pregnan-20-one maintenance dose.

[0174] In another aspect, the oral pharmaceutical composition or dosage form can be administered regardless of the presence or absence of food such as a meal, snack, appetizer, or beverage. In one example, administration without food may be during a fasting period of the subject. The food can include various forms of food having no fat and no calories, no fat and low calories, no fat and medium calories, no fat and high calories, low fat and low calories, low fat and medium calories, low fat and high calories, medium fat and low calories, medium fat and medium calories, medium fat and high calories, high fat and low calories, high fat and medium calories, and high fat and high calories. In one aspect, administration with food can be any of administration with no high-fat foods, administration with a diet having at least about 5% calories from fat, administration with a diet having less than about 20% calories from fat, administration with a diet having about 20% to about 35% calories from fat, and administration with a diet having about 35% to about 60% calories from fat. The amounts of fat and calories are classified by food regulations based on the Federal Food, Drug, and Cosmetic Act and its amendments.

[0175] In one aspect, the pharmaceutically acceptable compositions and methods described herein can be used for refractory patients having CNS disorders such as depression or epilepsy, or patients who have received a stable regimen of drugs for treating CNS disorders such as antiepileptic drugs (AEDs) or antidepressants, and who require intermittent use of 3αOH-5β-pregnan-20-one to control increased seizure activity (acute recurrent seizures) or acute severe depressive symptoms, and who may have unresolved symptoms. In another aspect, the pharmaceutically acceptable compositions and methods described herein can be used for patients who are receiving background antiepileptic or antidepressant treatment.

[0176] In another aspect, the pharmaceutically acceptable compositions and methods described herein can be used for patients having multiple CNS disorders such as epilepsy with anxiety or depression, depression with anxiety or psychosis, or bipolar disorder.

[0177] Also provided herein are compositions and methods for treating mood disorders or psychoses that coexist with epilepsy, seizures or convulsions. For example, mood disorders include clinical depression, postpartum depression or PPD, peripartum depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression due to chronic illness, treatment-resistant depression, refractory depression, suicidal ideation, suicidal thoughts, and suicidal behavior. In some embodiments, the compositions and methods described herein provide a therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0178] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, recurrent depression, is a mental disorder characterized by a broad and persistent lowering of mood, accompanied by a loss of self-esteem and loss of interest and pleasure in activities that are normally enjoyable. Some people with clinical depression also have sleep disturbances, weight loss, and are generally easily excitable and sensitive. Clinical depression affects the way a person feels, thinks, and behaves, and can cause various emotional and physical problems. Patients with clinical depression may have difficulty in their daily lives and may feel that life is not worth living.

[0179] Peripartum depression refers to depression during pregnancy. Symptoms include being irritable, crying, being restless, sleep disturbances, extreme fatigue (emotional and / or physical), changes in appetite, decreased concentration, increased anxiety and / or worry, lack of connection with the baby and / or fetus, and loss of interest in activities that were previously enjoyable.

[0180] Postpartum depression (PND), also known as PPD, refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and hypersensitivity. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is refractory depression (e.g., refractory depression as described herein). In some embodiments, a subject having PND has also experienced depression, or symptoms of depression, during pregnancy. This depression is referred to herein as perinatal depression. In embodiments, a subject who has experienced perinatal depression is at increased risk of experiencing PND.

[0181] Atypical depression (AD) is characterized by mood reactivity (such as anhedonia), positive, significant weight gain, increased appetite. There are also seen excessive sleep or drowsiness (hypersomnia), heaviness in the limbs, and significant social impairment as a result of hypersensitivity to interpersonal rejection.

[0182] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, non-responsiveness to pleasurable stimuli, depressive mood more prominent than sadness or a sense of loss, excessive weight loss, or excessive guilt. Psychotic major depression (PMD) or psychotic depression refers to major depressive episodes of a particularly melancholic nature and experiencing psychotic symptoms such as delusions and hallucinations. Catatonic depression refers to major depression accompanied by motor behavioral disorders and other symptoms. Becoming mute, stuporous, immobile, or exhibiting purposeless or strange movements.

[0183] Seasonal affective disorder (SAD) is a type of seasonal depression in which depressive episodes occur in a seasonal pattern in the fall or winter.

[0184] Dysthymia is a condition related to unipolar depression, with similar physical and cognitive problems. Such problems are not severe and tend to last longer (for example, at least two years). Double depression refers to a fairly depressive mood (dysthymia) that lasts for at least two years and is interrupted by periods of major depression. Depressive personality disorder (DPD) refers to a personality disorder with depressive characteristics. Recurrent brief depression (RBD) refers to a state in which depressive episodes occur about once a month, and the duration of each episode lasts for two weeks or less, typically less than two to three days.

[0185] Minor depressive disorder or minor depression refers to depression in which at least two symptoms last for two weeks. Bipolar disorder or manic depression causes extreme mood swings that include elevated mood (mania or hypomania) and depression (depressive state). During the manic phase, there may be feelings of abnormal happiness, energy, irritation, or behaviors. Patients with mania often make decisions without considering the consequences and with insufficient deliberation. The need for sleep usually decreases. During the depressive phase, there may be crying, difficulty in making eye contact with others, or having a negative outlook on life. The suicide risk of depressive patients is high, exceeding 6% over 20 years, and self-harm behaviors are seen in 30 - 40%. Bipolar disorder often co-occurs with other mental disorders such as anxiety disorders and substance use disorders. Depression caused by chronic diseases refers to depression caused by chronic diseases such as cancer, chronic pain, chemotherapy, and chronic stress. Treatment-resistant depression refers to a state in which symptoms do not improve even after receiving treatment for depression. For example, even after receiving antidepressants or psychological counseling (psychotherapy), the depressive symptoms of people with treatment-resistant depression are not alleviated. In some cases, the symptoms of patients with treatment-resistant depression may improve, but generally the symptoms recur. Treatment-refractory depression occurs in patients suffering from depression that is resistant to standard drug treatments such as tricyclic antidepressants, MAOIs, SSRIs, dual and triple uptake inhibitors, and / or anxiolytics, as well as non-drug treatments (for example, psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0186] Postoperative depression refers to depressive feelings that occur after a surgical procedure (e.g., as a result of having to face one's own death). For example, feelings of sadness or emptiness may persist, the joy or interest in hobbies and activities that were once enjoyed may disappear, feelings of worthlessness or despair may persist. Mood disorders associated with conditions or disorders related to women's health refer to mood disorders (e.g., depression) associated with (e.g., caused by) conditions or disorders related to women's health (e.g., those described herein). Suicide tendency, suicidal thoughts, and suicidal behavior refer to the tendency of an individual to commit suicide. Suicidal thoughts mean thoughts about suicide or an abnormal obsession with suicide. The scope of suicidal thoughts varies widely from momentary thoughts to extensive thoughts, detailed plans, role-playing, incomplete attempts, and even actual attempts. Symptoms include talking about suicide, obtaining means of suicide, withdrawing from social contact, brooding about death, feeling a sense of constriction or despair in situations, increased use of alcohol or drugs, engaging in dangerous or self-destructive behavior, saying goodbye to people as if one will never see them again, etc. Symptoms of depression include persistent feelings of anxiety or sadness, weakness, despair, pessimism, worthlessness, decreased energy, restlessness, sleep difficulties, insomnia, irritability, fatigue, movement disorders, loss of interest in enjoyable activities and hobbies, decreased concentration, loss of energy, decreased self-evaluation, lack of positive thoughts or plans, hypersomnia, overeating, loss of appetite, insomnia, self-harm behavior, suicidal thoughts, suicidal attempts, etc. The presence, severity, frequency, and duration of symptoms vary from case to case. The symptoms of depression and their alleviation can be confirmed by a physician or psychologist (e.g., a mental state examination).

[0187] Anxiety disorder: Provided herein are compositions and methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobia, post-traumatic stress disorder). Anxiety disorders are an umbrella term covering several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0188] Generalized anxiety disorder is a common chronic disorder characterized by persistent anxiety that is not focused on a specific object or situation. People with generalized anxiety disorder experience nonspecific, persistent fear and worry and become overly concerned about everyday matters. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0189] In panic disorder, individuals are troubled by sudden, intense episodes of fear and anxiety, often accompanied by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. Such panic attacks are defined by the APA as sudden onsets of fear or discomfort that peak within 10 minutes, but they can last for hours and may be triggered by stress, fear, or exercise. In addition to recurrent, unexpected panic attacks, the diagnosis of panic disorder requires that the attacks result in chronic consequences, such as worry about the potential effects of the attacks, persistent fear of future attacks, or significant changes in behavior related to the attacks. Thus, individuals with panic disorder experience symptoms even outside of specific panic episodes. Often, normal variations in heart rate are noticed by individuals with panic disorder, leading them to think that something is wrong with their heart and that a panic attack may occur. In some cases, during a panic attack, there is an increase in awareness of bodily functions (hyperarousal), and the perceived physical changes are interpreted as a life-threatening illness (i.e., hypochondriasis).

[0190] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized by the repetition of obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). The thought patterns in OCD may be likened to superstitions in that they involve believing in causal relationships that do not actually exist in reality. For example, an obsession may be used that one must walk in a certain pattern to relieve the obsession that harm is imminent. Also, often the obsessions are completely irrational and are simply impulses to complete rituals triggered by tension. In a small minority of cases, there are OCD patients who experience only obsessions without compulsions.

[0191] The largest category of anxiety disorders is phobias, which includes all cases where fear and anxiety are triggered by specific stimuli or situations. Patients typically anticipate a terrifying outcome from encountering the object of their fear, which can vary from animals to places, body fluids, etc.

[0192] Post-traumatic stress disorder (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can arise from extreme situations such as combat, rape, hostage situations, or major accidents. It can also occur when an individual is exposed to severe stress factors chronically, such as a soldier who can endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, depression, etc.

[0193] In one embodiment, a method for improving the symptoms of CNS or neuropsychiatric and neurodegenerative diseases in a subject comprises the step of orally administering to the subject an effective amount of any one of 3α-OH-5β-pregnan-20-one, its pharmaceutically acceptable salts, its isomers, and combinations thereof. In another embodiment, a method for improving the symptoms of CNS or neuropsychiatric and neurodegenerative diseases in a subject comprises the step of orally administering to the subject a composition comprising an amount of oral 3α-OH-5β-pregnan-20-one, its pharmaceutically acceptable salts, its isomers, and combinations thereof that can exceed any one of about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and 15% bioavailability compared to an equivalent dose of 3α-OH-5β-pregnan-20-one administered by IV infusion.

[0194] In another embodiment, the disclosed method for treating a CNS disorder may comprise the step of orally administering to the subject an amount of 3α-OH-5β-pregnan-20-one sufficient to enable binding to GABA A receptors in the subject such that the CNS disorder of the subject is substantially reduced or eliminated.

[0195] In one embodiment of the present invention, the disclosed method includes the step of orally administering to a subject a composition having orally bioavailable 3α-OH-5β-pregnan-20-one therein, wherein the subject has at least one of acute CNS disorders, episodic CNS disorders, intermittent CNS disorders, subchronic CNS disorders, chronic CNS disorders, and combinations thereof. When the CNS disorder is a subchronic CNS disorder or a chronic CNS disorder, the dosing regimen can range from at least once a day for a specified period of about 1 day to about 3 months, or a period exceeding 3 months, or an indefinite period.

[0196] In one embodiment of the present invention, a subject in need of an oral composition comprising orally bioavailable 3α-OH-5β-pregnan-20-one may have a CNS disorder such as a depressive disorder (e.g., PPD, postpartum substance use disorder, major depressive disorder, treatment-resistant depression, perinatal depression, menopausal depression, or postmenopausal depression).

[0197] In one aspect of the present invention, the disclosed composition can be used for the treatment, alleviation, or elimination of conditions, symptoms, or diseases associated with CNS disorders in males or females. In one aspect, the subject can be a pubescent male or an adult male. In a further aspect, the subject can be a pubescent female or an adult female. The adult female may be of childbearing age, premenopausal, peripartum, postpartum, pregnant, perimenopausal, or postmenopausal. In yet another aspect, the subject may be asymptomatic for CNS disorders or may have a disease associated with the CNS disorders described herein.

[0198] Clinical central nervous system activity can be evaluated by monitoring CNS vital signs such as complex memory, verbal memory, visual memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, executive function, non-verbal reasoning, social vision, sustained attention, working memory, simple motor speed, etc. Alternatively, CNS activity can also be evaluated by monitoring drowsiness, thirst, loss of consciousness, dizziness, somnolence, fatigue, sweating, pulse oximetry monitoring, saccadic eye velocity measurement, etc.

[0199] In one embodiment, a method of improving symptoms of CNS or neuropsychiatric and neurodegenerative diseases in a subject comprises orally administering to the subject any of an effective amount of 3α-OH-5β-pregnan-20-one, a pharmaceutically acceptable salt thereof, an isomer thereof, and combinations thereof. In another aspect, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative diseases in a subject is about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and 15% compared to an equivalent dose of 3α-OH-5β-pregnan-20-one administered by IV infusion. A method comprising orally administering to a subject a composition comprising an amount of oral 3α-OH-5β-pregnan-20-one, a pharmaceutically acceptable salt thereof, an isomer thereof, and combinations thereof that can exceed any of the bioavailabilities.

[0200] In one embodiment, a method of treating a CNS disorder comprises orally administering to a subject a pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of additives to provide an increase in the serum C max level of 3α-OH-5β-pregnan-20-one, an increase in the serum C avg level of 3α-OH-5β-pregnan-20-one, or both, wherein the increase of interest is greater than the increase obtained by administering to the subject at least one substantially equivalent amount of 3α-OH-5β-pregnan-20-one in an SBE-β-CD solution composition (cyclodextrin administration), 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a medium-chain triglyceride (MCT) composition (MCT administration), 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a polysorbate 80 suspension composition (polysorbate 80 administration), and 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a canola oil or peanut oil composition (edible oil administration).

[0201] In another aspect, 3α-OH-5β-pregnan-20-one may be in a form that increases the serum level of 3α-OH-5β-pregnan-20-one in a subject, and the increased serum level is greater than the serum level obtained by administering to the subject at least a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in an SBE-β-cyclodextrin solution composition (cyclodextrin administration), 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a medium-chain triglyceride (MCT) composition (MCT administration), 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a polysorbate 80 suspension composition (polysorbate 80 administration), and 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a canola oil or peanut oil composition (edible oil administration). In one example, the increased serum level of 3α-OH-5β-pregnan-20-one can be increased by at least about 1.2-fold compared to the serum level obtained by administering to the subject a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in an SBE-β-cyclodextrin solution composition (cyclodextrin administration), 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a medium-chain triglyceride (MCT) composition (MCT administration), 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a polysorbate 80 suspension composition (polysorbate 80 administration), and 3α-OH-5β-pregnan-20-one in a solution consisting essentially of a canola oil or peanut oil composition (edible oil administration).

[0202] In one aspect, the CNS disorder can be any one or more of sleep disorders (e.g., insomnia), mood disorders (e.g., PND, major depressive disorder, PPD, essential tremor, treatment-resistant depression, or perinatal depression, etc.), dysthymia disorders (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (such as obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorders (schizophrenia, schizophrenia type II, etc.), schizophrenia, schizoaffective disorder), seizure disorders (epilepsy, status epilepticus (SE), seizures, etc.), memory and / or cognitive disorders (attention disorders, attention deficit hyperactivity disorder (ADHD), etc.), dementia (such as Alzheimer's disease), Alzheimer's disease, Lewy body dementia, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorder (ASD) (e.g., autism, synapticopathy, Rett syndrome, fragile X syndrome, Angelman syndrome, etc., single genetic causes of autism), pain (e.g., neuropathic pain, injury-related pain syndromes, acute pain, chronic pain), traumatic brain injury (TBI), vascular diseases (e.g., stroke, ischemia, vascular malformations), substance use disorders and / or withdrawal syndromes (e.g., dependence on heroin, cocaine, and / or alcohol), tinnitus, and any combination thereof.

[0203] In another embodiment, the disclosed method for treating a CNS disorder comprises orally administering to a subject an amount of 3α-OH-5β-pregnan-20-one sufficient to enable binding of the GABA A receptor in the subject such that the CNS disorder of the subject is substantially reduced or eliminated.

[0204] In one embodiment of the present invention, the disclosed method includes the step of orally administering to a subject a composition having orally bioavailable 3α-OH-5β-pregnan-20-one therein, wherein the subject has at least one of an acute CNS disorder, an episodic CNS disorder, an intermittent CNS disorder, a subchronic CNS disorder, a chronic CNS disorder, and combinations thereof. When the CNS disorder is a subchronic CNS disorder or a chronic CNS disorder, the dosing regimen can range from at least once a day for a specified period of about 1 day to about 3 months, or a period exceeding 3 months, or an unspecified period.

[0205] In one embodiment of the present invention, a subject in need of an oral composition comprising orally bioavailable 3α-OH-5β-pregnan-20-one can have a CNS disorder such as a depressive disorder (e.g., PPD, postpartum substance use disorder, major depressive disorder, treatment-resistant depression, perinatal depression, perimenopausal or postmenopausal depression).

[0206] Generally, in one embodiment, the oral compositions and methods disclosed herein can be administered to treat CNS disorders (e.g., suicidal ideation, depression, anxiety, bipolar disorder, essential tremor, neuropathic pain syndrome, trigeminal neuralgia, etc.) in women with epilepsy. This is for the management of epilepsy in women with epilepsy, the management of epilepsy during menstruation, pregnancy, or around childbirth in women of childbearing age with epilepsy, and the management of epilepsy in postmenopausal or perimenopausal women.

[0207] In another embodiment, the oral compositions and methods disclosed herein can be administered to treat CNS disorders (e.g., suicidal ideation, depression, anxiety, bipolar disorder, essential tremor, neurogenic pain syndrome, trigeminal neuralgia, etc.) and to treat or manage epilepsy in adult epileptic men, pediatric epileptic men, and pediatric epileptic women.

[0208] In one embodiment of the present invention, the disclosed composition can be used for the treatment, alleviation, or elimination of conditions, symptoms, or diseases associated with CNS disorders in males or females. In one aspect, the subject may be a pubescent male or an adult male. In a further aspect, the subject may be a pubescent female or an adult female. The adult female may be of childbearing age, premenopausal, peripartum, postpartum, pregnant, perimenopausal, or postmenopausal. In yet another aspect, the subject may be asymptomatic for the CNS disorder or may have a disease associated with the CNS disorder described herein.

[0209] Exemplary diagnoses of clinical CNS disorders such as depression can be made by evaluating / implementing at least one of the following assessment scales / questionnaires or similar scales that include, for example, measuring the severity of depression in an individual: a. 17-item Hamilton Depression Rating Scale (HAM-D) The HAM-D is a 17-item questionnaire used for the diagnosis of depression and for the evaluation of recovery and remission. The HAM-D is the most common scale for evaluating the symptoms of depression and is administered by a trained physician. b. Montgomery-Åsberg Depression Rating Scale (MADRS) The MADRS is a clinician-administered scale used to examine the severity of depressive episodes in patients with mood disorders. The MADRS consists of 10 clinical interviews that progress from broad questions to more detailed questions. c. Columbia-Suicide Severity Rating Scale (C-SSRS) The C-SSRS is a suicidal thoughts and behaviors assessment scale used to evaluate suicide propensity. The C-SSRS consists of a baseline assessment that evaluates the subject's lifetime experience of suicidal thoughts and / or behaviors and a post-baseline assessment that focuses on the suicide risk since the previous visit. d. Clinical Global Impression Scale for Severity (CGI-S) and Improvement (CGI-I) The Clinical Global Impression Scale is a valid scale used in clinical research. By using this scale, clinicians can integrate multiple sources of information and summarize the condition of the subject into one evaluation. e.CGI-S CGI-S objectively measures the severity of patients at the time of evaluation by comparing with the clinician's past experience with patients receiving the same diagnosis. f.CGI-I CGI-I is a 7-item scale that evaluates the overall improvement of the patient's illness compared to the subject's baseline state. g. Hamilton Anxiety Rating Scale (HAM-A) HAM-A is a clinician-administered scale used to evaluate the severity of anxiety symptoms. HAM-A consists of 14 items, and each item is defined by a series of mental and physical anxiety symptoms. h. Edinburgh Postnatal Depression Scale (EPDS) EPDS is a self-administered questionnaire used to identify PPD during outpatient, home visit, or examination at 6 - 8 weeks after childbirth. EPDS consists of 10 items and evaluates depressive symptoms such as guilt, decreased energy, fatigue, sleep disturbance, and suicidal thoughts. i. Maternal Postpartum Attachment Scale (MPAS) MPAS is a self-administered questionnaire used to evaluate the attachment between mother and infant. MPAS consists of 19 items and evaluates the emotional bond between mother and infant. j. Center for Epidemiologic Studies Depression Scale (CES-D) CES-D is a 20-item measure that asks caregivers about the frequency of experiencing depression-related symptoms such as restless sleep, loss of appetite, and loneliness in the past week. CES-D also provides a cut-off score (e.g., 16 or above) useful for identifying individuals at risk of clinical depression, with high sensitivity, specificity, and internal consistency. k. Beck Depression Inventory (BDI) BDI is a 21-item self-report inventory that measures characteristic attitudes and symptoms of depression.

[0210] Clinical CNS activity can be evaluated by monitoring CNS vital signs such as complex memory, verbal memory, visual memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, executive function, non-verbal reasoning, social vision, sustained attention, working memory, simple motor speed, etc. Alternatively, CNS activity can also be evaluated by monitoring drowsiness, thirst, loss of consciousness, dizziness, drowsiness, fatigue, flushing, pulse oximetry monitoring, saccadic eye velocity measurement, etc.

[0211] Women's health disorders: Compositions and methods for treating conditions or disorders related to women's health are provided herein. Conditions or disorders related to women's health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, problems related to women's general health and well-being (such as menopausal disorders, etc.). Gynecological health and disorders affecting women include menstruation and menstrual irregularities, urinary tract health such as urinary incontinence and pelvic floor disorders, disorders such as bacterial vaginitis, vaginitis, uterine fibroids, vulvodynia, etc.

[0212] Premenstrual syndrome (PMS) refers to physical and mental symptoms that occur in the 1 - 2 weeks before a woman's period. The symptoms are diverse and include bleeding, mood swings, breast tenderness, loss of appetite, fatigue, irritability, acne, depression, etc.

[0213] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressive mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feelings of loss of control or being overwhelmed, sleep disorders, physical problems (e.g., abdominal bloating, breast tenderness, swelling, headache, joint pain or muscle pain).

[0214] Problems in pregnancy include preconception care and antenatal care, pregnancy loss (miscarriage and stillbirth), preterm birth and premature delivery, sudden infant death syndrome (SIDS), breastfeeding, and congenital defects.

[0215] A miscarriage refers to a pregnancy that ends naturally within 20 weeks of gestation. An abortion refers to the intentional termination of a pregnancy, which may be performed during the 28 weeks of pregnancy.

[0216] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency. Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a series of symptoms caused by an increase in male hormones in women. Many women with PCOS develop many small cysts in their ovaries. Symptoms of PCOS include irregular menstruation, or no menstruation, heavy menstrual bleeding, excessive body hair and facial hair, acne, pelvic pain, difficulty getting pregnant, and dark, thick, velvety skin patches. PCOS may be associated with diseases such as type 2 diabetes, obesity, obstructive sleep apnea syndrome, heart disease, mood disorders, and endometrial cancer. Other diseases and symptoms that only affect women include Turner syndrome, Rett syndrome, ovarian cancer, and cervical cancer. Issues related to women's overall health and wellness include violence against women, women with disabilities and their specific issues, osteoporosis and bone health, and menopause.

[0217] Menopause refers to 12 months after a woman's last menstrual period and means the end of the menstrual cycle. Menopause usually occurs in a woman's 40s or 50s. Physical symptoms such as hot flashes and emotional symptoms of menopause can interfere with sleep, reduce energy, and cause anxiety, sadness, and a sense of loss. Menopause includes natural menopause and surgical menopause. Surgical menopause is a type of menopause induced by surgery (hysterectomy, oophorectomy, cancer, etc.). This is induced when the ovaries are severely damaged by radiation therapy, chemotherapy, or other drugs.

[0218] The methods described herein can be used for the treatment of neuropsychiatric diseases (see the Wikipedia article on neuropsychiatric diseases) or neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders associated with the progressive loss of the structure or function of neurons, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including related symptoms of mild, moderate, or severe cognitive impairment), amyotrophic lateral sclerosis (ALS), anoxic and ischemic injury, ataxia and seizures (including the treatment and prevention of seizures caused by drugs used in the treatment of bipolar disorder or schizophrenia), benign forgetfulness, cerebral edema, cerebellar ataxia (see the latest web page item on neuroacanthocytosis) including McLeod neuroacanthocytosis syndrome (MLS), closed head injury, coma, contusion (e.g., spinal cord injury and head injury), dementia including multi-infarct dementia and senile dementia, disturbance of consciousness, Down syndrome, drug-induced or drug-induced Parkinsonism (including neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor), epilepsy, fragile X syndrome, Gilles de la Tourette syndrome, head trauma, hearing impairment and deafness, Huntington's disease, Lennox syndrome, levodopa-induced dyskinesia, mental retardation, movement disorders including akinesia and akinetic (rigid) syndrome (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS-dementia complex, Parkinson's disease, postencephalitic Parkinsonism, and progressive supranuclear palsy), myoclonus (including generalized myoclonus, focal myoclonus), tremor (rest tremor, postural tremor, intention tremor, etc.), dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, blepharospasm, jaw joint dystonia, dystonic speech disorder, torticollis, etc. of focal dystonia), nerve cell damage including eye injury, retinopathy or macular degeneration, stroke,Thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and neurotoxic injury following cardiac arrest, Parkinson's disease, seizures, status epilepticus, stroke, tinnitus, tubulosclerosis, neurodegeneration due to viral infection (e.g., due to acquired immunodeficiency syndrome (AIDS) or encephalopathy), including but not limited to. Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and neurotoxic injury following cardiac arrest.,

[0219] An epileptic seizure (see the "Absence Seizures" page on epilepsy.com) is a change in physical findings or behavior that occurs after an episode of abnormal electrical activity in the brain. When seizures become a persistent problem, the condition is called epilepsy. The term "seizure" is often used interchangeably with "convulsion." A convulsion is defined as the body shaking rapidly and uncontrollably. During a convulsion, a person's muscles contract and relax repeatedly. Seizures are broadly classified into two categories: generalized seizures and partial seizures (also called focal or local seizures), based on the type of behavior and brain activity. Classifying the type of seizure makes it easier for doctors to diagnose whether a patient has epilepsy. Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused by electrical impulses in a relatively small part of the brain (at least initially). The part of the brain that causes the seizure is sometimes called the focus. There are six types of generalized seizures. The most common, dramatic, and thus best-known is the generalized convulsion, also called the grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls. After losing consciousness, the body becomes rigid for 30 to 60 seconds (called the "tonic" phase of the seizure), then convulses violently for 30 to 60 seconds ("clonic" phase), and then the patient falls into a deep sleep (the "postictal" period or postictal phase). In a grand mal seizure, injuries or accidents can occur, such as biting the tongue or experiencing urinary incontinence. In an absence seizure, there are few or no symptoms, and there is a brief loss of consciousness (for just a few seconds). The patient (often a child) usually interrupts their activity and stares blankly. The seizure starts and ends suddenly. The patient usually does not notice they are having a seizure, except that they may be aware of losing track of time. Myoclonic seizures usually consist of sporadic twitching movements that occur on both sides of the body. Patients may describe this type of seizure as feeling like a short electrical shock. In severe cases, the patient may drop objects or throw things without meaning to.

[0220] Myoclonic seizures occur repeatedly and rhythmically, twitching simultaneously on both sides of the body. Tonic seizures are characterized by muscle rigidity. Atonic seizures are those in which the tension of the muscles, especially in the arms and legs, is suddenly and completely lost, often causing a fall. Seizures, with or without epilepsy, described in this specification may include epileptic seizures, acute recurrent seizures, cluster seizures, status epilepticus, non - continuous seizures, delayed seizures, recurrent seizures, status epilepticus with epileptic super - imposition, refractory convulsive status epilepticus, non - convulsive status epilepticus, refractory seizures, myoclonic seizures, tonic seizures, tonic - clonic seizures, simple partial seizures, complex partial seizures, secondarily generalized seizures, atypical absence seizures, absence seizures, childhood absence epilepsy (CAE), tonic seizures, benign Rolandic epilepsy, febrile seizures, emotional seizures, focal seizures, gelastic seizures, generalized seizures, infantile spasms, Jacksonian seizures, bilateral grand - monoclonic seizures, multifocal seizures, neonatal onset seizures, nocturnal seizures, occipital lobe seizures, post - traumatic seizures, petit mal seizures, Sylvan seizures, visual reflex seizures, or dissociative seizures. In some embodiments, the seizure is a generalized seizure associated with at least one of Dravet syndrome, Lennox - Gastaut syndrome, tuberous sclerosis complex, CDLK5 disorder, Rett syndrome, or PCDH19 - related childhood epilepsy in females. Juvenile myoclonic epilepsy (JME) is the most common generalized epilepsy syndrome.

[0221] Typically, epilepsy patients need to take antiseizure medications throughout their lives as monotherapy or polytherapy using multiple drugs for the treatment, prevention, reduction, and control of seizures and epilepsy.

[0222] In one embodiment, a method for treating or preventing a neurodegenerative disease by orally administering an oral composition containing an orally bioavailable 3α-OH-5β-pregnan-20-one also includes treating or preventing the loss of nerve cell function characteristic of neurodegenerative diseases such as status epilepticus (SE). Status epilepticus (SE) may include convulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, and periodic lateralized epileptiform discharges, etc. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and includes early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-line therapy, and second-line therapy is performed. Refractory status epilepticus is characterized by status epilepticus seizures that persist despite first-line and second-line therapies. Refractory status epilepticus is generally treated with general anesthetics. Super-refractory status epilepticus is characterized by status epilepticus seizures that persist for more than 24 hours despite first-line therapy, second-line therapy, and treatment with general anesthetics.

[0223] Non-convulsive status epilepticus may include focal non-convulsive status epilepticus, complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, mild non-convulsive status epilepticus, generalized non-convulsive status epilepticus, late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0224] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered as monotherapy to a subject having at least one of traumatic brain injury epilepsy, status epilepticus, convulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, cluster seizures, acute repetitive seizures, generalized periodic epileptiform discharges, and periodic lateralized epileptiform discharges, and can treat, prevent, reduce, or improve seizures or epilepsy.

[0225] In another embodiment, the pharmaceutically acceptable compositions and methods described herein are administered as monotherapy to a subject having at least one of four classified epilepsies including focal epilepsies such as frontal lobe epilepsy, generalized epilepsy, a mixture of generalized and focal epilepsy, simple or complex partial seizure epilepsy, and unknown epilepsies (including neonatal and infantile epilepsies), and can treat, prevent, reduce, or improve seizures or epilepsy.

[0226] In one aspect, the compositions and methods disclosed herein can be used to treat, prevent, reduce, or improve at least one of the generalized epilepsies, which include generalized tonic-clonic seizures (symptoms: loss of consciousness followed by body stiffness and then violent jerking after falling into a deep sleep), absence (or non-motor) seizures (symptoms: brief loss of consciousness), myoclonic seizures (symptoms: sporadic and brief jerking movements, usually occurring on both sides of the body), clonic seizures (symptoms: repetitive and rhythmic jerking movements, usually occurring on both sides of the body), etc. and can be used to treat, prevent, reduce, or improve at least one of the generalized epilepsies including myoclonic seizures (symptoms: brief loss of consciousness), myoclonic seizures (symptoms: sporadic and brief jerking movements, usually on both sides of the body), clonic seizures (symptoms: repetitive and rhythmic jerking movements on both sides of the body simultaneously), tonic seizures (symptoms: muscle stiffness and rigidity), and atonic seizures (symptoms: sudden and total loss of muscle tension in the limbs).

[0227] In another aspect, the compositions and methods disclosed herein can be used to treat, prevent, reduce, or improve at least one of the focal epilepsies, including focal aware seizures (motor / sensory / autonomic / psychic), focal impaired awareness seizures, focal motor seizures, focal non-motor seizures, and focal to bilateral tonic-clonic seizures.

[0228] In a further aspect, the compositions and methods disclosed herein can be used to treat, prevent, reduce, or improve at least one of the unknown (or idiopathic) epilepsies, including unclassified seizures such as unknown motor seizures, unknown non-motor seizures, and neonatal and infantile seizures. An unknown seizure is defined as a seizure that occurs during sleep or in a situation where the patient is alone or the eyewitness cannot describe it. An unclassified seizure is designated when the clinician is certain that it is a seizure but cannot explain it due to incomplete information.

[0229] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered as adjuvant therapy to a subject having at least one of traumatic brain injury epilepsy, status epilepticus, convulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, and periodic lateralized epileptiform discharges, and can treat, prevent, reduce, or improve seizures or epilepsy.

[0230] In another embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as adjuvant therapy to a subject having at least one of four classified epilepsies consisting of focal epilepsy, general epilepsy, generalized epilepsy, a mixture of generalized and focal epilepsy, and unknown epilepsy, and can treat, prevent, reduce, or improve seizures or epilepsy. In one aspect, the pharmaceutically acceptable compositions and methods described herein are administered as adjuvant therapy with at least one of anti-epileptic drugs such as bromide, phenobarbital, mephobarbital, phenytoin, acetazolamide, trimethadione, mephenytoin, paramethadione, corticosteroids, adrenocorticotropic hormone (ACTH), furosemide, phenacemide, primidone, mesuximide, ethotoin, ethosuximide, chlordiazepoxide, sulthiame, diazepam, carbamazepine valproate, clonazepam, clobazam, progabide, vigabatrin, zonisamide, lamotrigine, oxcarbazepine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin, sultiame, rufinamide, lacosamide, eslicarbazepine acetate, retigabine (ezogabine), perampanel, imepitoin, brivaracetam, everolimus, valproic acid, eslicarbazepine, cenobamate, fenfluramine, midazolam, alprazolam, etc. to treat, prevent, reduce, or improve seizures or epilepsy in a subject in need of treatment.

[0231] According to research, the incidence of epilepsy and non-provoked (or reflex) seizures is slightly lower in women than in men. This difference is usually thought to be due to men having a greater chance of being exposed to risk factors for lesional epilepsy and acute symptomatic seizures. Idiopathic generalized epilepsies (IGEs), which account for about 15 - 20% of all epilepsy, are more common in women. Also, in common epilepsy syndromes such as mesial temporal sclerosis, isolated auras are more common in women, and the spread of secondary seizures is more common in men, etc., and their behaviors may differ between men and women. For example, looking at the trends between men and women with epilepsy, the incidence of status epilepticus, the incidence of sudden unexpected death in epilepsy (SUDEP), prognosis, and mortality are more common in men. As another example, male children with epilepsy accompanied by myoclonic atonic seizures (Doose syndrome) develop about twice as often as female children. Also, focal seizures accompanied by hyperkinetic automatisms occur about twice as often in men as in women.

[0232] More women were diagnosed with idiopathic generalized epilepsy than men. There was no sex difference in localization-related epilepsy, but localization-related symptomatic epilepsy was more common in men, and idiopathic localization-related epilepsy was more common in women.

[0233] Epilepsy syndromes commonly seen in women include childhood absence epilepsy, typical early-onset absence epilepsy, photosensitive epilepsy, juvenile myoclonic epilepsy, menstruation-associated epilepsy, etc.

[0234] Subjects in need of the disclosed compositions and methods and for which the disclosed compositions and methods can be used include women of childbearing age (e.g., 12 - 49 years old, 15 - 49 years old, or 18 - 45 years old). More specifically, the disclosed compositions and methods can enable planned or unplanned pregnancy in nulliparous or multiparous (> 1 year postpartum or previous delivery), and more particularly, can be particularly useful for such women during the pre-pregnancy stage, pregnancy stage, labor stage, peripartum stage, and postpartum stage.

[0235] Women in the pre- and post-menopausal period are in the range of about 39 to about 50 years old during the pre- and post-menopausal period (for example, the age of menopause may be 40 to 50 years old).

[0236] Before the age of 10 (including infancy and childhood), pseudo-seizures are commonly seen in both boys and girls. After the age of 10 (up to the age of 18), pseudo-seizures are more commonly seen in girls. In adulthood (ages 18 to about 70 years old), women suffer from pseudo-seizures in 60 to 80% of cases. From puberty to the age of 30 and above 70 years old, epilepsy is more common in women than in men. Young men in puberty often work during their free time, and such work can lead to sleep deprivation and trigger epileptic seizures.

[0237] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to male or female children between the ages of 5 and 17 having at least one of traumatic brain injury epilepsy, status epilepticus, convulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, generalized periodic status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, acute repetitive seizures, and periodic lateral epileptiform discharges, and can be administered for the treatment, prevention, improvement, or improvement or control of seizures including breakthrough seizures in such subjects.

[0238] In another embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to male or female children between the ages of 5 and 17 having at least one of the four classified epilepsies including focal epilepsy, generalized epilepsy, the complex of generalized and focal epilepsy, and unknown epilepsy classified by the International League Against Epilepsy (ILAE) in 2017 to treat seizures or epilepsy in such subjects.

[0239] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to a male having at least one of traumatic brain injury epilepsy, status epilepticus, convulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, acute repetitive seizures, and periodic lateralized epileptiform discharges, and can treat seizures or epilepsy.

[0240] In another embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to a male having at least one of four classified epilepsies classified by the International League Against Epilepsy (ILAE) in 2017, including focal epilepsy, generalized epilepsy, a combination of generalized and focal epilepsy, and unknown epilepsy, and can treat seizures or epilepsy.

[0241] In adult males, either epilepsy or an antiepileptic drug (AED) can cause dysfunction at any level of the hypothalamic-pituitary-sexual system, resulting in possible sexual dysfunction. Epileptic seizures are often associated with hormonal disorders and cause the release of hypothalamic and pituitary hormones. Also, some AEDs can change the levels of sex hormones and induce their effects. An increase in prolactin during the interictal period is observed in both male and female epilepsy patients, regardless of the administration of antiepileptic drugs. Epileptic seizures can cause an increase in prolactin levels, which reach their maximum within a short time (~1 hour) after the seizure. In one aspect, the pharmaceutically acceptable compositions and methods described herein are administered to male epilepsy patients having symptoms of sexual dysfunction to reduce, prevent, improve, or treat epilepsy and / or its side effects, such as sexual dysfunction, increased prolactin, increased sex hormone-binding globulin (SHBG), and decreased free testosterone.

[0242] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to a female having at least one of traumatic brain injury epilepsy, status epilepticus, convulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, acute repetitive seizures, and periodic lateralized epileptiform discharges, and can treat seizures or epilepsy.

[0243] In another embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to a female having at least one of the four classified epilepsies, including focal epilepsy such as frontal lobe epilepsy, generalized epilepsy, combined generalized and focal epilepsy, and unknown epilepsy, classified by the International League Against Epilepsy (ILAE) in 2017, to treat seizures or epilepsy.

[0244] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to a perimenopausal or postmenopausal female having epilepsy or active epilepsy (controlled or uncontrolled seizures in the past 6 - 12 months before the start of other AED(s) or monotherapy or before adjunctive therapy) to improve, control, prevent, prevent exacerbation of, or treat seizures or epilepsy, including breakthrough seizures, and / or mood disorders, and / or sleep disorders.

[0245] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to a perimenopausal or postmenopausal female with a history of menstrual-associated epilepsy or active epilepsy (controlled or uncontrolled seizures in the past 6 - 12 months before the start of other AED(s) or prior to adjunctive therapy) to improve, control, prevent, prevent exacerbation of, or treat seizures or epilepsy, and / or mood / disorders, and / or sleep disorders.

[0246] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are for use in improving, controlling, preventing, preventing an increase in, or treating seizures or epilepsy (controlled or uncontrolled seizures during 6 to 12 months prior to the initiation of other AED(s) or monotherapy or adjunctive therapy), and / or mood disorders, and / or sleep disorders in menopausal or perimenopausal women having endogenous positive allosteric neuroactive steroid deficiency.

[0247] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are for use in improving, controlling, preventing, preventing an increase in, or treating seizures or epilepsy (controlled or uncontrolled seizures during 6 to 12 months prior to the initiation of other AED(s) or monotherapy or adjunctive therapy), and / or mood disorders, and / or sleep disorders in menopausal or perimenopausal women or women of childbearing age during hormone replacement therapy having endogenous positive allosteric modulator neuroactive steroid deficiency.

[0248] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are for use in improving, controlling, preventing, preventing an increase in, or treating seizures or epilepsy (controlled or uncontrolled seizures during 6 to 12 months prior to the initiation of other AED(s) or combination therapy), and / or mood disorders, and / or sleep disorders in menopausal or perimenopausal women or women of childbearing age at risk of impaired bone health.

[0249] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are for improving, controlling, preventing, preventing an increase in, or treating seizures or epilepsy, and / or mood disorders, and / or sleep disorders, and are administered to women of menopausal or perimenopausal age or women of childbearing age who have epilepsy with at least three or more seizures per month, immediately before the initiation of other AED(s) or monotherapy or as adjunctive therapy.

[0250] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are for improving, controlling, preventing, preventing an increase in, or treating seizures or epilepsy, and / or mood disorders, and / or sleep disorders, and are administered to women of menopausal or perimenopausal age or women of childbearing age who have epilepsy and who have had 25 days or fewer seizure-free days in the past two months before the initiation of other AED(s) or monotherapy or before the initiation of adjunctive therapy.

[0251] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to women of childbearing age who have epilepsy or active epilepsy, immediately before the initiation of other antiepileptic drugs or monotherapy or as adjuncts, and can improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders, regardless of the use of oral hormonal contraceptives.

[0252] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to women of childbearing age who have epilepsy or active epilepsy and who have a deficiency of endogenous progesterone or positive allosteric modulator neuroactive steroids, or excessive levels of testosterone or estrogen, immediately before the initiation of other AED(s) or monotherapy or as adjuncts, regardless of the use of oral hormonal contraceptives, for improving, controlling, preventing, preventing an increase in, or treating seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0253] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age with epilepsy or active epilepsy without regard to drug-drug interactions (DDIs) that would impair either the contraceptive effect or the seizure control effect of co-administered drugs to improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0254] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to women of childbearing age who have epilepsy or active epilepsy and menstrual disorders such as premenstrual syndrome, premenstrual dysphoric disorder (PMDD), and ovulatory disorders, and can improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0255] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as an adjunct to other antiepileptic drugs (AEDs) to women of childbearing age with epilepsy to prevent breakthrough seizures or to maintain seizure control as the dose of the AED is adjusted in women planning to become pregnant.

[0256] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as adjunctive therapy or monotherapy with other AED(s) to women of childbearing age with epilepsy to replace all or substantially all of the dosage of such AED(s) that have a teratogenic risk in women planning to become pregnant.

[0257] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as adjunctive therapy or monotherapy with other AED(s) to women of childbearing age with epilepsy to reduce or eliminate dependence on polytherapy with such AEDs for seizure suppression doses in women planning to become pregnant.

[0258] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age with epilepsy as adjunctive therapy or monotherapy with other AEDs to reduce or eliminate dependence on polytherapy with such AEDs at seizure-suppressing doses by providing physiological levels of endogenous neuroactive steroids in women planning pregnancy.

[0259] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as adjunctive therapy to other AED(s) to improve, control, prevent, prevent an increase in, or treat at least one of seizure management, depression, anxiety, sleep disorder, and suicidal ideation in women of childbearing age with epilepsy or active epilepsy who are pregnant, planning pregnancy, or at risk of pregnancy.

[0260] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as adjunctive therapy or monotherapy to other AED(s) to improve, control, prevent, prevent an increase in, or treat at least one of seizure management, depression, anxiety, sleep disorder, and suicidal ideation in pregnant women of childbearing age without increasing the AED dose.

[0261] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as adjunctive therapy or monotherapy to other AED(s) to improve, control, prevent, prevent an increase in, or treat seizure management and at least one of the associated co-morbidities such as depression, anxiety, sleep disorder, and suicidal ideation in women of childbearing age with epilepsy or active epilepsy who are pregnant, planning pregnancy, or at risk of pregnancy.

[0262] In one aspect, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age having at least one of childhood absence epilepsy, typical childhood absence epilepsy, photosensitive epilepsy, juvenile myoclonic epilepsy, acute repetitive seizures, and menstruation-associated epilepsy to treat seizures, epilepsy, or related symptoms. In another aspect, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age having menstruation-associated epilepsy, which is 1) epilepsy associated with premenstrual withdrawal of anticonvulsant action mediated through the action of endogenous neuroactive steroids on the GABA A receptor, changes in GABA A receptor subunits, and subsequent changes in neural inhibition, 2) peak estrogen on the day before ovulation, and 3) increased frequency of anovulatory cycles due to dysregulation of the hypothalamic-pituitary-gonadal axis, and as a result, low progesterone luteal phase, including treatment of seizures or epilepsy. The pattern of menstruation-associated epilepsy is classified into three types according to the time of the menstrual cycle: 1) perimenstrual pattern (C1 pattern: related to the decrease in progesterone, from day 25 to day 3), 2) periovulatory pattern (C2 pattern: related to the rapid increase in estrogen, from day 10 to day 15), and 3) luteal phase pattern (C3 pattern: related to an inappropriate luteal phase cycle due to a decrease in progesterone level, resulting in anovulatory cycles, from day 10 of one cycle to day 3 of the next cycle). Premenstrual (or perimenstrual) pattern epilepsy, or C1 pattern epilepsy, is the most frequent epilepsy in women of childbearing age with menstruation-associated epilepsy.

[0263] In one aspect, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age having at least one of perimenstrual menstrual epilepsy, preovulatory menstrual epilepsy, and luteal phase menstrual epilepsy to treat seizures or epilepsy.

[0264] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to postmenopausal or perimenopausal women having epilepsy (a type of focal epilepsy) associated with low estrogen and low progesterone levels, epilepsy not associated with hormonal levels (a type of generalized epilepsy), and epilepsy of unknown cause, and can treat seizures or epilepsy.

[0265] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to pregnant women having epilepsy, including focal epilepsy, generalized epilepsy, a mixture of generalized and focal epilepsy, and epilepsy of unknown type, to treat seizures or epilepsy. For some pregnant women, particularly those with sleep deprivation or those who do not take medications as prescribed, pregnancy can increase the frequency of seizures. In one aspect, the pharmaceutically acceptable compositions and methods described herein are administered to pregnant women having epilepsy to treat symptoms or disorders caused by epilepsy during pregnancy, such as a decrease in fetal heart rate, a decrease in oxygen to the fetus, fetal injury, premature placental abruption (abruptio placentae) from the uterus, miscarriage due to trauma (e.g., a fall during an epileptic seizure), preterm labor, sudden infant death syndrome, difficulty breastfeeding, congenital abnormalities, preterm birth, etc.

[0266] In one embodiment, the pharmaceutically acceptable compositions and methods described herein are administered to women in the peripartum period (late pregnancy and postpartum) having seizures or three types of seizures, namely, 1) exacerbation of known existing seizure disorders (mainly epilepsy), 2) onset of new seizures due to problems unrelated to pregnancy, and 3) seizures associated with the pregnancy state, and can treat seizures or epilepsy. Seizures associated with pregnancy fall into two categories: i) those focused on eclampsia and ii) newly onset seizures associated with pregnancy, and the symptoms include at least one of reversible posterior leukoencephalopathy syndrome, reversible cerebral vasoconstriction syndrome, cerebral venous sinus thrombosis, thrombotic thrombocytopenic purpura, amniotic fluid embolism, air embolism.

[0267] Also described herein are methods and compositions for treating movement disorders. As used herein, the term "movement disorder" refers to various diseases and disorders associated with hyperkinetic movement disorders and related abnormalities of muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and Parkinson's syndrome (particularly as defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremors (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

[0268] The methods and compositions described herein can be used to treat tremors such as cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiologic tremor, psychogenic tremor, and rubral tremor. Tremors include genetic diseases, degenerative diseases, and idiopathic diseases such as Wilson's disease, Parkinson's disease, and essential tremor. Tremors can be caused by or associated with metabolic diseases (e.g., thyroid and parathyroid, liver, and hypoglycemia), peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy Levy disease, diabetes, complex regional pain syndrome), toxins (e.g., nicotine, mercury, lead, CO, manganese, arsenic, and toluene), certain drugs (e.g., narcolepsy drugs, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, vincristine, etc.) and psychogenic diseases. Clinical tremors are classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classical essential tremor, primary orthostatic tremor, task / position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Tremor is an involuntary, sometimes rhythmic contraction and relaxation of muscles, which may be accompanied by vibration or convulsion of one or more body parts (hands, arms, eyes, face, head, vocal cords, trunk, legs, etc.). Cerebellar tremor or intention tremor is a slow, extensive tremor of the extremities that occurs after purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum due to tumors, strokes, diseases (such as multiple sclerosis, hereditary degenerative diseases, etc.). Dystonic tremor occurs in patients with dystonia, a movement disorder in which continuous involuntary muscle contractions cause twisting, repetitive movements, and / or abnormal postures or positions accompanied by pain. Dystonic tremor can affect muscles throughout the body. Dystonic tremor occurs irregularly and often improves with complete rest. Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and non-progressive, or it may progress slowly and affect both sides within 3 years, starting from one side of the body.The hands are most frequently affected, but the head, voice, tongue, legs, and trunk may also be affected. The frequency of tremors decreases with age, but the severity of tremors increases. Emotional arousal, stress, fever, physical fatigue, hypoglycemia, etc. may induce tremors or increase the severity of tremors. The symptoms generally progress over time and may persist visibly after onset.

[0269] Orthostatic tremor is characterized by rapid (e.g., exceeding 12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. The patient may feel tremors in the thighs and legs and may shake uncontrollably when instructed to stand in one place. Orthostatic tremor may be seen in patients with essential tremor.

[0270] Tremors in Parkinson's disease are caused by damage to the brain structures that control movement. Parkinsonian tremors are often prodromal symptoms of Parkinson's disease and typically show an action like "rolling a pill" with the hand, and may also affect the jaw, lips, legs, and trunk. Tremors in Parkinson's disease usually begin after the age of 60. The movement starts from one side of the hands, feet, or body and may progress to the opposite side.

[0271] Physiological tremors are also seen in healthy individuals and have no clinical significance. They may be present in all voluntary muscle groups. Physiological tremors may be caused by certain drugs, alcohol withdrawal symptoms, medical conditions such as hyperthyroidism and hypoglycemia. The frequency of physiological tremors is usually about 10 Hz.

[0272] Psychogenic tremor or hysterical tremor occurs at rest, in a posture, or during movement. Patients with psychogenic tremor may have conversion disorder or other mental disorders. Rubral tremor is characterized by a coarse, slow tremor seen in any of rest, posture, or intentional tremor. Rubral tremor is associated with diseases that affect the red nucleus of the midbrain and typical abnormal strokes.

[0273] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. The Parkinsonian syndrome is characterized by tremors, bradycardia, rigidity, and postural instability. The Parkinsonian syndrome shares symptoms with those seen in Parkinson's disease but is more of a symptom complex rather than a progressive neurodegenerative disease. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal and often repetitive movements and postures. Dystonic movements can be patterned, twisted, or tremulous. Dystonia is often induced or exacerbated by voluntary movement and involves excessive muscle activation.

[0274] Sydenham's chorea is a neurological disorder characterized by involuntary, jerky movements that occur in the shoulders, waist, face, etc. Huntington's disease is a hereditary disorder in which the nerve cells in the brain degenerate. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing. Ataxia refers to the complete loss of control of body movements and can affect the fingers, hands, arms, legs, body, speech, and eye movements. Myoclonus and startle are responses to sudden, unexpected stimuli caused by auditory, tactile, visual, or vestibular stimulation.

[0275] Tic disorder usually begins suddenly with involuntary movements that are short, repetitive but non-rhythmic, often imitating normal actions, and frequently occurring against the background of normal activities. Tics are classified into motor tics and vocal tics. Motor tics are related to movement, and vocal tics are related to voice. Tics can be simple or complex. For example, simple motor tics involve only a few muscles limited to a specific part of the body. Tourette syndrome is a hereditary neuropsychiatric and neurodegenerative disorder that develops in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0276] Restless leg syndrome is a neurological sensorimotor disorder characterized by an overwhelming urge to move the legs at rest. Stiff-person syndrome is a progressive movement disorder characterized by muscle cramps and rigidity with involuntary pain, usually affecting the lower back and legs. Stiff-person syndrome typically presents as a rigid gait with exaggerated lumbar lordosis. Characteristic abnormalities in EMG recordings with continuous motor unit activity of paraspinal muscles are also usually observed. Its variants usually include "stiff limb syndrome" which causes local rigidity affecting the distal legs and feet.

[0277] Gait disorders refer to abnormalities in the way of walking or gait, which are caused by neuromuscular, arthritis, and other physical changes. Gait disorders are classified according to the cause system of movement abnormalities and include hemiplegic gait, hemiplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, tremor gait, ataxic gait, and sensory gait.

[0278] Also, compositions and methods for treating mood disorders are provided herein. For example, mood disorders include clinical depression, postpartum depression or PPD, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic diseases, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, and suicidal behavior. In some embodiments, the compositions and methods described herein provide a therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, mood disorders are associated with the diseases or disorders described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), female health disorders or conditions).

[0279] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a broad and persistent mood decline accompanied by a decrease in self-esteem and a loss of interest and pleasure in activities that are usually enjoyable. Patients with clinical depression may experience sleep disorders and weight loss, and some may generally feel excited or hypersensitive. Clinical depression can affect a person's feelings, thoughts, and behaviors, and may cause various emotional and physical problems. Patients with clinical depression may have difficulties in their daily lives and may feel as if their lives are worthless.

[0280] Perinatal depression refers to depression during pregnancy. Symptoms may include irritability, crying, restlessness, insomnia, extreme fatigue (emotional and / or physical), changes in appetite, decreased concentration, increased anxiety and / or worry, a lack of connection with the baby and / or fetus, and a loss of interest in activities that were previously enjoyable.

[0281] Postpartum depression (PND), also called PPD, refers to a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and hypersensitivity. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is refractory depression (e.g., refractory depression as described herein). In some embodiments, a subject having PND has also experienced depression, or symptoms of depression, during pregnancy. This depression is referred to herein as perinatal depression. In embodiments, a subject who has experienced perinatal depression has an increased risk of experiencing PND.

[0282] Atypical depression (AD) is characterized by mood reactivity (such as anhedonia) and features such as increased positive affect, significant weight gain, and increased appetite. Patients suffering from AD may also exhibit excessive sleep or drowsiness (hypersomnia), heaviness in the limbs, and significant social impairment as a result of hypersensitivity to interpersonal rejection.

[0283] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, lack of response to pleasurable stimuli, a depressed mood more prominent than sadness or a sense of loss, excessive weight loss, or excessive guilt. Psychotic major depression (PMD) or psychotic depression refers especially to major depressive episodes of a melancholic nature and involves experiencing psychotic symptoms such as delusions and hallucinations. Catatonic depression refers to major depression accompanied by motor behavioral disorders and other symptoms. Becoming mute and stuporous, not moving the body, or showing purposeless or strange movements.

[0284] Seasonal affective disorder (SAD) is a type of seasonal depression that has a seasonal pattern in which depressive episodes occur in the fall or winter.

[0285] Dysthymia refers to a condition related to unipolar depression, with similar physical and cognitive problems. Such problems are not severe and tend to last longer (e.g., at least two years). Double depression refers to a fairly depressive mood (dysthymia) that lasts at least two years and is interrupted by periods of major depression. Depressive personality disorder (DPD) refers to a personality disorder with depressive characteristics. Recurrent brief depression (RBD) refers to a state in which an individual experiences depressive episodes about once a month, with each episode lasting two weeks or less, typically less than two to three days.

[0286] Minor depressive disorder or minor depression refers to depression in which at least two symptoms persist for two weeks. Bipolar disorder or manic depression causes extreme mood swings that include elevated mood (mania or hypomania) and depression (depressive episodes). During a manic episode, a person may feel or act with unusual happiness, energy, irritability. People with mania often make impulsive decisions without considering the consequences. The need for sleep usually decreases. During a depressive episode, a person may cry, have trouble making eye contact with others, and have a negative outlook on life. The risk of suicide in people with depression is high, exceeding 6% over 20 years, and self-harm is seen in 30-40%. Bipolar disorder often co-occurs with other mental disorders such as anxiety disorders and substance use disorders. Depression caused by chronic diseases refers to depression caused by chronic diseases such as cancer, chronic pain, chemotherapy, and chronic stress. Treatment-resistant depression refers to a state in which symptoms do not improve even after treatment for depression. For example, the symptoms of treatment-resistant depression do not improve even after taking antidepressants or receiving psychological counseling (psychotherapy). In some cases, the symptoms of treatment-resistant depression may improve, but generally, the symptoms recur. Treatment-resistant depression occurs in patients who suffer from depression that is resistant to standard drug treatments such as tricyclic antidepressants, MAOIs, SSRIs, dual and triple uptake inhibitors, and / or anti-anxiety drugs, as well as non-drug treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0287] Postoperative depression refers to depressive feelings that occur after a surgical procedure (e.g., as a result of having to face one's own death). For example, feelings of sadness or emptiness may persist, the joy and interest in hobbies and activities that were once enjoyed may disappear, feelings of worthlessness and despair may persist. Mood disorders associated with conditions or disorders related to women's health refer to mood disorders (e.g., depression) associated with (e.g., caused by) conditions or disorders related to women's health (e.g., those described in this specification). Suicide tendency, suicidal thoughts, and suicidal behavior refer to the tendency of an individual to commit suicide. Suicidal thoughts mean thoughts about suicide or abnormal obsession with suicide. The range of suicidal thoughts is extremely diverse, from momentary thoughts to extensive thoughts, detailed plans, role-playing, incomplete attempts, and even more. Symptoms include talking about suicide, obtaining means of suicide, withdrawing from social contact, brooding about death, feeling a sense of constriction and despair in the situation, increased use of alcohol and drugs, engaging in dangerous and self-destructive behavior, saying goodbye to people as if one will never see them again, etc. Symptoms of depression include persistent feelings of anxiety and sadness, powerlessness, despair, pessimism, worthlessness, decreased energy, restlessness, sleep difficulties, insomnia, irritability, fatigue, movement disorders, loss of interest in enjoyable activities and hobbies, decreased concentration, loss of energy, decreased self-evaluation, lack of positive thoughts and plans, hypersomnia, overeating, loss of appetite, insomnia, self-harm behavior, suicidal thoughts, suicidal attempts, etc. The presence, severity, frequency, and duration of symptoms vary from case to case. The symptoms of depression and their alleviation can be confirmed by a physician or a psychologist (e.g., a mental state examination).

[0288] Anxiety disorder: Provided herein are compositions and methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobia, post-traumatic stress disorder). Anxiety disorders are inclusive terms that encompass several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0289] Generalized anxiety disorder is a common chronic disorder characterized by persistent anxiety that does not focus on a specific object or situation. People suffering from generalized anxiety disorder experience non-specific, persistent fears and worries and become overly concerned about everyday matters. Generalized anxiety disorder is the most common anxiety disorder affecting the elderly.

[0290] In panic disorder, individuals are troubled by sudden, intense episodes of fear and anxiety, often accompanied by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. Such panic attacks are defined by the APA as sudden onsets of fear or discomfort that peak within 10 minutes, but they can last for hours and may be triggered by stress, fear, or exercise. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder requires that the attacks result in chronic consequences, such as worry about the potential effects of the attacks, persistent fear of future attacks, or significant changes in behavior related to the attacks. Thus, patients with panic disorder experience symptoms even outside of specific panic episodes. Often, normal variations in heart rate are noticed by individuals with panic disorder, leading them to think that something is wrong with their heart and that a panic attack may occur. In some cases, heightened awareness of bodily functions (hyperarousal) occurs during a panic attack, and the perceived physical changes are misinterpreted as a life-threatening illness (i.e., extreme hypochondriasis).

[0291] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized by the recurrence of obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). The thought patterns in OCD may be likened to superstitions in that they involve believing in causal relationships that do not actually exist in reality. For example, an obsession may be used to alleviate the obsession that harm is imminent, such as having to walk in a certain pattern. Also, in many cases, the obsession is completely inexplicable and is simply an impulse to complete the ritual triggered by tension. Although rare, there are also OCD patients who experience only obsessions without compulsions.

[0292] The largest category of anxiety disorders is phobias, which includes all cases where fear and anxiety are triggered by specific stimuli or situations. Patients typically anticipate terrible outcomes from encountering the object of their fear (which can be anything, such as animals, places, body fluids, etc.).

[0293] Post-traumatic stress disorder (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can arise from extreme situations such as combat, rape, hostage situations, or major accidents. It can also occur when an individual is exposed to severe stress factors chronically, such as soldiers who can endure individual battles but not continuous combat. Common symptoms include flashbacks, avoidance behaviors, and depression.

[0294] The first embodiment of the present invention is a method and composition for treating epilepsy in a subject. In the first embodiment, the method preferably includes the steps of identifying a subject having epilepsy or having a predisposition to epilepsy (e.g., identified as having a genetic predisposition to epilepsy), and orally administering an anti-epileptic drug (AED) to the subject. The administration may include an administration regimen that includes administering a predetermined amount of AED (e.g., one or more capsules of AED) at a predetermined frequency (e.g., once or more per day) for a predetermined period (e.g., a single administration or daily administrations for several days). The subject preferably includes women with epilepsy (WWE), more particularly WWE of childbearing age. The composition preferably includes a neuroactive steroid (NAS), more particularly an endogenous NAS (ENAS), and more particularly, the composition preferably includes 3α-OH-5β-pregnan-20-one. The method preferably results in the prevention of epileptic seizures, or a reduction in frequency or magnitude.

[0295] In some embodiments, the oral compositions and methods disclosed herein are intended to treat central nervous system (CNS) disorders including sleep disorders (e.g., insomnia), mood disorders (e.g., PND, major depressive disorder, postpartum depression (PPD), essential tremor, treatment-resistant depression, or peripartum depression), anhedonia, mood dysregulation disorders (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), seizure disorders (e.g., epilepsy, absence seizures, status epilepticus (SE)), epileptic seizures, acute seizures, catamenial epilepsy), memory and / or cognitive impairments (e.g., attention deficit disorder, attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewy body dementia, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorder (ASD) (e.g., autism, single-gene causes of autism such as synapticopathy (see the "Synapticopathy" entry in Wikipedia), Rett syndrome, fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, trauma-related pain syndromes, acute pain, chronic pain), traumatic brain injury (TBI), vascular diseases (e.g., stroke, ischemia, vascular malformations), substance use disorders and / or withdrawal syndromes (e.g., dependence on opium, cocaine, alcohol), and tinnitus.

[0296] In one embodiment, the oral compositions and methods disclosed herein are formulated for treating CNS disorders including depression. For example, depression can include major depressive disorder, persistent depressive disorder (e.g., dysthymia), PPD, antenatal depression, essential tremor, treatment-resistant depression, bipolar disorder (e.g., manic-depressive disorder), and seasonal affective disorder (SAD).

[0297] In one aspect, the oral compositions and methods disclosed herein are designed for the treatment of CNS disorders (e.g., suicidal thoughts, depression, anxiety) in epileptic women of childbearing age, the management of epilepsy during menstruation, the management of epilepsy during pregnancy, the management of epilepsy around and after childbirth, or the management of epilepsy in postmenopausal or perimenopausal women.

[0298] In one embodiment, the 3α-OH-5β-pregnan-20-one compositions and oral dosage forms can be formulated to provide a therapeutically effective amount or peak level of 3α-OH-5β-pregnan-20-one for treating CNS disorders when orally administered to a subject. For example, in one aspect, the compositions and oral dosage forms can include a plurality of pharmaceutically acceptable additives that provide a serum 3α-OH-5β-pregnan-20-one level sufficient to treat CNS disorders when orally administered to a subject.

[0299] In one embodiment, the present invention is an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of additives, wherein oral administration of the composition to a subject having at least one of a neuropsychiatric disorder and a neurodegenerative disorder results in a serum level of said 3α-OH-5β-pregnan-20-one in the subject such that at least one of the neuropsychiatric disorder and the neurodegenerative disorder is substantially reduced, improved, or eliminated.

[0300] In one embodiment, the present invention is an oral pharmaceutical composition comprising an immediate-release form of α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides an increase in the 3α-OH-5β-pregnan-20-one level in the subject as compared to the 3α-OH-5β-pregnan-20-one level provided by a composition that contains an equal amount of 3α-OH-5β-pregnan-20-one but does not contain a solubilizing agent and / or a dispersing agent.

[0301] In another embodiment, the disclosed oral pharmaceutical composition comprises an immediate-release form of 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives. When the composition is administered with food, the composition provides a serum level greater than that resulting from an equivalent cyclodextrin solution administration. In a further embodiment, the disclosed oral pharmaceutical composition comprises a fast-disintegrating form of 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives.

[0302] In one embodiment, a 3α-OH-5β-pregnan-20-one composition or oral dosage form can be formulated to efficiently provide a therapeutically effective amount of 3α-OH-5β-pregnan-20-one for treating CNS disorders when orally administered to a subject. In another aspect, the 3α-OH-5β-pregnan-20-one in the composition may be in a form that enables it to provide an effective level of 3α-OH-5β-pregnan-20-one when orally administered to a subject. In another aspect, 3α-OH-5β-pregnan-20-one may be in a form that increases the level of 3α-OH-5β-pregnan-20-one in a subject when orally administered to the subject. In another aspect, the composition of the present invention, when orally administered to a subject, is suspended in edible oil and is expected to increase the level of 3α-OH-5β-pregnan-20-one in the subject as compared to a composition containing an equal amount of micronized or non-micronized (e.g., crystalline) 3α-OH-5β-pregnan-20-one orally administered to the subject.

[0303] In yet another embodiment, a dosing regimen and method for treating CNS disorders in a subject are provided, which may include orally administering a composition comprising a therapeutically effective amount of 3α-OH-5β-pregnan-20-one.

[0304] In one embodiment, the composition and oral dosage form can include a plurality of pharmaceutically acceptable additives including at least one of alpha-tocopherol, glyceryl monocaprylate, glyceryl monocaprylocaprate, propylene glycol monolaurate, PEG-35 castor oil, PEG-40 hydrogenated castor oil, and combinations thereof, and provide a therapeutically effective level of 3α-OH-5β-pregnan-20-one in an amount sufficient to treat CNS disorders when orally administered to a subject.

[0305] In one aspect, the amount of 3α-OH-5β-pregnan-20-one in the composition is a therapeutically effective level of 3α-OH-5β-pregnan-20-one sufficient to treat CNS disorders (e.g., average serum level, C avg , or peak serum level, C max ). In another aspect, the 3α-OH-5β-pregnan-20-one in the composition may be in an immediate-release form that provides a therapeutically effective level of 3α-OH-5β-pregnan-20-one to treat CNS disorders in a subject. In another aspect, the 3α-OH-5β-pregnan-20-one in the composition may be in a solubilized or amorphous form that provides a therapeutically effective level of 3α-OH-5β-pregnan-20-one to treat CNS disorders in a subject. In a further aspect, the 3α-OH-5β-pregnan-20-one in the compositions disclosed herein may be in a form treated with a plurality of additives including at least one surfactant that provides a therapeutically effective level of 3α-OH-5β-pregnan-20-one effective to treat CNS disorders in a subject. In yet another aspect, 3α-OH-5β-pregnan-20-one can be formulated with a plurality of additives that provide a therapeutically effective level of 3α-OH-5β-pregnan-20-one to treat CNS disorders in a subject.

[0306] Figure 4 is an exemplary plot of a PK profile showing the plasma concentration of a single oral dose of a drug as a function of time. The PK profile can be used to characterize the absorption / bioavailability of 3α-OH-5β-pregnan-20-one in the blood of a subject over time. The most common PK parameters are C max max, T max max and the area under the curve (AUC). As shown in Figure 4, the plasma concentration observed with a single dose of the drug increases until it reaches the peak concentration C max max. As shown in Figure 4, the time until C max max is reached is called T max max. Referring to Figure 4, an exemplary AUC 0-24 (AUC from time 0 to 24 hours) of the drug concentration is the integrated area under the observed curve of plasma concentration versus time. AUC 0-24 represents drug exposure in the systemic circulation over a certain period. Unless otherwise specified, the measured pharmacokinetic parameters are the mean values reported from the subject group, and the parameter T max max is not the mean value but the median value reported from the subject group.

[0307] AUC 0-24 refers to the area under the curve from 0 hours to 24 hours, but PK profile parameters for treatments beyond 24 hours can be evaluated using AUC 0-t (AUC for the period from 0 hours to the end of treatment observation / sampling), and can also be extended to the total drug exposure observed in plasma using AUC 0-∞ . Here, AUC 0-∞ is the total exposure, and is extracted from AUC 0-t +C t max / k el . Here, C t max is the drug concentration observed in plasma at time t, and k el is the drug excretion rate. Further, similar to C max max, another PK parameter that can provide insight into the minimum effective dose required for treatment is C min,t That is. By understanding the minimum effective plasma concentration required for the treatment of interest, the understanding of the minimum dosage concentration that must be used can be determined. Unless otherwise specified, the time used in the description of AUC 0-t or C min,t is related to the time (in hours) after the first administration.

[0308] The pharmaceutical composition cannot be used by itself to determine the target serum drug concentration in a subject. As an example, referring to FIG. 5, which is an exemplary plot of two simulated single-dose PK profiles of a first orally administered composition containing treated (e.g., micronized, micronized and labeled, solid black line) 3α-OH-5β-pregnan-20-one and untreated (e.g., unmicronized and labeled, gray dotted line) 3α-OH-5β-pregnan-20-one, the first orally administered composition containing treated 3α-OH-5β-pregnan-20-one has a better blood level (higher C max and AUC 0-t ) than the first orally administered composition containing untreated 3α-OH-5β-pregnan-20-one. FIG. 5 shows exemplary plots of treated and untreated embodiments of the active form, but multiple modulations can provide a similar effect on the serum drug concentration. As an additional example, similar effects can be observed when a pharmaceutical composition (e.g., a 300 mg tablet dosage form) is treated and has a composition containing at least 7.5% surfactant (e.g., poloxamer 407; w / w%) and a second pharmaceutical composition is substantially similar except that it has no surfactant or less than 0.5%. The serum drug concentrations of the sample containing 7.5% surfactant and the sample without surfactant are substantially similar to the serum drug concentrations observed in FIG. 5 between the micronized and non-micronized examples. Thus, to achieve the target blood concentrations (C max and AUC 0-t ) and biological sensitivity of a particular orally administered composition, it is necessary to implement all conditions for preparing said dosage.

[0309] Accordingly, 3α-OH-5β-pregnan-20-one in the oral pharmaceutical composition may preferably be in a processed form. More preferably, in an oral solid composition (e.g., 225 mg or 450 mg tablet dosage form) containing 3α-OH-5β-pregnan-20-one, 3α-OH-5β-pregnan-20-one may be in a processed form. The active agent in an oral pharmaceutical composition in a solid form that is at least partially crystalline may further comprise at least one polymorph of the active agent. In some embodiments, the active agent 3α-OH-5β-pregnan-20-one is substantially crystalline. In some embodiments, 3α-OH-5β-pregnan-20-one may be processed as described above.

[0310] Accordingly, there remains an unmet need for compositions and methods that enable higher, faster, more reliable, and appropriate serum levels of 3α-OH-5β-pregnan-20-one to be generated in a biologically acceptable manner such that desirable release and subsequent effective absorption of 3α-OH-5β-pregnan-20-one are possible for treating subjects in need thereof for treating CNS disorders. In some aspects, the oral compositions and methods of the present invention have surprisingly been found to be effective in producing desirable or required levels of the effectiveness of 3α-OH-5β-pregnan-20-one without high sensitivity to the effects of food / meal.

[0311] Furthermore, the pharmacodynamic efficacy of treatment for a subject having epilepsy of at least one classification can be identified by monitoring the photoparoxysmal response (PPR) range in individuals with photosensitive epilepsy. Photosensitivity refers to the ability to produce an epileptic-like response upon light stimulation. This EEG pattern is called the photoparoxysmal response (PPR). In a photosensitivity proof-of-concept model, patients who show PPR in response to flickering diffuse white light are used as subjects. By eliciting the upper and lower limits of sensitivity to intermittent light stimulation (IPS), the photosensitivity range of each subject can be determined. This photosensitivity range is defined as the difference between the highest and lowest flash rates that consistently induce PPR and can be used as a quantitative measure of photosensitivity and, by extension, epileptogenicity. In a photosensitivity test, the photosensitivity range is measured repeatedly (up to 8 times) over the course of a day. The decrease in the photosensitivity range can be easily quantified after a single dose of ASM. This decrease has been used as proof of the antiepileptic effect of many currently marketed or developing ASMs, particularly levetiracetam, lamotrigine, brivaracetam, carisbamate, cenobamate, and valproate. When the PPR decreases by at least 2 points compared to placebo or compared to the pre-dose value, the treatment for dealing with epilepsy is considered effective. In another embodiment, the PPR can decrease by at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points compared to placebo or compared to the pre-dose value. When the PPR decreases by at least 2 points, the treatment for dealing with epilepsy is considered effective. In another embodiment, the PPR can decrease by at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points. In another embodiment, the PPR can decrease more than in the placebo-treated group in orally administered 3α-OH-5β-pregnan-20-one. In another embodiment, the PPR can decrease to zero (complete response).

[0312] Examples The following examples are provided to facilitate a clear understanding of specific embodiments of the present invention and are in no way intended to limit it.

[0313] Example 1. An oral pharmaceutical composition containing 3α-OH-5β-pregnan-20-one The following examples of oral pharmaceutical compositions are provided to facilitate a clear understanding of specific embodiments of the present invention related to the treatment of subjects (female and / or male) in need of treatment for CNS disorders and are in no way intended to limit it.

[0314] The following tables (Tables A to C8) represent oral compositions or dosage forms containing 3α-OH-5β-pregnan-20-one in a form comprising at least one of the forms of solvate, partial solvate, dissolved substance, partial dissolved substance, amorphous solid, solid dispersion, solid solution, and eutectic mixture. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0315] The oral pharmaceutical composition containing 3α-OH-5β-pregnan-20-one described in this specification can be formulated into a liquid (e.g., solution, suspension, emulsion, drink, etc.) or a dosage form of encapsulated gelatin or non-gelatin capsules known to those skilled in the art. The capsules can be soft gelatin or non-gelatin capsules, or hard gelatin or non-gelatin capsules. The hard capsules may typically be two-piece standard capsules including a first capsule portion at the bottom and a second capsule portion at the top. The soft capsules may be two-piece capsules with the two parts sealed together, or a one-piece sealed cap.

[0316] As shown in Table D and Table E below, the oral composition or dosage form of the present invention may contain a completely solubilized form or an amorphous form (e.g., non-crystalline) of 3α-OH-5β-pregnan-20-one. The oral composition of the present disclosure can be formulated to provide a release rate (%) that can result in an enhanced therapeutic level of 3α-OH-5β-pregnan-20-one for the treatment of depressive disorders. The in vitro % release rate of 3α-OH-5β-pregnan-20-one from these oral compositions can be obtained by measuring the release rate of 3α-OH-5β-pregnan-20-one during a 4-hour exposure of the composition using an HPLC method in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate at 75 rpm and 37 °C using a USP type-II dissolution apparatus. [Table 11] [Table 12]

[0317] As shown in Table E, the oral dosage forms disclosed herein can provide a ratio of 3α-OH-5β-pregnan-20-one to α-tocopherol of less than 1.3, for example, any one of about 0.1 to 1.3, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, and about 1.3.

[0318] In one example, the oral dosage form can provide a ratio of 3α-OH-5β-pregnan-20-one to medium-chain monoglyceride of about 0.4 or less, about 0.3 or less, about 0.2 or less, about 0.15 or less, for example, about 0.15, about 0.13, about 0.11, about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, and about 0.01 or less.

[0319] In another example, the oral dosage form can provide a ratio of α-tocopherol to hydrophilic additive of about 0.05 to about 4.2, for example, about 0.05, about 0.1, about 0.3, about 0.5, about 0.7, about 0.9, about 1.1, about 1.3, about 1.4, about 1.7, about 2.0, about 2.3, about 2.6, about 2.9, about 3.2, about 3.5, and about 4.2. [Table 13] [Table 14] [Table 15]

[0320] In one embodiment, the oral solid dosage form of the present disclosure can be formulated to include about 50 mg to about 600 mg of processed 3α-OH-5β-pregnan-20-one, and a plurality of additives including at least one surfactant. In another embodiment, the oral solid dosage form can include about 150 mg to about 500 mg of processed 3α-OH-5β-pregnan-20-one, and a plurality of additives including at least one surfactant. In yet another embodiment, the oral solid dosage form can include about 50 mg to about 450 mg of processed 3α-OH-5β-pregnan-20-one, and a plurality of additives including at least one surfactant. In another embodiment, the oral solid dosage form can include about 225 mg to about 450 mg of processed 3α-OH-5β-pregnan-20-one, and a plurality of additives including at least one surfactant. In yet another embodiment, the oral solid dosage form can include about 300 mg to about 450 mg of processed 3α-OH-5β-pregnan-20-one, and a plurality of additives including at least one surfactant.

[0321] The solid form of 3α-OH-5β-pregnan-20-one in the composition can constitute about 5 wt% to about 60 wt% of the oral solid dosage form described herein. In one embodiment, 3α-OH-5β-pregnan-20-one can constitute about 10 wt% to about 45 wt% of the oral solid dosage form. In the compositions and forms of the present invention, 3α-OH-5β-pregnan-20-one may be processed as needed. In another embodiment, the oral solid dosage form can include a combination of these forms. In another embodiment, 3α-OH-5β-pregnan-20-one may be present or added as a processed form such as amorphous, micronized, nano-sized, pulverized, sieved form, or a combination thereof, to an oral solid dosage form including at least one surfactant. 3α-OH-5β-pregnan-20-one may be dispersed within the oral solid dosage form. The dispersed portion of 3α-OH-5β-pregnan-20-one may be partially or completely micronized, nano-sized, pulverized, sieved, amorphous form, or a combination thereof.

[0322] In the oral solid dosage form of the present invention, 3α-OH-5β-pregnan-20-one can be in a partially or completely high-energy solid form, whereby the release rate in an aqueous medium is significantly increased compared to the untreated crystalline form (low-energy form). Examples of the high-energy solid forms of 3α-OH-5β-pregnan-20-one include amorphous forms, solid dispersion forms, solid solution forms, eutectic forms, etc. after association with additives in the composition. In one embodiment, the high-energy form of 3α-OH-5β-pregnan-20-one in the present invention can be physicochemically stable for at least one month. In yet another embodiment, the high-energy form of 3α-OH-5β-pregnan-20-one may be physically and / or chemically bonded to at least one additional substance such as, for example, alcohol, pyrrolidone, cellulose, poloxamer, polyol, polyethylene glycol, dextrin, cyclodextrin, etc. In the present invention, several methods known in the art such as co-precipitation, solid solution, co-melting, co-grinding, hot melt extrusion, hot melt spraying, spray drying with a co-solvent, controlled precipitation from a supersaturated solution, solidified supersaturated solution, and combinations thereof may be used to generate the high-energy form of 3α-OH-5β-pregnan-20-one.

[0323] The oral solid dosage form of the present disclosure may include one or more pharmaceutically acceptable additives. The pharmaceutically acceptable additives can be selected from a wide range of compounds and classes of compounds. The pharmaceutically acceptable additives can constitute from 40 wt% to about 99.5 wt% of the oral solid dosage form. In one embodiment, the pharmaceutically acceptable additives can constitute from about 50 wt% to about 90 wt% of the oral dosage form. In one embodiment, the pharmaceutically acceptable additives can constitute from about 50 wt% to 85 wt% of the oral solid dosage form. In yet another embodiment, the pharmaceutically acceptable additives can constitute from about 50 wt% to 70 wt% of the oral solid dosage form.

[0324] Non-limiting examples of compounds that can be used as at least a portion of a pharmaceutically acceptable additive include, but are not limited to, cellulose, dextrin, gum, carbomer, methacrylate, sugar, lactose, inorganic carbonate, oxide, chloride, sulfate, calcium salt, magnesium salt, fatty acid salt, inorganic and organic acids, bases and salts, propylene glycol, glycerol, fatty acid, fatty alcohol, fatty acid ester, glycerol ester, mono-, di- or triglyceride, edible oil, omega oil, vegetable oil, hydrogenated vegetable oil, partially or fully hydrogenated vegetable oil, glycerol ester of fatty acid, wax, alcohol, gelatin polyethylene glycol, polyethylene oxide copolymer, silicate, antioxidant, tocopherol, sugar stearate, starch, shellac, resin, protein, acrylate, methyl copolymer, polyvinyl alcohol, starch, phthalic acid ester, and combinations thereof.

[0325] It is important to note that the additives in the compositions used in the present invention can serve multiple functional purposes within an oral solid dosage form. For example, an additive can also function as a filler, binder, diluent, disintegrant, lubricant, preservative, sweetener, flavor, coating agent, coloring agent, antioxidant, or release modifier.

[0326] The oral solid dosage form is not limited with respect to size, shape, or general configuration and can be formulated into various dosage forms including, but not limited to, two-piece hard gelatin capsules, soft gelatin capsules, beads, beadlets, granules, spheres, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets, or combinations thereof. Other oral solid dosage forms known to those skilled in the art can also be used. In one aspect, the oral solid dosage form can be a capsule or a tablet. In one embodiment, the oral solid dosage form can be a matrix tablet.

[0327] The coating can be applied by conventional techniques such as a pan coater, a rotary granulator, and a fluidized bed coater (such as top spray, tangential spray or bottom spray (Wurster coating), etc.), and most preferably can be applied by the latter. One preferred coating solution consists of about 40 wt% EUDRAGIT L30 - D55 and 2.5 wt% triethyl citrate dissolved in about 57.5 wt% water. This enteric coating solution can be used to coat the core of an oral dosage form using a pan coater. Using the above enteric coating material, a 3α - OH - 5β - pregnane - 20 - one - containing mixture can be granulated. The resulting granules can be filled into capsules or compressed to form tablets or caplets. The release of 3α - OH - 5β - pregnane - 20 - one from the components of the oral dosage form or dosage form (e.g., granules) of the present disclosure can be controlled or delayed.

[0328] Some oral dosage forms containing the solid form of 3α - OH - 5β - pregnane - 20 - one are prepared using the components as described in Tables H and I. Examples of the oral dosage forms described herein can generally be prepared as solid dosage forms such as tablets. In one aspect, the oral dosage form is prepared by mixing a processing aid and at least one surfactant with 3α - OH - 5β - pregnane - 20 - one to form a homogeneous powder mixture. In another aspect, the amount of surfactant in the composition may exceed 0.5% (w / w) of the composition. The powder mixture can be directly compressed or compressed after a dry or wet granulation process to form tablets. In the case of wet granulation, a solution of a binder (e.g., PVP K30) may be used for granulation. The binder solution can optionally contain a part (or all) of the amount of at least one surfactant if the surfactant is present in the dosage form. After granulation, the resulting product can be dried, sieved, and compressed into tablets.

[0329] Solid dosage forms of 3α-OH-5β-pregnan-20-one can include crystalline or amorphous solid forms of 3α-OH-5β-pregnan-20-one. The final form of 3α-OH-5β-pregnan-20-one in the dosage form may be the result of processing techniques employed such as size reduction, coating, spraying, drying, hot melt extrusion, etc. The final form of 3α-OH-5β-pregnan-20-one in the solid dosage form may be ground, micronized, nano-sized, amorphous, solid solution or dispersion, or eutectic mixture. The solid dosage form may be in the form of capsules, tablets, powders, granules, pellets.

[0330] Oral compositions containing the solid form of 3α-OH-5β-pregnan-20-one of the present disclosure can be formulated to provide a release rate % that can result in an enhanced therapeutic effect of 3α-OH-5β-pregnan-20-one for the treatment of CNS disorders. The in vitro release rate of 3α-OH-5β-pregnan-20-one from these oral compositions can be obtained by inserting the oral composition into a USP type II dissolution apparatus and measuring the release rate of 3α-OH-5β-pregnan-20-one using HPLC method in an aqueous medium under sedimentation conditions at 37 °C at about 75 - 100 rpm for at least 4 hours.

[0331] In one aspect, an oral composition containing the processed solid form of 3α-OH-5β-pregnan-20-one in the present invention can disintegrate in an aqueous medium in less than 25 minutes. In another aspect, an oral composition containing the processed solid form of 3α-OH-5β-pregnan-20-one in the present invention can disintegrate in an aqueous medium in less than 20 minutes. In a further aspect, an oral composition containing the processed solid form of 3α-OH-5β-pregnan-20-one in the present invention can disintegrate in an aqueous medium in less than 20 minutes, for example, less than one of 19 minutes, 18 minutes, 16 minutes, 15 minutes, 14 minutes, 13 minutes, 12 minutes, 11 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, and 1 minute.

[0332] In one aspect, the oral dosage forms disclosed herein can be formulated using 3α-OH-5β-pregnan-20-one processed from the original powder of 3α-OH-5β-pregnan-20-one. As an example, the processed 3α-OH-5β-pregnan-20-one in the present invention is a micronized powder of 3α-OH-5β-pregnan-20-one, which can have a particle size distribution with D90 < 20 μm. For example, one of the processed 3α-OH-5β-pregnan-20-one in the present invention is a micronized powder of 3α-OH-5β-pregnan-20-one, which has a particle size distribution with D90 = 16 μm. Further, as another example, another one of the processed 3α-OH-5β-pregnan-20-one in the present invention is a micronized powder of 3α-OH-5β-pregnan-20-one, which has a particle size distribution with D90 = 13 μm. In another aspect, the oral dosage form can be prepared for immediate release to improve bioavailability, including at least one processing aid and surfactant together with the processed 3α-OH-5β-pregnan-20-one to form a homogeneous powder mixture. Table G shows some exemplary oral solid compositions of the present invention, including the processed solid form of 3α-OH-5β-pregnan-20-one for immediate release with any surfactant.

Table 16

[0333] In another example, Table H shows some preferred oral compositions of the present invention, including the solid form of 3α-OH-5β-pregnan-20-one for immediate release with any surfactant.

Table 17

[0334] Example 2. Oral dosage form containing 3α-OH-5β-pregnan-20-one Solubility, dispersibility, and degradation tests were conducted and compared among various exemplary oral dosage forms containing 3α-OH-5β-pregnan-20-one in solid, liquid, and suspension forms. Table I presents various exemplary oral dosage forms containing 3α-OH-5β-pregnan-20-one to evaluate the effect of the formulation on the solubility, dispersibility, and degradability that may affect the bioavailability (or absorption into the body) of 3α-OH-5β-pregnan-20-one for subjects in need of 3α-OH-5β-pregnan-20-one therapy.

Table 18

[0335] The 3α-OH-5β-pregnan-20-one release rate was obtained one by one from each of the formulation #1, #2, and #3 of each composition by exposing 1 gram of each composition to 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate at 75 rpm and 37 °C in a USP type II dissolution apparatus. The results were compared with the release rates of compositions consisting of a conventional tablet formulation without surfactant (formulation #4), a formulation of a crystalline 3α-OH-5β-pregnan-20-one suspension in canola oil (formulation #5), and a formulation of a crystalline 3α-OH-5β-pregnan-20-one suspension in polysorbate 80 (formulation #6). The dose of 3α-OH-5β-pregnan-20-one per unit used in the release test shown in Figure 2 was 52 mg / g, 65 mg / g, 85 mg / g, 93 mg / g, 30 mg / g, and 30 mg / g for formulations #1, #2, #3, #4, #5, and #6, respectively.

[0336] The dispersibility of the disclosed oral compositions containing 3α-OH-5β-pregnan-20-one (formulations #9 and #10) was carried out with aqueous dilution (x100) with simulated intestinal fluid at pH 6.8 according to USP 26. The dispersibility results were compared with those of compositions containing solubilized 3α-OH-5β-pregnan-20-one in medium-chain triglycerides (e.g., MIGLYOL 812, formulation #7) and canola oil (formulation #8).

[0337] Release performance in Figure 2 Figure 2 shows a plot comparing the release rates of 3α-OH-5β-pregnan-20-one obtained for Formulations #1, #2, and #3 with those of the conventional compositions of Formulations #4, #5, and #6. The dosage per unit of 3α-OH-5β-pregnan-20-one used in the release test shown in Figure 2 was 52 mg / g, 65 mg / g, 85 mg / g, 93 mg / g, 30 mg / g, and 30 mg / g for Formulations #1, #2, #3, #4, #5, and #6, respectively. The 3α-OH-5β-pregnan-20-one in these formulations was processed (e.g., micronized) before formulation of the composition.

[0338] In one example, as shown in Figure 2, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, the composition of the present invention may release at least 45 mg of 3α-OH-5β-pregnan-20-one after 30 minutes.

[0339] In another example, as shown in Figure 2, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, the composition of the present invention may release at least 70% of 3α-OH-5β-pregnan-20-one after 30 minutes.

[0340] In a further example, as shown in Figure 2, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, the composition of the present invention may release more than about 35 mg of 3α-OH-5β-pregnan-20-one after 15 minutes.

[0341] In yet another example, as shown in Figure 2, the composition of the present invention, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, may release at least 50% of 3α-OH-5β-pregnan-20-one after 15 minutes.

[0342] In yet another example, as shown in Figure 2, the composition of the present invention, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, may release more than at least 25% of 3α-OH-5β-pregnan-20-one after 30 minutes as compared to a composition consisting essentially of a conventional tablet formulation without surfactant (Formulation #4), a formulation of crystalline 3α-OH-5β-pregnan-20-one suspension in canola oil (Formulation #5), and a formulation of crystalline 3α-OH-5β-pregnan-20-one suspension in polysorbate 80 (Formulation #6).

[0343] In one example not shown in Figure 2, the composition of the present invention, when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, may release more than at least 20% of 3α-OH-5β-pregnan-20-one after 30 minutes as compared to a composition of a tablet formulation (Formulation #12) having less than 0.5% (w / w) surfactant in the composition. In another example, the composition of the present invention has a disintegration time faster (e.g., less than 25 minutes) than tablet forms (Formulations #4 and #12) containing less than 0.5% (w / w) surfactant in the composition.

[0344] In yet another example, as shown in Figure 2, a conventional solid form composition without surfactant (e.g., Formulation #4), when measured at 75 rpm and 37 °C in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate using a USP Type II dissolution apparatus, may release less than about 45 mg of 3α-OH-5β-pregnan-20-one after 30 minutes.

[0345] In yet another embodiment, in a method of using the compositions disclosed herein, the initial 30-minute release rate of 3α-OH-5β-pregnan-20-one of the composition is at least one of 10%, 15%, 20%, and 25% greater than A) the 3α-OH-5β-pregnan-20-one release rate 30 minutes after the start of the in vitro test of a first comparative composition consisting essentially of treated 3α-OH-5β-pregnan-20-one suspended in Tween80, B) the 3α-OH-5β-pregnan-20-one release rate 30 minutes after the start of the in vitro test of a second comparative composition consisting essentially of treated 3α-OH-5β-pregnan-20-one suspended in canola oil, and, C) the 3α-OH-5β-pregnan-20-one release rate 30 minutes after the start of the in vitro test of a third comparative composition comprising treated crystalline 3α-OH-5β-pregnan-20-one and a plurality of additives comprising a surfactant in an amount of 0.5 wt% or less.

[0346] Dispersion evaluation after dilution with SIF in FIG. 3 FIG. 3 shows a comparative image of the dispersibility of the disclosed oral compositions containing the amorphous 3α-OH-5β-pregnan-20-one form (formulations #9 and #10) exposed to an aqueous diluent (x100) containing simulated intestinal fluid at pH 6.8 according to USP26, compared to the dispersibility of compositions containing 3α-OH-5β-pregnan-20-one solubilized in medium-chain triglycerides (e.g., MIGLYOL 812, formulation #7) and canola oil (formulation #8).

[0347] As shown in Figure 3, Formulations #7 and #8 (each containing 3α-OH-5β-pregnan-20-one solubilized in MIGLYOL 812 and canola oil, respectively) were not dispersed or solubilized in simulated intestinal fluid at pH 6.8 diluted 100-fold according to USP26 (the oily content on the surface was completely separated from the aqueous medium), but the disclosed compositions of the present invention (Formulations #9 and #10) were well dispersed. The UV absorbance measured at 450 nm was not measurable for Formulations #7 and #8, but 1.3 Abs and 3.2 Abs were measured for Formulations #9 and #10, respectively.

[0348] Example 3. Oral dosage forms containing untreated 3α-OH-5β-pregnan-20-one Oral compositions containing the crystalline form of untreated 3α-OH-5β-pregnan-20-one are expected to have a slower release rate of 3α-OH-5β-pregnan-20-one due to the particle size distribution of 3α-OH-5β-pregnan-20-one in the composition. Table J shows various exemplary oral dosage forms containing untreated 3α-OH-5β-pregnan-20-one and the predicted release rate with sink conditions of the 3α-OH-5β-pregnan-20-one measured at about 75 rpm in 900 mL of aqueous medium at 37 °C using a USP Type II dissolution apparatus. [Table 19]

[0349] Example 4. PK values of oral compositions of 3α-OH-5β-pregnan-20-one Exemplary non-aqueous oral dosage forms I2 (e.g., formulation 2 from Table I) and H8 (e.g., formulation 8 from Table H) were prepared, administered as single doses at different dose concentrations, and the serum drug concentrations were monitored over 24 hours. Composition I2 can be prepared to contain doses D1 and D2 of 3α-OH-5β-pregnan-20-one and 1 in a manner substantially similar to the method described for composition I2 in relation to Table I. Composition I2 can be prepared to have 6.5% 3α-OH-5β-pregnan-20-one (% w / w). Composition I2 can be administered as doses D1 and D2 in a fed diet state, and dose D2 can also be administered in a fasted diet state. Composition H4 can be prepared as dose D3 in a manner substantially similar to the method described for composition 4 in relation to Table H. Composition H4 can be prepared to have 16.9% 3α-OH-5β-pregnan-20-one (% w / w). Composition H4 can be administered as dose D3 in a fasted diet state. Composition H8 can be prepared as dose D4 in a manner substantially similar to the method described for composition 8 in relation to Table H. Composition H8 may be administered as dose D4 in a fasted diet state, and similarly dose D4 can also be administered in a postprandial diet state. This table shows the formulation, the dose of 3α-OH-5β-pregnan-20-one administered, the diet state, the mean PK parameters C max and AUC 0-t as shown.

Table 20

[0350] Referring to Table K, the PK parameters of formulations I2, H4 and H8 are the PK parameters AUC 0-t (area under the curve measured from 0 hour to the end of the treatment observation), AUC 0-t / 用量 , C max , C max / 用量 and T max It is calculated for comparison. Composition I2 is in a liquid, encapsulated form of 3α-OH-5β-pregnan-20-one that is non-aqueous and cyclodextrin-free, and compositions H4 and H8 are solid dosage forms (also non-aqueous and cyclodextrin-free) that contain treated 3α-OH-5β-pregnan-20-.

[0351] In another aspect, enabling time-specified drug exposure (e.g., immediate release, medium release, or extended release) may further benefit drug administration efficacy. For example, rapid release (e.g., T max ) less than 2.5 hours is preferred for treating disorders that require rapid onset such as ARS, while other treatments will benefit from extended drug exposure that enables medium release (e.g., T max ) such as in generalized epilepsy for 2 - 8 hours. For example, embodiments of the present disclosure may be used to control the T max of drug treatment to be less than 2 hours or about 2 hours, greater than 2 hours, or less than 8 hours or about 8 hours. As another example, the T max of drug treatment may be about 1 hour or more, about 2.5 hours or more, about 3 hours or more, about 3.5 hours or more, about 6 hours or more, or about 8 hours or more.

[0352] As an example, embodiments of the present disclosure may be used to control PK exposure. For example, C max may be 4.25 ng mL -1 or more, 6.32 ng mL -1 or more, 11.0 ng mL -1 or more, 40.0 ng mL -1 , 17.9 ng mL -1 or more, 48.5 ng mL -1 or more, 53.6 ng mL -1 or more, or 48.6 ng mL -1 or more. As another example, AUC 0-t may be about 22.9 ng h mL -1 or more, about 54.8 ng h mL -1 or more, about 72.0 ng h mL -1 or more, about 86.4 ng h mL -1 、 about 73.5 ng h mL -1 or more, about 171.7 ng h mL -1 or more, about 226.5 ng h mL -1 or more, or about 243.8 ng h mL -1 may be higher.

[0353] In another aspect, a composition comprising 3α-OH-5β-pregnan-20-one disclosed herein can be in a form that provides a therapeutically effective amount / blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject. In yet another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one lipophilic additive sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject. In another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one surfactant sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject. In another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one lipophilic additive, at least one surfactant, and at least one hydrophilic additive sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject. In one aspect, the composition is in a solid dosage form or a non-liquid dosage form. In another aspect, the 3α-OH-5β-pregnan-20-one form in the starting 3α-OH-5β-pregnan-20-one composition is in a solid form or a solid crystalline form or a non-fully solubilized form.

[0354] In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one is appropriate or sufficient, or required, to treat CNS disorders or the C max and / or AUC 0-t can be provided.

[0355] In another aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can provide a C of 3α-OH-5β-pregnan-20-one of at least about 4.25 ng / mL, about 6 ng / mL, about 11 ng / mL, about 18 ng / mL, about 40 ng / mL, about 48 ng / mL, and about 50 ng / mL. max can be provided.

[0356] In yet another embodiment, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can provide at least one of about 0.06 ng / mL mg, about 0.07 ng / mL mg, about 0.09 ng / mL mg, about 0.11 ng / mL mg, about 0.12 ng / mL mg, about 0.16 ng / mL mg, and about 0.27 ng / mL mg. In another aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can provide a minimum C of 3α-OH-5β-pregnan-20-one of at least about 4.25 ng / mL, and / or a dose-normalized maximum C of at least about 0.27 ng / mL mg. -1 mg -1 about 0.07 ng / mL mg -1 mg -1 about 0.09 ng / mL mg -1 mg -1 about 0.11 ng / mL mg -1 mg -1 about 0.12 ng / mL mg -1 mg -1 about 0.16 ng / mL mg -1 mg -1 and about 0.27 ng / mL mg -1 mg -1 In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one can provide a minimum C of 3α-OH-5β-pregnan-20-one of at least about 4.25 ng / mL, and / or a dose-normalized maximum C of at least about 0.27 ng / mL mg. In one aspect, the minimum threshold of C and / or dose-normalized C is achieved by the compositions and methods of the present invention, where the composition is a solid dosage form, a non-liquid dosage form, a capsule-containing liquid dosage form, a cyclodextrin-free liquid dosage form, a non-aqueous liquid dosage form, or a dosage form containing less than 250 mg / ml or mg / g of cyclodextrin. In another aspect, C and / or dose-normalized AUC max and / or a dose-normalized C of at least about 0.27 ng / mL mg -1 mg -1 can be provided. In one aspect, C max and / or dose-normalized C max and / or dose-normalized C max is achieved by the compositions and methods of the present invention, where the composition is a solid dosage form, a non-liquid dosage form, a capsule-containing liquid dosage form, a cyclodextrin-free liquid dosage form, a non-aqueous liquid dosage form, or a dosage form containing less than 250 mg / ml or mg / g of cyclodextrin. In another aspect, C max and / or dose-normalized AUC 0-t The minimum threshold is achieved by a composition containing the 3α-OH-5β-pregnan-20-one form in the composition, and the starting form of 3α-OH-5β-pregnan-20-one after formulation or treatment or formulation / treatment is substantially a solid form, a solid crystalline form, an encapsulated fully solubilized form, a substantially water-insoluble solubilized form, an aqueous solubilized form without cyclodextrin, or a solid / solubilized form containing less than 250 mg / ml or mg / g of cyclodextrin. In another embodiment, C max and / or dose normalization C max The minimum threshold is achieved by oral administration of the composition, with or without food, or in a fasting state.

[0357] In another embodiment, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one provides at least one minimum AUC of 3α-OH-5β-pregnan-20-one of about 20 ng*h / mL, about 55 ng*h / mL, about 70 ng*h / mL, about 85 ng*h / mL, about 170 ng*h / mL, about 225 ng*h / mL, and about 245 ng*h / mL 0-t In yet another embodiment, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one provides at least one dose-normalized minimum AUC of about 0.46 h / L, about 0.48 h / L, about 0.50 h / L, about 0.54 h / L, and about 0.58 h / L 0-t In another embodiment, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one provides a minimum AUC of 3α-OH-5β-pregnan-20-one of at least about 20 ng*h / mL 0-t and / or a dose-normalized minimum AUC of at least about 0.46 h / L 0-t In one embodiment, AUC 0-t and / or dose-normalized AUC 0-t The minimum threshold is achieved by the compositions and methods of the present invention, and the compositions are solid dosage forms, non-liquid dosage forms, encapsulated liquid dosage forms, cyclodextrin-free liquid dosage forms, non-aqueous liquid dosage forms, or dosage forms containing less than 250 mg / ml or mg / g of cyclodextrin.

[0358] In another aspect, the AUC 0-t and / or the dose-normalized AUC 0-t The minimum threshold of is achieved by a composition comprising the 3α-OH-5β-pregnan-20-one form, wherein the starting form of 3α-OH-5β-pregnan-20-one after formulation or treatment or formulation / treatment is substantially in solid form, solid crystalline form, encapsulated fully solubilized form, substantially non-aqueous solubilized form, cyclodextrin-free aqueous solubilized form, or solid / solubilized form containing less than 250 mg / ml or less than mg / g of cyclodextrin. In another aspect, the AUC 0-t and / or the dose-normalized AUC 0-t The minimum threshold of is achieved by oral administration of the composition regardless of food / meal.

[0359] In another aspect, a composition comprising 3α-OH-5β-pregnan-20-one disclosed herein can be in a form that provides a therapeutically effective amount / blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject. In yet another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one lipophilic additive sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject. In another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives including at least one surfactant sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders in a subject. In one aspect, the composition is in solid dosage form or non-liquid dosage form. In another aspect, the 3α-OH-5β-pregnan-20-one form in the starting 3α-OH-5β-pregnan-20-one composition is in solid form, or solid crystalline form, or non-fully solubilized form.

[0360] Also, in yet another embodiment, C max and / or dose-normalized C max The minimum threshold of is achieved by the compositions and methods of the present invention, where the composition is in a solid dosage form or a non-liquid dosage form or an encapsulated liquid dosage form or a cyclodextrin-free liquid dosage form or a non-aqueous liquid dosage form. In another aspect, C max and / or dose-normalized AUC 0-t The minimum threshold of is achieved by a composition comprising a 3α-OH-5β-pregnan-20-one form in a composition where the starting form of 3α-OH-5β-pregnan-20-one after formulation or process or formulation / process is substantially in a solid form or a solid crystalline form or an encapsulated completely solubilized form or a substantially water-insoluble form or a cyclodextrin-free water-soluble form. In another aspect, C max and / or dose-normalized C max The minimum threshold of is achieved by oral administration of the composition, regardless of food / diet or in a fasting state.

[0361] In another aspect, AUC 0-t and / or dose-normalized AUC 0-t The minimum threshold of is achieved by a composition comprising a 3α-OH-5β-pregnan-20-one form in the composition, where the starting form of 3α-OH-5β-pregnan-20-one after formulation or process or formulation / processing is substantially in a solid form, or a solid crystalline form, or an encapsulated completely solubilized form, or a substantially non-solubilized form, or a cyclodextrin-free solubilized form. In another aspect, AUC 0-t and / or dose-normalized AUC 0-t The minimum threshold of is achieved by oral administration of the composition regardless of food / diet.

[0362] In one embodiment, a 3α-OH-5β-pregnan-20-one composition and an oral dosage form can be formulated to provide a therapeutically effective blood level or peak blood level of 3α-OH-5β-pregnan-20-one for treating CNS disorders when orally administered to a subject. For example, in one aspect, the composition and oral dosage form can include a plurality of pharmaceutically acceptable additives that provide a sufficient amount / level of serum 3α-OH-5β-pregnan-20-one to treat CNS disorders when orally administered to a subject.

[0363] In one embodiment, there is provided an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of additives, wherein oral administration of the composition to a subject having at least one neuropsychiatric disorder and neurodegenerative disorder results in a serum level of 3α-OH-5β-pregnan-20-one in the subject such that the at least one neuropsychiatric disorder and neurodegenerative disorder are substantially eliminated, improved, or reduced.

[0364] In one embodiment, there is provided an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides a serum level of 3α-OH-5β-pregnan-20-one that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one (cyclodextrin solution administration) in a composition consisting essentially of an unencapsulated SBE-β-CD aqueous solution. max level and a serum C of 3α-OH-5β-pregnan-20-one avg level, providing at least one of the levels to the subject.

[0365] In one embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject in a fasting state, the composition has a serum level of 3α-OH-5β-pregnan-20-one greater than that provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of an unencapsulated SBE-β-CD aqueous solution (cyclodextrin solution administration), serum C max or dose-normalized C max level and / or serum C avg or dose-normalized C avg is provided to the subject for at least one of.

[0366] In one embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject with food, the composition has a serum level of 3α-OH-5β-pregnan-20-one greater than that provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of an unencapsulated SBE-β-CD aqueous solution (cyclodextrin solution administration), serum C max or dose-normalized C max level and / or serum C avg or dose-normalized C avg is provided to the subject for at least one of.

[0367] In one embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject regardless of diet / food, the composition has a serum level of 3α-OH-5β-pregnan-20-one greater than that provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of an unencapsulated SBE-β-CD aqueous solution (cyclodextrin solution administration) in the subject, serum C max level or dose-normalized C max and / or serum C of 3α-OH-5β-pregnan-20-one avg Level or dose normalized C avg Provide for at least one of the levels.

[0368] In another embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides in the subject a serum C of 3α-OH-5β-pregnan-20-one that is higher than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of a medium-chain triglyceride solution (MCT administration). max Level, serum C of 3α-OH-5β-pregnan-20-one avg Provide at least one of the levels.

[0369] In yet another embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides in the subject a serum C of 3α-OH-5β-pregnan-20-one that is higher than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of a polysorbate-80 suspension (polysorbate 80 administration). max Level, serum C of 3α-OH-5β-pregnan-20-one avg Is expected to provide at least one of the levels.

[0370] In yet another embodiment, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, in the subject, a serum C of 3α-OH-5β-pregnan-20-one that is higher than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnan-20-one in a composition consisting essentially of canola oil or peanut oil (edible oil administration). max Level, serum C of 3α-OH-5β-pregnan-20-one avg It is expected to provide at least one level.

[0371] In one embodiment, a 3α-OH-5β-pregnan-20-one composition or oral dosage form or method can be formulated to efficiently provide an expected serum level of 3α-OH-5β-pregnan-20-one that is therapeutically effective for treating CNS disorders when orally administered to a subject. In another aspect, 3α-OH-5β-pregnan-20-one can be in a form that maximizes the serum level of 3α-OH-5β-pregnan-20-one when orally administered to a subject. In another aspect, 3α-OH-5β-pregnan-20-one can be in a form that increases the serum level of 3α-OH-5β-pregnan-20-one when orally administered to a subject. In another aspect, the compositions and methods of the present invention increase the serum level of 3α-OH-5β-pregnan-20-one compared to a composition containing an equivalent amount in a processed crystalline (micronized) form consisting essentially of 3α-OH-5β-pregnan-20-one suspended in edible oil when orally administered to a subject.

[0372] In yet another embodiment, a dosing regimen and method for treating CNS disorders in a subject are provided, which may include orally administering a composition comprising a therapeutically effective amount of 3α-OH-5β-pregnan-20-one.

[0373] In one embodiment, the composition and oral dosage form can include a plurality of pharmaceutically acceptable additives, the additives being at least one of α-tocopherol, sterol, glyceryl monocaprylate, propylene glycol monolaurate, PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil, poloxamer, and combinations thereof that provide an appropriate level of 3α-OH-5β-pregnan-20-one in an amount sufficient to treat CNS disorders when orally administered to a subject.

[0374] In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one provides a serum level of 3α-OH-5β-pregnan-20-one (e.g., average serum level: C avg or peak serum level: C max ) sufficient to treat a CNS disorder. In another aspect, a therapeutically effective amount of 3α-OH-5β-pregnan-20-one in a composition can be in a form that provides a therapeutically effective serum level of 3α-OH-5β-pregnan-20-one after oral administration for treating a CNS disorder in a subject. In a further aspect, 3α-OH-5β-pregnan-20-one in the compositions disclosed herein can be in a form treated with a plurality of additives including at least one surfactant that provides a therapeutically effective level of 3α-OH-5β-pregnan-20-one effective to treat a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnan-20-one can be combined with a plurality of additives sufficient to provide a therapeutically effective serum level of 3α-OH-5β-pregnan-20-one after its oral administration for treating a CNS disorder in a subject.

[0375] In yet another embodiment, the dosing regimens and methods for treating CNS disorders in females in the present invention are for female infants, females under 5 years old, females aged 5 - 18 years, non-pregnant women of childbearing age (e.g., women aged 15 - 45 years), pregnant women, women who gave birth within at least one of the periods of 1 month, 6 months, and 12 months, women in the perimenopausal period (e.g., women aged 45 - 50 years), or postmenopausal women.

[0376] In one embodiment, the oral composition described herein may not contain any regulator that slows the release rate of 3α-OH-5β-pregnan-20-one in an aqueous medium or in vivo. In an embodiment, the composition may be non-aqueous. In another more specific embodiment, the composition may be encapsulated.

[0377] In another embodiment, the composition may contain less than 250 mg / ml or less than mg / g of SBE-β-CD. In another more specific embodiment, the composition may be substantially free of SBE-β-CD.

[0378] In another embodiment, the composition is a non-aqueous composition filled in a capsule or tablet dosage form.

[0379] In another embodiment, the oral solid dosage form(s) described herein may not have the synchronous release characteristics of 3α-OH-5β-pregnan-20-one with a solubilizing agent in an aqueous medium such that the dosage form can release more than 90% of 3α-OH-5β-pregnan-20-one within 4 hours after administration or in an in vitro test. Or, in other words, the release of the active agent may not be synchronous with the release of the lipophilic additive. For example, the release of the active agent may not be at the same rate as the release rate of the additive.

[0380] In one aspect, the composition can be formulated as an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one. In another aspect, when the composition is orally administered to a subject, the C of 3α-OH-5β-pregnan-20-one exceeding about 4.25 ng / ml, as measured using LC-MS or GC-MS, regardless of food intake max is expected to be provided, and can be formulated as an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnan-20-one.

[0381] The oral pharmaceutical composition containing 3α-OH-5β-pregnan-20-one can be administered as an oral dosage form such as a solid, liquid, or partially or fully solubilized oral dosage form, which is traditionally intended to substantially release and deliver 3α-OH-5β-pregnan-20-one in the digestive tract across the oral cavity and / or buccal cavity.

[0382] In certain embodiments, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one can be administered as a solid dosage form known to those skilled in the art. Examples of solid dosage forms include, but are not limited to, two-piece hard gelatin capsules, soft gelatin capsules, beads, beadlets, granules, spheres, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets, or combinations thereof.

[0383] In certain embodiments, an oral pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one can be administered as a liquid (e.g., solution, suspension, beverage, etc.) or in a form partially or fully solubilized in a gelatin capsule or non-gelatin capsule known to those skilled in the art. The gelatin capsule can be a soft gelatin capsule, a hard gelatin capsule, or other capsules. The hard gelatin capsule can typically be a standard two-piece gelatin capsule comprising a first capsule portion at the bottom and a second capsule portion at the top. The soft gelatin capsule can be a two-piece capsule with two parts sealed together or a one-piece sealed capsule.

[0384] In one embodiment, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative diseases in a subject comprises the step of orally administering to the subject an effective amount of 3α-OH-5β-pregnan-20-one or a pharmaceutically acceptable salt, or polymorph, or a combination thereof. In another embodiment, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative diseases in a subject comprises the step of orally administering to the subject a composition comprising any of an effective amount of orally administered 3α-OH-5β-pregnan-20-one, a pharmaceutically acceptable salt thereof, a polymorph thereof, and combinations thereof. In one embodiment, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative diseases in a subject, when administered to the subject, is about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and 15% compared to the blood concentration obtained from an equivalent dose of 3α-OH-5β-pregnan-20-one orally administered by an oral aqueous non-encapsulated cyclodextrin-containing composition. It contains an amount of any of orally administered 3α-OH-5β-pregnan-20-one, a pharmaceutically acceptable salt thereof, a polymorph thereof, and combinations thereof, which may exceed the blood concentration.

[0385] In one embodiment, a method of treating a CNS disorder comprising the step of orally administering to a subject a pharmaceutical composition comprising 3α-OH-5β-pregnan-20-one and a plurality of additives, in the subject, the serum C of 3α-OH-5β-pregnan-20-one max Level increase and serum C of 3α-OH-5β-pregnan-20-one avg It is expected to provide at least one increase in level, where the indicated increase is greater than the increase obtained by administering substantially equivalent amounts to at least one of 3α-OH-5β-pregnan-20-one in an unencapsulated aqueous SBE-β-CD solution containing at least 250 mg / ml SBE-β-CD (cyclodextrin administration), 3α-OH-5β-pregnan-20-one in a medium-chain triglyceride (MCT) solution (MCT administration), 3α-OH-5β-pregnan-20-one in a polysorbate 80 suspension (polysorbate 80 administration), and 3α-OH-5β-pregnan-20-one in canola oil or peanut oil (edible oil administration).

[0386] In another aspect, 3α-OH-5β-pregnan-20-one in the present composition of the invention can be in a form that increases the serum level of 3α-OH-5β-pregnan-20-one, where the indicated increase is greater than the increase obtained by administering at least one of substantially equivalent amounts of cyclodextrin administration, MCT administration, polysorbate 80 administration, and edible oil administration to a subject. In one example, the serum level of 3α-OH-5β-pregnan-20-one can increase by at least about 20% compared to the serum level obtained by administering substantially equivalent amounts of cyclodextrin administration, MCT administration, polysorbate 80 administration, and edible oil administration to a subject.

[0387] In one embodiment, when the composition is administered to a subject in a fasting state, the T max of 3α-OH-5β-pregnan-20-one in the subject will be at least one of less than about 1.5 hours, less than about 2 hours, and less than about 3 hours after administration.

[0388] In one embodiment, when the composition is administered to a subject regardless of diet, the Tmax of 3α-OH-5β-pregnan-20-one in the subject will be at least one of less than about 1.5 hours, less than about 2 hours, less than about 2.5 hours, and less than about 3 hours after administration.

[0389] In one embodiment, when a non-solid or liquid composition is administered to a subject regardless of diet, the Tmax of 3α-OH-5β-pregnan-20-one in the subject is less than about 1.5 hours, less than about 2 hours, less than about 2.5 hours, and less than about 3 hours after administration, at least one of which is satisfied.

[0390] In one embodiment, when a composition is administered to a subject regardless of diet, if 3α-OH-5β-pregnan-20-one is solubilized, in an amorphous form, or in a micronized or nanosized crystalline form, in the subject, a Tmax of 3α-OH-5β-pregnan-20-one of at least one of less than about 1.5 hours, less than about 2 hours, less than about 2.5 hours, and less than about 3 hours after administration is obtained.

[0391] In one embodiment, when the subject is in a fed state, administration of the composition to the subject results in a T of 3α-OH-5β-pregnan-20-one in the subject max being at least one of greater than or equal to about 3 hours, greater than or equal to about 6 hours, and greater than or equal to about 8 hours after administration.

[0392] In one embodiment, the dosage includes at least one of a QD dosage, a BID dosage, a TID dosage, a QID dosage, and a dosage greater than the QID dosage.

[0393] In one embodiment, the treatment period can be at least one of at least 1 day, 2 days, 2.5 days, 3 days, 5 days, 7 days, and 14 days.

[0394] In another embodiment, the disclosed method of treating a CNS disorder includes orally administering to the subject an amount of 3α-OH-5β-pregnan-20-one sufficient to enable binding of GABA A receptors in the subject such that the CNS disorder of the subject is substantially reduced or eliminated.

[0395] In one embodiment of the present invention, the disclosed method includes the step of orally administering to a subject a composition having an orally bioavailable 3α-OH-5β-pregnan-20-one therein, wherein the subject has at least one of an acute CNS disorder, an episodic CNS disorder, an intermittent CNS disorder, a subchronic CNS disorder, a chronic CNS disorder, and combinations thereof. When the CNS disorder is subchronic or chronic, the dosing regimen can range from at least once a day for about 1 day to about 3 months, or a specific period exceeding 3 months.

[0396] In one embodiment of the present invention, the disclosed method includes the step of orally administering to a subject a composition having an orally bioavailable 3α-OH-5β-pregnan-20-one therein, wherein the subject has at least one of an acute CNS disorder, an episodic CNS disorder, an intermittent CNS disorder, a subchronic CNS disorder, a chronic CNS disorder, and combinations thereof. The treatment period can range from at least once a day or episodic treatment as needed, to a specific period of about 1 day to about 3 months, or a period exceeding 3 months or an unspecified period.

[0397] In one embodiment, a subject in need of an oral composition comprising an orally bioavailable 3α-OH-5β-pregnan-20-one described herein may have a CNS disorder such as a depressive disorder (e.g., postpartum depression, postpartum substance use disorder, major depressive disorder, treatment-resistant depression, perinatal depression, premenopausal or postmenopausal depression).

[0398] In some embodiments, an oral composition consisting of being usable for the treatment, alleviation, or enhancement of a condition, symptom, or disease associated with a CNS disorder described herein can be for use in males or females. In one aspect, the subject can be a young or adult male. In a further aspect, the subject can be a female in puberty, adulthood, of childbearing age, premenopausal, peripartum, postpartum, pregnant, perimenopausal, or postmenopausal. In yet another aspect, the subject can have a disease associated with a CNS disorder described herein or a disease caused by a CNS disorder even if not showing symptoms of the CNS disorder.

Claims

1. An oral composition for treating, improving or managing a condition in a human subject that is associated with at least one of seizures, convulsions and epilepsy, wherein the oral composition comprises 3α-OH-5β-pregnane-20-one, and in response to administration of the oral composition, the following results are obtained: Target C ｍａｘ The minimum threshold is 4.25 ng mL －１ That is, Target T ｍａｘ It is within approximately 2.5 hours. Target T ｍａｘ It is within approximately 2.0 hours. Target T ｍａｘ It is within approximately 1.5 hours. Target AUC ０－ｔ The minimum threshold is 22.9 ng h mL －１ , and, The target PPR decreases by at least 2 points. An oral composition in which at least one of the following is achieved.

2. An oral composition according to claim 1, wherein the result is achieved regardless of at least one of the feeding state and the fasting state of the subject.

3. An oral composition according to claim 1, wherein the composition comprises at least one of a capsule and a tablet.

4. An oral composition according to claim 3, wherein the 3α-OH-5β-pregnane-20-one comprises at least one of partially crystalline 3α-OH-5β-pregnane-20-one and amorphous 3α-OH-5β-pregnane-20-one.

5. An oral composition according to claim 1, wherein the composition comprises a surfactant in an amount of at least about 0.5% of the composition.

6. An oral composition according to claim 1, wherein the 3α-OH-5β-pregnane-20-one comprises solubilized 3α-OH-5β-pregnane-20-one.

7. In the oral composition according to claim 1, the treatment, improvement or management is After the administration, there should be no recurrence of seizures for at least one of the following periods: approximately 2 hours, approximately 4 hours, approximately 6 hours, and approximately 8 hours. Within approximately 28 days after administration, the reduction in the seizure rate of the subject relative to the baseline seizure rate is at least one of approximately 10%, 20%, 30%, 40%, and 50%. An oral composition comprising at least one of the following.

8. An oral composition according to claim 1, wherein the epilepsy comprises focal-onset epilepsy (FOE) and the seizure comprises ARS.

9. An oral composition according to claim 8, wherein the ARS comprises at least one of cluster seizures, serial seizures, crescendo seizures, paroxysmal sudden seizures, recurrent seizures, and periodic seizures.

10. In the oral composition according to claim 1, the subject is The necessity of treating the aforementioned condition, Multiple CNS failures, History of anti-epileptic treatment, History of antidepressant treatment, Unresolved epilepsy symptoms, Unresolved depressive symptoms, Anxiety disorder, Depression, and, mental illness An oral composition having at least one of the following.

11. An oral composition according to claim 1, wherein the subject includes WWE women of childbearing age.

12. An oral composition for treating, improving or managing a condition in a human subject that is associated with at least one of seizures, convulsions and epilepsy, wherein the oral composition comprises 3α-OH-5β-pregnan-20-one, and in response to administration of the oral composition, regardless of whether the subject is feeding or fasting, the following results are obtained: Target C ｍａｘ has a minimum threshold of 4.25 ng / mL －１ and is Target T ｍａｘ It is within approximately 2.5 hours. Target T ｍａｘ It is within approximately 2.0 hours. Target T ｍａｘ It is within approximately 1.5 hours. Target AUC ０－ｔ The minimum threshold is 22.9 ng h mL －１ , and, The target PPR decreases by at least 2 points. An oral composition in which at least one of the following is achieved.

13. An oral composition according to claim 12, wherein the composition comprises at least one of a capsule and a tablet.

14. An oral composition according to claim 13, wherein the 3α-OH-5β-pregnane-20-one comprises at least one of partially crystalline 3α-OH-5β-pregnane-20-one and amorphous 3α-OH-5β-pregnane-20-one.

15. An oral composition according to claim 12, wherein the composition comprises a surfactant in an amount of at least about 0.5% of the composition.

16. An oral composition according to claim 12, wherein the 3α-OH-5β-pregnane-20-one comprises solubilized 3α-OH-5β-pregnane-20-one.

17. In the oral composition according to claim 12, the treatment, improvement or management is After the administration, there should be no recurrence of seizures for at least one of the following periods: approximately 2 hours, approximately 4 hours, approximately 6 hours, and approximately 8 hours. Within approximately 28 days after administration, the reduction in the seizure rate of the subject relative to the baseline seizure rate is at least one of approximately 10%, 20%, 30%, 40%, and 50%. An oral composition comprising at least one of the following.

18. An oral composition according to claim 12, wherein the epilepsy comprises FOE and the seizure comprises ARS.

19. An oral composition according to claim 18, wherein the ARS comprises at least one of cluster seizures, serial seizures, crescendo seizures, paroxysmal sudden seizures, recurrent seizures, and periodic seizures.

20. In the oral composition according to claim 12, the subject is The necessity of treating the aforementioned condition, Multiple CNS failures, History of anti-epileptic treatment, History of antidepressant treatment, Unresolved epilepsy symptoms, Unresolved depressive symptoms, Anxiety disorder, Depression, and, mental illness An oral composition having at least one of the following.

21. An oral composition according to claim 12, wherein the subject includes WWE women of childbearing age.

22. An oral composition according to Claim 1, wherein, in response to the administration, the target PPR decreases by at least 2 points.

23. The oral composition according to claim 1, wherein the result in response to the administration includes the following: The minimum threshold for target C max is 4.25 ng mL - 1. The target T-max is within approximately 2.5 hours. The target T-max is approximately 2.0 hours or less. The target T-max is approximately 1.5 hours or less, and The minimum threshold for the target AUC 0-t is 22.9 ng h mL - 1. An oral composition that achieves multiple of the above.

24. An oral composition according to claim 12, wherein, in response to the administration, the target PPR is reduced by at least 2 points.

25. The oral composition according to claim 12, wherein the result in response to the administration includes the following: The minimum threshold for target C max is 4.25 ng mL - 1. The target T-max is within approximately 2.5 hours. The target T-max is approximately 2.0 hours or less. The target T-max is approximately 1.5 hours or less, and The minimum threshold for the target AUC 0-t is 22.9 ng h mL - 1. An oral composition that achieves multiple of the above.

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