Methods and compositions for treating epilepsy

Abstract

Methods and compositions for treating CNS disorders in a subject are disclosed. In one embodiment, the method preferably comprises the ordered steps of identifying a subject suffering from or susceptible to epilepsy, and orally administering AED to the subject. The application preferably includes an application regimen of a predetermined amount of the AED at a predetermined frequency and for a predetermined duration. The subjects preferably include subjects undergoing a population of epileptic seizures, WWEs, and more particularly childbearing WWEs. The composition preferably comprises NAS, and more particularly ENAS. The methods preferably result in prevention of epileptic seizures, or reduced frequency or amplitude.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This PCT patent application claims the benefit under PCT Section 4.10 of co-pending U.S. patent application No. 63 / 348,045, filed on June 2, 2022, which is expressly incorporated herein by this reference in its entirety. Background Art

[0003] Various compositions suitable for pharmaceutical use and administration to mammals in need thereof are disclosed in the following U.S. patents and applications (all of which are expressly incorporated herein by reference in their entirety): 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 (Patent). Technical Field

[0004] The present disclosure relates to compositions, and more particularly to oral compositions, dosage forms and regimens and methods for treating subjects with CNS disorders and more particularly for treating epilepsy. Thus, the present disclosure relates to the fields of chemistry, pharmaceutical sciences, medicine and other health sciences.

[0005] Neuroactive steroids represent a class of endogenous steroids that are expressed in the brain, adrenal glands, and gonads in response to GABA in synaptic and extrasynaptic locations. A The receptors have a strong and selective effect. When neuroactive steroids activate synaptic GABA A When the neuroactive steroid activates the extrasynaptic GABA A When the receptor is activated, a gradual, constant chloride current is produced, which is called tonic inhibition.

[0006] 3α-OH-5β-pregnane-20-one, with Figure 1 The chemical structure shown is characterized by a β-oriented hydrogen at the C5 position of the first carbon ring. 3α-OH-5β-Pregnane-20-one has low water solubility and high lipophilicity. The melting point of 3α-OH-5β-Pregnane-20-one is about 150°C. Therefore, the required therapeutic serum level after oral administration remains difficult to determine, possibly due to insufficient release or solubilization in the gastrointestinal tract.

[0007] There is currently no acceptable method to achieve an oral dosage form comprising 3α-OH-5β-pregnane-20-one that provides therapeutically effective levels of 3α-OH-5β-pregnane-20-one for the treatment of patients with CNS disorders or other disorders requiring 3α-OH-5β-pregnane-20-one. Although synthetic chemical modifications of endogenous neuroactive steroids are often used 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., their unknown safety profiles need to be clarified or studied before they can be used for potential therapeutic purposes.

[0008] Epilepsy is defined as: 1) at least two unprovoked seizures occur more than 24 hours apart, 2) an unprovoked seizure occurs and is likely to reoccur within the next 10 years, and / or 3) a diagnosis of an epilepsy syndrome. Epilepsy is a brain disorder that causes seizures, affects people's physical, mental and social well-being, and is associated with a mortality rate that is 2 to 3 times higher than that of the general population. About 60-65% of epilepsy is idiopathic and about 30% of patients are refractory (i.e., epilepsy that is not well managed with currently available anti-epileptic seizure medications ("Anti-Seizure Medication, ASM") or also characterized as anti-epileptic drugs (Anti Epilepsy Drug, AED)). Epilepsy is the most common neurological disorder during pregnancy. People with epilepsy are more likely to comorbid with other conditions (including depression and anxiety). People with epilepsy are at increased risk of death from the direct effects of epileptic seizures (e.g., status epilepticus, etc.) and the indirect effects of epileptic seizures (e.g., suicide, car accidents, cardiovascular effects, etc.).

[0009] It is estimated that approximately 900,000 women of childbearing (CB) age in the United States have active epilepsy. CB-age women with epilepsy face many additional challenges such as hormonal influences on seizure activity and endocrine function at different stages of their reproductive cycle, and approximately 30% of patients with epilepsy cannot be effectively controlled by available ASMs, making it important to consider newer pharmacological treatment development options. Management of uncontrolled seizures in CB-age women with active epilepsy (WWE) is a major goal during the preconception, pregnancy, and postpartum periods. Therefore, uncompromised ASM efficacy with acceptable variability and few or no drug-drug interactions achieved at the lowest possible monotherapy dose to allay concerns about fetal toxicity remains a high unmet need. In addition, seizure control, including prevention of breakthrough seizures, is critical when planning pregnancy and during pregnancy, as it can also lead to undesired falls or car accidents and impair freedom to drive.

[0010] ASMs may induce contraceptive failure, reproductive hormone imbalance, anxiety, and depression. There is an unmet need for ASMs without the above disadvantages, low to no fetal-neonatal toxicity, and any breastfeeding concerns, as well as the potential to treat associated comorbidities. Although more than 30 molecules have been approved in the United States for the treatment of epilepsy, no epilepsy drugs have been approved specifically for use in CB-age WWE. Several ASMs are known to be teratogenic to the developing fetus (consistent evidence from registry studies suggests that valproate has the highest risk, followed by carbamazepine and topiramate). Other commonly prescribed ASMs (including older generation agents such as phenobarbital and phenytoin) are associated with higher risks compared with lamotrigine, levetiracetam, clonazepam, and gabapentin (Vajda et al., 2014; Voinescu and Pennell, 2015). In addition, the risks associated with ASMs are considerable in early pregnancy; therefore, counseling, monitoring, and adjustment of CB-age WWE before pregnancy are necessary to adapt to the most appropriate ASM. CB age WWE It is preferred to discuss seizure control with a physician at least 6 months before pregnancy and, if possible, discontinue ASM therapy or use the lowest effective dose of a single anticonvulsant, depending on the type of epilepsy and fetal toxicity of ASM. Women who are concerned about unplanned pregnancy or late confirmation of pregnancy (planned or unplanned) may experience anxiety, depression, nonadherence to ASM, and / or contraceptive failure. ASM may reduce the efficacy of oral contraceptives, thereby exacerbating this problem.

[0011] There are complex multidirectional interactions between estrogen, seizures, and ASM. Most hormones act like neuroactive steroids (NAS) and thus modulate brain excitability. Any changes in endogenous or exogenous hormone levels may affect the occurrence of seizures directly or via PK interactions, thereby altering plasma levels of ASM (Harden, 2008). The PK interaction between oral contraceptives and ASM is bidirectional (Johnston and Crawford, 2014). The efficacy of hormonal contraception may be reduced in women taking ASM, which induces CYP-P450 enzymes. Epilepsy is not a medical condition that contraindicates contraceptive use. Contraceptive failure, which may be related to ASM, may be responsible for up to a quarter of unplanned pregnancies in WWE (approximately 12.5% ​​of all WWE pregnancies), compared to an unplanned pregnancy rate of 1% in healthy women. More specifically, there are gender-specific unmet needs. For example, there remains a need for safe and sufficiently orally bioavailable compositions and methods and treatments comprising 3α-OH-5β-pregnane-20-one for women with epilepsy (before pregnancy, pregnancy, labor / delivery, postpartum, or during perimenopause and menopause).

[0012] More than 150,000 people with uncontrolled epilepsy in the United States also experience seizure clusters. Treatment of seizures (such as acute repetitive seizures or ARS, cluster seizures, serial seizures, crescendo seizures, seizure flurries, recurrent seizures, or cyclical seizures) is critical because, if left untreated, seizure clusters increase the risk of physical injury, neurological damage, and status epilepticus. Despite the impact of seizure clusters, many diagnosed patients may not receive treatment due to the inconvenience of currently available treatment options.

[0013] The current options for treating or preventing ARS require rectal or nasal administration. Rectal administration presents challenges wrt plasma concentrations, which can be affected by drug expulsion, defection or oozing, social concerns about rectal administration, difficulty in administration in overweight patients, reluctance of patients or caregivers to administer, and requiring patients to lie on their sides. Nasal administration is less complicated than rectal administration, but requires patients or caregivers to carry a spray device. In addition, dose limitations, nasal discomfort, throat irritation, tearing, respiratory depression, and drowsiness are also challenges for treatment.

[0014] There remains an unmet need for new mechanisms of action, such as by selectively enhancing GABA receptor responses while being well tolerated. The potential utility of 3α-OH-5β-pregnane-20-one in treating epilepsy, a CNS disorder, through positive allosteric modulation (PAM) of GABAA receptors has been demonstrated in a mouse electroshock seizure model. Achieving effective serum levels of 3α-OH-5β-pregnane-20-one remains elusive. Thus, there is an unmet need for oral compositions and methods that can produce sufficient serum levels of 3α-OH-5β-pregnane-20-one to treat a variety of CNS disorders, thereby enabling the desired release and subsequent effective absorption to treat subjects in need of 3α-OH-5β-pregnane-20-one to treat CNS disorders. We have surprisingly discovered oral compositions and methods that can rapidly produce the desired levels of 3α-OH-5β-pregnane-20-one, have therapeutic bioavailability, are portable, easy to administer, have a favorable safety profile, and have a long shelf life at ambient temperature. Summary of the invention

[0015] The present disclosure encompasses compositions and oral dosage forms and regimens including 3α-OH-5β-pregnane-20-one and related methods. Compositions and oral dosage forms can be formulated to include a therapeutically effective amount of 3α-OH-5β-pregnane-20-one and a variety of pharmaceutically acceptable additives. On the one hand, when orally administered to a subject, the pharmaceutically acceptable additives of the composition or dosage form can provide 3α-OH-5β-pregnane-20-one in an amount sufficient to treat CNS disorders. On the other hand, the composition or dosage form may include a fast-release or dissolved or solubilized form of 3α-OH-5β-pregnane-20-one that, when orally administered to a subject, can enhance, increase or maximize the bioavailability of 3α-OH-5β-pregnane-20-one (e.g., C maxand / or AUC). For example, in one aspect, when orally administered to a subject by the compositions and methods of the present invention, the in vitro release, in vivo solubilization, absorption and / or CNS activity of 3α-OH-5β-pregnane-20-one is increased. In another aspect, when orally administered to a subject by the compositions and methods of the present invention, the absorption and / or CNS activity of 3α-OH-5β-pregnane-20-one is relatively increased compared to a composition comprising an equal amount of 3α-OH-5β-pregnane-20-one in an untreated crystalline form or a cyclodextrin solution composition when orally administered to a subject.

[0016] The present disclosure encompasses compositions and oral dosage forms and dosing regimens including 3α-OH-5β-pregnane-20-one and related methods. Compositions and oral dosage forms can be formulated to include a therapeutically effective amount of 3α-OH-5β-pregnane-20-one and a variety of pharmaceutically acceptable additives. In one aspect, when orally administered to a subject, the pharmaceutically acceptable additives of the composition or dosage form can provide a daily amount of 3α-OH-5β-pregnane-20-one sufficient to treat a CNS disorder. In another aspect, the composition or dosage form or method includes a dose and dosing regimen that, when orally administered to a subject, can achieve a therapeutically effective amount of 3α-OH-5β-pregnane-20-one. max and / or AUC 0-t To assess the effective rate and extent of oral absorption or to provide C normalized by dose max and / or AUC 0-t Effective oral absorption / bioavailability of the evaluation or enhancing, increasing or maximizing the absorption / bioavailability of 3α-OH-5β-pregnane-20-one. For example, in one aspect, when orally administered to a subject by the compositions and methods of the present invention, the absorption of 3α-OH-5β-pregnane-20-one can be effectively achieved and the relevant CNS activity of 3α-OH-5β-pregnane-20-one can be obtained or improved.

[0017] In one embodiment, the composition can be formulated into an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnane-20-one. 3α-OH-5β-pregnane-20-one can be processed before being formulated into an oral composition or dosage form to form a ground, sieved, milled, micronized or nanosized form, or can be formed into an amorphous or fully solubilized form after being formulated into a composition or dosage form. The treated crystalline form of 3α-OH-5β-pregnane-20-one includes at least one of the following particle size distributions: D90 less than 75 μm, D90 less than 20 μm, D90 of 16 μm, D90 of 13 μm, D10 greater than 1 μm, and D50 of at least one of 0.15 μm to 50 μm, 30 μm to 50 μm, 0.3 to 30 μm, and 2 μm to 8 μm.

[0018] In one embodiment, the dosage of the composition includes about 10 mg to about 1200 mg of 3α-OH-5β-pregnane-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, sprinkle, tablet, chew, cream, ointment, paste, pasty composition or drink.

[0019] In yet another embodiment, a method for treating a CNS disorder in a subject may include orally administering to a subject a therapeutically effective amount of 3α-OH-5β-pregnane-20-one. In one aspect, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be an amount of 3α-OH-5β-pregnane-20-one sufficient to treat a CNS disorder. In another aspect, the composition disclosed herein including 3α-OH-5β-pregnane-20-one may be in a form that provides a therapeutically effective amount of 3α-OH-5β-pregnane-20-one for use in treating a CNS disorder in a subject. In another aspect, 3α-OH-5β-pregnane-20-one may be combined with a variety of additives, including at least one lipophilic additive sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnane-20-one for use in treating a CNS disorder in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Features and advantages of various embodiments will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which together illustrate, by way of example, various features of the present disclosure; and wherein:

[0021] Figure 1 It is a graphic representation of the chemical structure of 3α-OH-5β-pregnane-20-one;

[0022] Figure 2 A graph showing the release rate of 3α-OH-5β-pregnane-20-one from one gram of each composition of the present invention (Formulations #1, #2 and #3 in Example 2) as compared to a conventional tablet composition (Formulation #4 in Example 2), a suspension composition of micronized crystalline 3α-OH-5β-pregnane-20-one in a composition consisting mainly of canola oil (Formulation #5 in Example 2), and a suspension composition of crystalline 3α-OH-5β-pregnane-20-one in a composition consisting mainly of polysorbate 80 (Formulation #6 in Example 2), the release rate being measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate;

[0023] Figure 3is an image of the comparative dispersibility of oral compositions of the present invention comprising 3α-OH-5β-pregnane-20-one (Formulations #9 and #10 in Example 2) after aqueous dilution (100-fold) with pH 6.8 simulated intestinal fluid according to USP 26 as compared to the dispersibility of compositions comprising solubilized 3α-OH-5β-pregnane-20-one in solutions consisting primarily of medium chain triglycerides (e.g., MIGLYOL 812, Formulation #7 in Example 2) and in solutions consisting primarily of canola oil (Formulation #8 in Example 2);

[0024] Figure 4 This is a typical pharmacokinetic profile.

[0025] Figure 5 is a graph of pharmacokinetic profiles of exemplary embodiments of a drug in two different compositions; and

[0026] Figure 6 is a graph of exemplary AUC values ​​in a single-dose administration trial in humans under different meal states (eg, fasted and fed). DETAILED DESCRIPTION

[0027] Before describing the embodiments of the present invention, it should be understood that the present disclosure is not limited to the specific structures, method steps or materials disclosed herein, but extends to equivalents thereof that will be recognized by ordinary technicians in the relevant field. It should also be understood that the terms used herein are only for the purpose of describing specific examples or embodiments, and are not intended to be limiting.

[0028] In addition, the described features, structures or characteristics may also be combined in one or more embodiments in any suitable manner. In the following description, many specific details are provided, such as examples of compositions, dosage forms, treatments, etc., to provide a thorough understanding of various invention embodiments. However, those skilled in the relevant art will recognize that these detailed embodiments do not limit the overall inventive concept set forth herein, but are merely representative thereof.

[0029] definition

[0030] It should be noted that the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes reference to one or more of such excipients, and reference to "the additive" includes reference to one or more of such additives.

[0031] As used herein, the terms "treat", "treatment", "treating", and the like refer to the administration of a therapeutic agent to an asymptomatic or symptomatic subject. In other words, "treatment" may refer to the action of reducing or eliminating a condition (i.e., manifested symptoms), or it may refer to preventive treatment (i.e., administering to a subject who does not manifest symptoms to prevent their occurrence). Such preventive treatment may also be referred to as preventing a condition, preventive action, preventive measures, and the like.

[0032] As used herein, the terms "therapeutic agent," "active agent," and the like are used interchangeably and refer to an agent or substance that has a measurable specific or selected physiological activity when administered to a subject in a significant or effective amount. It should be understood that the term "drug" is expressly encompassed in this definition, as a variety of drugs and prodrugs are known to have specific physiological activities. These technical terms are well known in the pharmaceutical and medicinal arts. In addition, when these terms are used, or when a specific active agent is specifically identified by name or class in this written description, it should be understood that such a description is intended to include explicit support for the active agent itself and 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-pregnane-20-one also includes explicit support for the active metabolite.

[0033] 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 aspects, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents and additives or other excipients. In addition, the term "dosage form" can include one or more formulations or compositions provided in a form for administration to a subject. For example, an "oral dosage form" can be suitable for administration to the mouth of a subject. A "topical dosage form" can be suitable for administration to the skin of a subject by rubbing, etc.

[0034] As used herein, "pharmaceutically acceptable additives" or "additives" are used interchangeably and refer to pharmaceutically acceptable agents or ingredients that can be combined with an active agent as part of a composition or dosage form. In some aspects, a pharmaceutically acceptable additive can affect the form or behavior of the active agent. For example, in some aspects, a pharmaceutically acceptable additive can completely or partially dissolve or solubilize an active agent (e.g., 3α-OH-5β-pregnane-20-one) in a pharmaceutical composition, or achieve a non-crystalline form of the active agent. In other aspects, a pharmaceutically acceptable additive can be formulated with an active agent (e.g., 3α-OH-5β-pregnane-20-one) in a pharmaceutical composition comprising a crystalline form of the active agent. On the one hand, a composition wherein 3α-OH-5β-pregnane-20-one comprises 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.

[0035] In addition, in some aspects, additives can affect or control the properties and performance of the composition or dosage form. For example, in some aspects, additives can affect or control the pharmacokinetic (PK) performance or characteristics of the composition and / or dosage form (e.g., the release rate and / or release extent of the active agent). In addition, in some aspects, additives can also affect or control pharmacodynamic (PD) performance or characteristics (e.g., reducing photoparoxysmal response).

[0036] As used herein, "semi-liquid" or "semi-solid" corresponds to a partially solubilized active agent, while "liquid" corresponds to a fully solubilized active agent at room temperature.

[0037] As used herein, "subject" refers to a mammal that can benefit from the administration of a pharmaceutical composition, dosage form, or dosage regimen or method disclosed herein. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals. In a specific aspect, the subject is a human. In another aspect, the subject is a female. In another aspect, the subject is a female of childbearing age. In another aspect, the female has given birth to a baby within the past 1-12 months. In another aspect, the subject is a male.

[0038] As used herein, "in need of treatment" and the like refer to a subject who suffers from a disease, condition or disorder, or is suspected of suffering from a disease, condition or disorder, or is in need of treatment or is indicated for treatment according to various diagnostic criteria generally used in practice. Thus, "in need of treatment" may include the operation of identifying a subject in need of treatment.

[0039] As used herein, "identifying a subject in need of treatment" may include the following operations: obtaining a biological sample from the subject and determining the level of one or more biomarkers described herein; evaluating the biological sample obtained from the subject; performing imaging analysis on the subject; evaluating one or more clinical characteristics of the subject (e.g., evaluating symptoms or overt symptoms); or a combination thereof.

[0040] As used herein, the terms "disease," "disease," "condition," "symptom," and "disorder" are used interchangeably and refer to an abnormal or improper functioning of any part, group, or system of a subject's physiology, regardless of cause and effect. For example, a mental illness or mood disorder may be caused by environmental factors, genetic factors, physiological events, past experiences, and other influences, or a combination thereof.

[0041] As used herein, an "acute" condition refers to a condition that can develop rapidly and have noticeable symptoms that require urgent or semi-urgent care. In contrast, a "chronic" condition refers to a condition that generally develops more slowly and persists or otherwise progresses over time. Some examples of acute conditions may include, but are not limited to, asthma attacks, bronchitis, heart attacks, pneumonia, etc. Some examples of chronic conditions may include, but are not limited to, arthritis, diabetes, hypertension, dyslipidemia, etc.

[0042] The terms "serum level", "serum amount", "serum concentration", "plasma level", "plasma concentration", "blood level", "blood concentration" and the like are used interchangeably herein and refer to the total amount of an analyte (e.g., an identified metabolite or active agent) identified in the blood of a subject, including free, bioavailable and bound fractions. For example, "serum 3α-OH-5β-pregnane-20-one" or "serum 3α-OH-5β-pregnane-20-one level" or "serum 3α-OH-5β-pregnane-20-one concentration" or "plasma 3α-OH-5β-pregnane-20-one concentration" or "3α-OH-5β-pregnane-20-one concentration in the blood" refers to the total 3α-OH-5β-pregnane-20-one concentration, which is the sum of the 3α-OH-5β-pregnane-20-one fractions present, including substantially free and bound 3α-OH-5β-pregnane-20-one concentrations. It should be understood that in this written description, such terms provide explicit support for total analyte or agent levels, as well as various applicable fractions thereof, including bioavailable fraction, bound fraction, and substantially free fraction. Unless otherwise specified, these values ​​are "observed" concentrations or amounts, without adjustment or correction for the baseline serum levels of the subject(s). As with any bioanalytical measurement, to improve consistency, the method used to measure initial serum levels should be consistent with the method used to monitor and remeasure serum levels during clinical testing and treatment of the subject. As used herein, the term "C avg” refers to the average serum concentration level during the period from 0 to t (e.g., the average daily serum concentration level, i.e., the daily C avg , with AUC 0-24 / 24 hours), while the term “C max ” refers to the maximum serum concentration level sustained over this period of time following a single dose.

[0043] Immunoassay-based measurements of serum 3α-OH-5β-pregnane-20-one and its isomers are not as accurate as typical radioimmunoassay methods (RIA) because RIAs are generally not specific for the target analyte. To measure the target analyte, the assay should be based on a chromatography-mass spectrometry-based method (e.g., LC-MS or GC-MS), which can provide reliable data to assess the true PK and pharmacodynamic (PD) potential of 3α-OH-5β-pregnane-20-one. Therefore, data and results related to oral 3α-OH-5β-pregnane-20-one are only available at the level of NAS or NAS levels for the required GABA. A The adequacy of receptor modulation is reliable when determined for specificity and accuracy by analytical procedures amenable to a single analyte separation step, such as liquid chromatography (LC), gas chromatography (GC), liquid chromatography tandem mass spectrometry (LC-MS), or gas chromatography-mass spectrometry (GC-MS).

[0044] In one aspect, the PK values ​​(e.g., serum concentrations, calculated ratios) of an analyte of interest (e.g., 3α-OH-5β-pregnane-20-one) derived from the compositions and methods of the invention are based on LC, LC-MS, GC, or GC-MS measurements.

[0045] 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 an analyte of interest (e.g., 3α-OH-5β-pregnane-20-one) in a subject prior to administration of an active agent. For example, the baseline level of 3α-OH-5β-pregnane-20-one in a subject would be the subject's 3α-OH-5β-pregnane-20-one serum level prior to the start of (e.g., immediately prior to) administration of 3α-OH-5β-pregnane-20-one or treatment.

[0046] The term "oral administration" refers to any method of administration in which the active agent can be administered by swallowing, chewing, sucking or drinking the composition or dosage form. Oral administration may be intended for enteral delivery of the active agent or transmucosal delivery of the active agent. In some embodiments, the compositions and dosage forms disclosed herein may be mixed with food or drink prior to oral administration, or may be co-administered with food or meals in other ways.

[0047] As used herein, the terms "release" and "release rate" are used interchangeably and refer to the expulsion or liberation of a substance (including but not limited to a drug) from a composition or dosage form into the surrounding environment (such as an aqueous medium) in vitro or in vivo. On the other hand, the term "disintegration" refers to the release of a substance (including but not limited to a drug) from a composition or dosage form into the surrounding environment (such as an aqueous medium) in vitro or in vivo. <701> Disintegration, USP 43, is a physical process associated with the mechanical disintegration of a tablet into smaller particles / granules, representing the disruption of inter-particle interactions produced during the formation of a tablet by compacting granulated particles of an active pharmaceutical ingredient (API) and excipients. On the other hand, the term "disintegration" is a physical process associated with the opening or rupture of a capsule. As used herein, the term "disintegration time" refers to the amount of time required for disintegration to occur.

[0048] As used herein, the term "dissolution" refers to the solubilization of an active substance from a composition or dosage form into the surrounding environment (eg, aqueous medium) in vitro or in vivo.

[0049] As used herein, "dosing regimen" or "regimen" (such as "initial dosing regimen" or "starting dose" or "maintenance dosing regimen") refers to how, when, how much and how long the dose of the disclosed composition or dosage form can be administered to a subject. For example, the subject's initial or starting dosing regimen can provide a total daily dose of about 10 mg to about 3400 mg, divided daily, at least 4 hours apart, administered with meals, repeated for 30 days.

[0050] As used herein, a "daily dose" refers to the amount of 3α-OH-5β-pregnane-20-one administered to a subject over a 24-hour period. The daily dose can be administered in one or more administrations during a 24-hour period. In one embodiment, the daily dose provides for two or three or four or six or eight administrations over a 24-hour period. With this in mind, an "initial dose" or "initial daily dose" refers to the dose administered in the initial regimen or period of a dosing regimen.

[0051] As used herein, an "effective amount" or "therapeutically effective amount" of a drug refers to a nontoxic but sufficient amount of a drug to achieve a therapeutic result in treating a condition for which the drug is known to be effective. It should be understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an "effective amount" or "therapeutically effective amount" may depend on such biological factors in some cases. In addition, although the achievement of a therapeutic effect can be measured by a physician or other qualified medical personnel using assessments known in the art, it should be recognized that individual differences and responses to treatment can make the achievement of a therapeutic effect a somewhat subjective decision. The determination of an effective amount is well within the capabilities of those of ordinary skill in the pharmaceutical and medical arts. See, for example, Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis," Monographs in Epidemiology and Biostatistics , Vol. 8 (1986), which is incorporated herein by reference.

[0052] As used herein, "single unit" when used to describe administration to a subject means that the dosage form is a single dosage form, such as a single tablet, capsule, pump or spray of a gel or solution, etc. In contrast, when used to describe administration to a subject, "multi-unit" refers to an amount including two or more dosage forms, such as 2 capsules, 3 tablets, 2-4 pumps or injectors, etc. It is worth noting that multi-unit dosage forms are usually dosage forms of the same type (i.e., tablets or capsules), but are not required to be of the same dosage form type. In addition, tablets can be scored or pre-scored so that half or a quarter of a single tablet can be applied in the present disclosure. Scoring and / or pre-scoring can describe the scoring that will divide the tablet into a quarter or a half.

[0053] In the present disclosure, "comprises / comprising", "containing", and "having", etc. may have the meanings assigned to them by U.S. patent law and may mean "includes / including", etc., and are generally understood as open terms. The term "consisting of / consists of" is a closed term and includes only the components, structures, steps, etc. specifically listed with such term, as well as the components, structures, steps, etc. that comply with U.S. patent law. "Consisting essentially of / consists essentially of / essentially consisting" has the meaning generally assigned to them by U.S. patent law. In particular, such terms are generally closed terms, with the exception that the inclusion of additional items, materials, components, steps, or elements that do not substantially affect the basic and novel characteristics or functions of the item(s) used in connection therewith is permitted. For example, trace elements that are present in the composition but do not affect the properties or characteristics of the composition would be permitted if present under the term "consisting essentially of", even if not explicitly recited in the listing of items following such term. When open-ended terms such as "including" or "comprising" are used in this written description, it should be understood that direct support should also be provided to the phrase "consisting essentially of" and the phrase "consisting of", as if explicitly stated, and vice versa.

[0054] The terms "first", "second", "third", "fourth", etc. (if any) in the description and claims are used to distinguish similar elements and are not necessarily used to describe a particular sequence or chronological order. It should be understood that the terms so used are interchangeable where appropriate, such that the embodiments described herein are, for example, capable of operating in a sequence other than that shown or otherwise described herein. Similarly, if a method is described herein as comprising a series of steps, the order of such steps presented herein is not necessarily the only order in which such steps may be performed, and some of the steps described may also be omitted and / or some other steps not described herein may also be added to the method.

[0055] The appearances of the phrase "in one embodiment" or "an aspect" herein are not necessarily all referring to the same embodiment or aspect.

[0056] As used herein, comparative terms, such as "increase / elevate", "decrease / lower", "better", "worse", "higher", "lower", "enhance", "improve", "maximize", "minimize", etc., refer to a property of a device, component, composition, biological response, biological state, or activity that is measurably different from other devices, components, compositions, biological responses, biological states, or activities located in surrounding or adjacent areas, similarly located, in a single device or composition or in multiple comparable devices or compositions, in one group or category, in multiple groups or categories, or compared to an original (e.g., untreated) or baseline state or known state of the art. For example, a composition or dosage form comprising 3α-OH-5β-pregnane-20-one that "increases / elevates" serum levels of 3α-OH-5β-pregnane-20-one in a subject or provides elevated 3α-OH-5β-pregnane-20-one in a subject compared to serum levels at a previous time point, such as a baseline level (e.g., before treatment), or compared to an earlier treatment with a different dose (e.g., a lower dose). Alternatively, a composition or dosage form that provides an "increase / elevation" of serum levels of 3α-OH-5β-pregnane-20-one, when orally administered to a subject, can provide such an increase / elevation compared to an alternative known composition or dosage form, e.g., compared to an equivalent amount of 3α-OH-5β-pregnane-20-one using a suboptimal additive, or a composition comprising crystalline 3α-OH-5β-pregnane-20-one, or a composition consisting primarily of 3α-OH-5β-pregnane-20-one suspended / dissolved in an edible oil such as canola oil or peanut oil or a medium chain triglyceride, or a composition consisting primarily of 3α-OH-5β-pregnane-20-one solubilized / dissolved in a cyclodextrin solution, or a composition consisting primarily of 3α-OH-5β-pregnane-20-one suspended in Tween 80.

[0057] As used herein, the term "substantially" refers to a complete or nearly complete degree or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" closed will mean that the object is either completely closed or nearly completely closed. In some cases, the exact permissible degree of deviation from absolute completeness may depend on the specific context. However, in general, close to completion will achieve the same overall result, as if absolute and total completion was obtained. When used in a negative sense, the use of "substantially" is equally applicable, referring to a complete or nearly complete lack of action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free of" particles either completely lacks particles or nearly completely lacks particles, and its effect is like a complete lack of particles. In other words, a composition that is "substantially free of" a certain ingredient or element may actually still contain such items as long as it does not have a measurable effect.

[0058] As used herein, the term "completely" refers to the complete degree or extent of an action, characteristic, property, state, structure, item, or result.

[0059] As used herein, the term "about" is used to provide flexibility for numerical range endpoints by specifying that a given value can be "slightly above" or "slightly below" the endpoint. Unless otherwise indicated, the use of the term "about" in terms of specific numbers or numerical ranges should also be understood to provide support for such numerical terms or ranges that do not contain the term "about". For example, for convenience and brevity, a numerical range of "about 50 angstroms to about 80 angstroms" should also be understood to provide support for the range of "50 angstroms to 80 angstroms". In addition, it should also be understood that in this specification, even when the term "about" is used together with it, support for actual numerical values ​​is provided. For example, the description of "about" 30 should be interpreted as providing support not only for values ​​slightly above and slightly below 30, but also for the actual numerical value of 30.

[0060] As used herein, for convenience, multiple items, structural elements, compositional elements and / or materials may be presented in a common list. However, these lists should be interpreted as if each member of the list was independently identified as a separate and unique member. Therefore, in the absence of contrary indications, any individual member of such a list should not be interpreted as a de facto equivalent of any other member of the same list solely based on its presentation in a common group.

[0061] As used herein, the term "GABA" refers to gamma-aminobutyric acid (see: Wikipedia entry gamma-aminobutyric acid).

[0062] Concentration, amount, level and other numerical data can be represented or presented in range format herein.It should be understood that such range format is only used for convenience and brevity, and therefore should be flexibly interpreted as not only including the numerical value clearly described as range limit, but also including all single numerical values ​​or sub-ranges or decimal units contained in the range, as if each numerical value and sub-range are clearly described.As an illustration, the numerical range of "about 1 to about 5" should be interpreted as not only including the value of about 1 to about 5 clearly described, but also including the single value and sub-range in the indicated range.Therefore, included in this numerical range are single values ​​such as 2,3 and 4 and sub-ranges such as 1-3,2-4 and 3-5, etc., and single 1,2,3,4 and 5.This same principle is applicable to the scope of only narrating a numerical value as minimum or maximum value.In addition, no matter how the breadth of described range or characteristic is, this explanation is applicable.

[0063] References to "example" throughout this specification mean that a particular feature, structure, or characteristic described in connection with the example is included in at least one embodiment. Therefore, the phrase "in one example" appearing in multiple places throughout this specification does not necessarily refer to the same embodiment.

[0064] describe

[0065] Reference will now be made in detail to preferred embodiments of the invention. Although these embodiments will be described in detail, the present disclosure is not limited to such embodiments. On the contrary, the present invention is intended to cover alternatives, variations, modifications and equivalents that may be included within the spirit and scope of the present disclosure.

[0066] The following provides a preliminary overview of the technical implementation, and then further describes the specific technical implementation in detail later. This preliminary overview is intended to help readers understand the technology more quickly, but is not intended to identify the key features or essential features of the technology, nor is it intended to limit the scope of the subject matter claimed.

[0067] Some of these neuromodulatory and protective effects of 3α-OH-5β-pregnane-20-one can produce anticonvulsant, antidepressant, anxiolytic, and neuroprotective effects in experimental animals and in tissue and cell cultures.

[0068] Some efforts have been made to increase the bioavailability of 3α-OH-5β-pregnane-20-one after oral administration. However, there are no studies that provide adequate levels of GABA after oral administration. A Receptor modulators to achieve therapeutic utility, particularly compositions or methods of administration for producing higher and faster amounts of serum 3α-OH-5β-pregnane-20-one.

[0069] Achieving desired serum 3α-OH-5β-pregnane-20-one levels or adequate oral dosing for efficacy in CNS indications remains elusive and challenging for a variety of reasons.

[0070] Therefore, there remains an unmet need for compositions and methods that can produce higher, faster, more reliable and sufficient serum levels of 3α-OH-5β-pregnane-20-one for treating various CNS disorders in a biologically acceptable manner, thereby enabling the desired release and subsequent effective absorption of 3α-OH-5β-pregnane-20-one for treating subjects in need of 3α-OH-5β-pregnane-20-one for treating CNS disorders. In certain aspects, we surprisingly found that the oral compositions and methods of the present invention can effectively produce the desired levels of 3α-OH-5β-pregnane-20-one.

[0071] References throughout this specification to "one embodiment," "an embodiment," or similar terms mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment of the present invention. Thus, the phrases "in one embodiment," "in an embodiment," and similar terms appearing throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0072] Without departing from the spirit or essential features of the present invention, the present invention may be embodied in other specific forms. The described embodiments are considered to be merely illustrative in all respects, rather than restrictive. Therefore, the scope of the present invention is indicated by the appended claims rather than the preceding description. All changes falling within the meaning and equivalent scope of the claims are included within their scope.

[0073] In one embodiment of the present invention, an oral pharmaceutical composition may include a therapeutically effective amount of 3α-OH-5β-pregnane-20-one and a variety of pharmaceutically acceptable additives, which, when orally administered to a subject, provide 3α-OH-5β-pregnane-20-one in an amount sufficient to treat CNS depression. In some aspects, when administered to a subject, the additive may maximize, accelerate, or otherwise increase the absorption of 3α-OH-5β-pregnane-20-one from the composition. In some aspects, when administered to a subject, the additive may increase the release rate and / or release amount of 3α-OH-5β-pregnane-20-one. In some aspects, when administered to a subject, the additive may increase the solubilization of 3α-OH-5β-pregnane-20-one. In some aspects, the additive, ingredient, shape, and / or size of the dosage form (e.g., tablet or capsule) of the composition may increase the disintegration rate of the dosage form, such as to 25 minutes or less.

[0074] In some aspects of the invention, the form of 3α-OH-5β-pregnane-20-one in the composition can increase the release rate and / or amount of 3α-OH-5β-pregnane-20-one when tested in vitro or when administered to a subject. In some aspects, the form of 3α-OH-5β-pregnane-20-one in the composition can increase the solubilization of 3α-OH-5β-pregnane-20-one when administered to a subject.

[0075] When using sulfobutyl ether-β-cyclodextrin (SBE-β-CD) oral compositions with solubilized or semi-solid 3α-OH-5β-pregnane-20-one, loading the appropriate amount of 3α-OH-5β-pregnane-20-one to deliver effective serum levels of 3α-OH-5β-pregnane-20-one may be challenging due to limitations regarding the solubility of 3α-OH-5β-pregnane-20-one in various cyclodextrin solutions (including unencapsulated SBE-β-CD). In addition, the high amount of cyclodextrin required for the formulation of 3α-OH-5β-pregnane-20-one may also present safety issues. In some aspects, the compositions and dosage forms of the present invention are capable of loading larger amounts of 3α-OH-5β-pregnane-20-one than unencapsulated SBE-β-CD or any cyclodextrin solution composition.

[0076] In another aspect, a specified weight percentage of 3α-OH-5β-pregnane-20-one in a composition or dosage form can be solubilized. In one example, about 50% to about 100% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized. In another example, about 50% to about 65% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized. In yet another example, about 65% to about 85% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized. In another example, about 85% to about 100% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized. In another example, about 85% to about 100% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized in a variety of additives that are substantially free of SBE-β-CD.

[0077] In another embodiment, an oral pharmaceutical composition or oral dosage form may include an amount of GABA that, when administered to a subject, provides the desired amount of GABA in a therapeutically effective amount for treating a CNS disorder. A Receptor binding efficiency of 3α-OH-5β-pregnane-20-one.

[0078] In one embodiment, 3α-OH-5β-pregnane-20-one compositions and oral dosage forms can be formulated to provide an amount or peak level of 3α-OH-5β-pregnane-20-one that is therapeutically effective for treating a CNS disorder when orally administered to a subject. For example, in one aspect, the compositions and oral dosage forms can include a variety of pharmaceutically acceptable additives that, when orally administered to a subject, provide serum 3α-OH-5β-pregnane-20-one in an amount sufficient to treat a CNS disorder.

[0079] In one embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of additives, wherein oral administration of the composition to a subject suffering from at least one neuropsychiatric and neurodegenerative disorder results in a serum level of 3α-OH-5β-pregnane-20-one in the subject such that the at least one neuropsychiatric and neurodegenerative disorder is substantially eliminated, improved or reduced.

[0080] In one embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of a SBE-β-CD solution (administration of a cyclodextrin solution). max Serum C levels and 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0081] In another embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of a medium chain triglyceride solution (MCT administration). max Serum C levels and 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0082] In yet another embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition is intended to provide a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of a polysorbate-80 suspension (polysorbate 80 administration). max Serum C levels and 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0083] In yet another embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition is expected to provide a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of a canola oil or peanut oil solution (edible oil administration). max Serum C levels and 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0084] In one embodiment, the 3α-OH-5β-pregnane-20-one composition or oral dosage form or method can be formulated to effectively provide an expected serum level of 3α-OH-5β-pregnane-20-one, which is therapeutically effective for treating CNS disorders when orally administered to a subject. On the other hand, when orally administered to a subject, 3α-OH-5β-pregnane-20-one can be in a form that maximizes the serum level of 3α-OH-5β-pregnane-20-one. On the other hand, 3α-OH-5β-pregnane-20-one can be in a form that increases the serum level of 3α-OH-5β-pregnane-20-one when orally administered to a subject. On the other hand, when orally administered to a subject, the composition and method of the present invention increase the serum level of 3α-OH-5β-pregnane-20-one compared to a composition comprising an equivalent amount of a processed crystalline (micronized) form of 3α-OH-5β-pregnane-20-one mainly composed of 3α-OH-5β-pregnane-20-one suspended in an edible oil.

[0085] In one embodiment, the composition of the present invention can be formulated into an oral dosage form having about 50 mg to about 600 mg of 3α-OH-5β-pregnane-20-one. In one aspect, the oral dosage form can be a liquid, semi-liquid, semi-solid, spray, emulsion, dispersion, granule, syrup, suspension, capsule, tablet, chewable or drink.

[0086] In yet another embodiment, dosage regimens and methods 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-pregnane-20-one.

[0087] In one embodiment, the compositions and oral dosage forms may include a plurality of pharmaceutically acceptable additives, wherein the additives include at least one of alpha-tocopherol, glyceryl monocaprylate, propylene glycol monolaurate, PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil, poloxamers, and combinations thereof, which, when orally administered to a subject, provide sufficient levels of 3α-OH-5β-pregnane-20-one in an amount sufficient to treat a CNS disorder.

[0088] The present disclosure encompasses compositions and oral dosage forms and regimens including 3α-OH-5β-pregnane-20-one and related methods. Compositions and oral dosage forms can be formulated to include a therapeutically effective amount of 3α-OH-5β-pregnane-20-one and a variety of pharmaceutically acceptable additives. On the one hand, when orally administered to a subject, the pharmaceutically acceptable additives of the composition or dosage form can provide 3α-OH-5β-pregnane-20-one in an amount sufficient to treat CNS disorders. On the other hand, the composition or dosage form may include a fast-release or dissolved or solubilized form of 3α-OH-5β-pregnane-20-one, which, when orally administered to a subject, can enhance, increase or accelerate the bioavailability of 3α-OH-5β-pregnane-20-one (e.g., C max and / or AUC). For example, in one aspect, when orally administered to a subject by the compositions and methods of the present invention, the in vitro release, in vivo solubilization, absorption and / or CNS activity of 3α-OH-5β-pregnane-20-one is increased. In another aspect, when orally administered to a subject by the compositions and methods of the present invention, the absorption and / or CNS activity of 3α-OH-5β-pregnane-20-one is relatively increased compared to a composition comprising an equal amount of 3α-OH-5β-pregnane-20-one in an untreated crystalline form or a cyclodextrin solution composition when orally administered to a subject.

[0089] In one embodiment, the composition can be formulated into an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnane-20-one. The 3α-OH-5β-pregnane-20-one can be processed before being formulated into an oral composition or dosage form to form a ground, sieved, milled, micronized or nanoscale form, or can be formed into an amorphous or fully solubilized form after being formulated into a composition or dosage form. The treated crystalline form of 3α-OH-5β-pregnane-20-one includes at least one of the following particle size distributions: D90 less than 75 μm, D90 less than 20 μm, D90 of 16 μm, D90 of 13 μm, D10 greater than 1 μm, and D50 of at least one of 0.15 μm to 50 μm, 30 μm to 50 μm, 0.3 to 30 μm, and 2 μm to 8 μm. In addition, the treated crystalline form of 3α-OH-5β-pregnane-20-one comprises at least one of the following particle size distributions: D90 less than 40 μm, D10 greater than 1 μm, and D50 of at least one of 0.15 μm to 50 μm, 30 μm to 50 μm, 0.3 μm to 30 μm, and 2 μm to 8 μm.

[0090] In yet another embodiment, a method for treating a CNS disorder in a subject may include orally administering to a subject a therapeutically effective amount of 3α-OH-5β-pregnane-20-one. In one aspect, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be an amount of 3α-OH-5β-pregnane-20-one sufficient to treat a CNS disorder. In another aspect, the composition disclosed herein including 3α-OH-5β-pregnane-20-one may be in a form that provides a therapeutically effective amount of 3α-OH-5β-pregnane-20-one for use in treating a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnane-20-one may be combined with a variety of additives, including at least one lipophilic additive sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnane-20-one for use in treating a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnane-20-one can be combined with additives including at least one lipophilic additive and a hydrophilic additive sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject.

[0091] In yet another aspect, 3α-OH-5β-pregnane-20-one can be combined with additives including at least one lipophilic additive and a surfactant sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnane-20-one to treat a CNS disorder in a subject.

[0092] In yet another aspect, 3α-OH-5β-pregnane-20-one may be combined with additives including at least one lipophilic additive and at least greater than 0.5% of a surfactant sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnane-20-one to treat a CNS disorder in a subject.

[0093] In yet another aspect, 3α-OH-5β-pregnane-20-one can be combined with additives including at least one lipophilic additive and at least greater than 0.5% but not greater than at least one of 25%, 35%, and 50% of a surfactant sufficient to provide a therapeutically effective amount of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject.

[0094] As discussed above, when the prior art compositions are orally administered to a subject by using a composition or dosage form consisting primarily of 3α-OH-5β-pregnane-20-one solubilized in an unencapsulated SBE-β-CD solution, a crystalline 3α-OH-5β-pregnane-20-one suspension in polysorbate 80, 3α-OH-5β-pregnane-20-one solubilized in an edible oil (e.g., medium chain triglycerides or canola or peanut oil), or crystalline 3α-OH-5β-pregnane-20-one in an edible oil, or a plurality of additives or methods, the reported post-administration activity of 3α-OH-5β-pregnane-20-one at the doses studied is not expected to produce sufficient levels of 3α-OH-5β-pregnane-20-one to effectively treat CNS disorders. In addition, administration of oral 3α-OH-5β-pregnane-20-one with these compositions may result in low 3α-OH-5β-pregnane-20-one levels and inconsistent PD effects. Therefore, enhanced oral compositions and methods for treating CNS disorders would be needed.

[0095] In one embodiment, the oral pharmaceutical composition of the present invention may include a therapeutically effective amount of 3α-OH-5β-pregnane-20-one and a variety of pharmaceutically acceptable additives, which are expected to provide sufficient 3α-OH-5β-pregnane-20-one serum levels to treat CNS depression when orally administered to a subject. In some aspects, when administered to a subject, the additive can maximize, accelerate or otherwise achieve or affect the effective absorption of 3α-OH-5β-pregnane-20-one or its bioavailability from the composition. In some aspects, when administered to a subject or tested in vitro, the additive can affect the release amount of 3α-OH-5β-pregnane-20-one. In some aspects, when administered to a subject or tested in vitro, the additive can affect the solubilization of 3α-OH-5β-pregnane-20-one. In some aspects, when administered to a subject or tested in vitro, the additive can affect the release rate and / or amount of 3α-OH-5β-pregnane-20-one.

[0096] In some aspects, the form of 3α-OH-5β-pregnane-20-one in the composition can affect the amount of 3α-OH-5β-pregnane-20-one released when administered to a subject or tested in vitro. In some aspects, the form of 3α-OH-5β-pregnane-20-one in the composition can affect the solubilization of 3α-OH-5β-pregnane-20-one when administered to a subject or tested in vitro. In some aspects, the physical form of 3α-OH-5β-pregnane-20-one in the composition can affect the release rate and / or amount of 3α-OH-5β-pregnane-20-one when administered to a subject or tested in vitro.

[0097] When using sulfobutyl ether-β-cyclodextrin (SBE-β-CD) oral compositions including solubilized or semi-solid 3α-OH-5β-pregnane-20-one, loading the appropriate amount of 3α-OH-5β-pregnane-20-one to deliver effective serum levels of 3α-OH-5β-pregnane-20-one may be challenging due to limitations regarding the solubility of 3α-OH-5β-pregnane-20-one in various cyclodextrin solutions including SBE-β-CD (e.g., the solubility of 3α-OH-5β-pregnane-20-one in a 24% w / v unencapsulated SBE-β-CD solution is only about 6 mg / ml). When the 3α-OH-5β-pregnane-20-one concentration is above 8 mg / ml, the solubilized portion of 3α-OH-5β-pregnane-20-one begins to decrease as observed by precipitation. The amount of 3α-OH-5β-pregnane-20-one in the cyclodextrin solution can only be achieved with a loading of about 0.6% w / w of the composition fill. In addition, the high amount of cyclodextrin required to solubilize 3α-OH-5β-pregnane-20-one also presents safety issues. In some aspects, the compositions and dosage forms of the present invention can include a higher loading of 3α-OH-5β-pregnane-20-one than compositions and dosage forms formulated in unencapsulated SBE-β-CD or any cyclodextrin solution composition.

[0098] In some aspects, the compositions and dosage forms of the invention include a loading of 3α-OH-5β-pregnane-20-one of at least greater than 0.6% w / w or 1% w / w when fully solubilized in the composition. Figure 2 A graph showing the release rate of 3α-OH-5β-pregnane-20-one from one gram of each of the compositions disclosed herein (Formulations I-1 and I-2) compared to conventional compositions (Formulations I-3, I-4, and I-5). Figure 2 As shown, the composition according to the present invention is capable of releasing more than 30 mg of 3α-OH-5β-pregnane-20-one or releasing at least 25% more 3α-OH-5β-pregnane-20-one compared to a composition mainly consisting of a) a conventional tablet formulation without a surfactant (Formulation I-3), b) a suspension formulation of crystalline 3α-OH-5β-pregnane-20-one in canola oil (Formulation I-4), and c) a suspension formulation of crystalline 3α-OH-5β-pregnane-20-one in polysorbate 80.

[0099] In another aspect, when measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate, after 30 minutes, the composition according to the present invention can release greater than about 30 mg or at least 50% of 3α-OH-5β-pregnane-20-one. On the other hand, when measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate, after 15 minutes, the composition according to the present invention can release greater than about 20 mg or at least 40% of 3α-OH-5β-pregnane-20-one. In some aspects, when administered to a subject, the daily dose or dosing regimen can affect the absorption of 3α-OH-5β-pregnane-20-one. In some aspects, the daily dose or dosing regimen of 3α-OH-5β-pregnane-20-one can affect the absorption of 3β-OH-5α-pregnane-20-one (or an isomer of 3α-OH-5β-pregnane-20-one) when administered to a subject.

[0100] On the other hand, the 3α-OH-5β-pregnane-20-one in the composition can be in a form that maximizes, accelerates or otherwise causes an increase in the solubilization level and / or serum level of 3α-OH-5β-pregnane-20-one in the gastrointestinal tract of the subject when orally administered to the subject. In one embodiment, when orally administered to the subject, the 3α-OH-5β-pregnane-20-one in the composition can be in a form that increases the serum level of 3α-OH-5β-pregnane-20-one compared to a composition comprising an equivalent amount of 3α-OH-5β-pregnane-20-one in an unencapsulated SBE-β-CD solution. For example, by orally administering a composition disclosed herein, the serum level of 3α-OH-5β-pregnane-20-one in a subject can be increased by at least about 10% when compared to orally administering a composition comprising an equivalent amount of 3α-OH-5β-pregnane-20-one in an unencapsulated SBE-β-CD solution.

[0101] In a composition administered to a subject to treat a CNS disorder, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one can vary. In one example, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one in a composition or oral dosage form is greater than one or more of the following fill amounts: 0.0001wt%, 0.001wt%, 0.01wt%, 0.1wt%, 0.5wt%, 1.0wt%, 2.0wt%, 5.0wt%, 10.0wt%, 15.0wt%, 20.0wt%, 30.0wt%, 40wt%, 50wt% or a combination thereof. In another example, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one can be present in an amount of about 0.0001wt% to about 10wt% of a composition or oral dosage form. In another example, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be present in an amount of about 10wt% to about 20wt%. In another example, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be present in an amount of about 20wt% to about 30wt%. In a further example, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be present in an amount of about 30wt% to about 40wt%. In yet another example, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be present in an amount of about 40wt% to about 50wt%. In another example, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be present in an amount of 10wt% to about 40wt% or 3wt% to 10wt%. In one aspect, the compositions and methods of the present invention include 3α-OH-5β-pregnane-20-one in a form that results in rapid release (e.g., at least 40% of the 3α-OH-5β-pregnane-20-one is released after 15 minutes when measured using a USPI Type II dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate). At least one of the following: substantially solubilized, partially solubilized, substantially unsolubilized, substantially crystalline, partially crystalline, substantially non-crystalline, amorphous, solid, dispersion, and eutectic mixture.

[0102] As used herein, "additive" refers to an agent that can completely or partially dissolve or solubilize 3α-OH-5β-pregnane-20-one in a pharmaceutical composition. On the one hand, a wide variety of additives can be used to completely or partially solubilize 3α-OH-5β-pregnane-20-one in a pharmaceutical composition to provide a therapeutically effective level of 3α-OH-5β-pregnane-20-one to improve CNS disorders.

[0103] Therapeutically effective amounts of 3α-OH-5β-pregnane-20-one can be combined with a variety of pharmaceutically acceptable additives to provide an amount of 3α-OH-5β-pregnane-20-one sufficient to treat CNS depression when administered to a subject. In some embodiments, a variety of additives can be used to fully or partially solubilize or disperse 3α-OH-5β-pregnane-20-one in a pharmaceutical composition to provide therapeutically effective levels of 3α-OH-5β-pregnane-20-one to treat CNS disorders. Examples of suitable additives may include, but are not limited to: (i) tocopherol (e.g., vitamin E) or its derivatives; (ii) fatty acids or their salts; (iii) glycerol fatty acid esters; (iv) PEG glycerol esters 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 oils, such as omega fatty acids, fish oil, linseed oil, algae oil, etc., or combinations thereof.

[0104] Examples of suitable solubilizers may include, but are not limited to, tocopherol or its derivatives, fatty acids or their salts, glycerol fatty acid esters, PEG glycerides of fatty acid esters, polyglycerol fatty acid esters, triglycerides, hydrogenated polyoxylated vegetable oils or glycerides, propylene glycol fatty acid esters, vegetable oils, and sterols or their derivatives.

[0105] On the one hand, vitamin E or its derivatives may include, but are not limited to: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol acetate, tocopherol linoleate, tocopherol succinate, tocotrienols (α-, β-, γ- or δ-), tocosolone or TPGS (PEG derivative of α-tocopherol), etc., or a combination thereof.

[0106] In one embodiment, the fatty acid or its salt includes but is not limited to caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linoelaidic acid, sodium caproate, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate, sodium oleate, sodium stearate, sodium lauryl sulfate, sodium lauryl sarcosinate, dioctyl sodium sulfosuccinate, sodium cholate and sodium taurocholate.

[0107] On the other hand, glyceryl fatty acid esters may include, but are not limited to, glyceryl monooleate, glyceryl monooleate / linoleate, glyceryl monolinoleate, glyceryl ricinoloeate, glyceryl monolaurate, glyceryl monopalmitate, glyceryl monostearate, glyceryl mono / dioleate, glyceryl palmitate / stearate, glyceryl acetate, glyceryl laurate, glyceryl citrate / lactic / oleic / linoleate, glyceryl caprylate, glyceryl caprylate / caprate, glyceryl dicaprylate / dicaprate, mono / diacetylated monoglycerides, glyceryl monostearate, glyceryl dilaurate, glyceryl dioleate, the like, or combinations thereof.

[0108] In yet another aspect, the PEG glyceryl esters of fatty acid esters may include, but are not limited to, PEG fatty acid monoesters, PEG glyceryl fatty acid esters, PEG fatty acid diesters, PEG fatty acid monoester / diester mixtures, PEG triglycerides of fatty acid esters, and the like, or combinations thereof. PEG glyceryl fatty acid esters may 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, and the like, or combinations thereof. PEG fatty acid monoesters may include, but are not limited to, esters of caprylic acid, capric acid, lauric acid, oleic acid, and stearic acid, and the like, or combinations thereof. Examples of PEG fatty acid monoesters can include 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) monococonutate, etc., or a combination thereof. PEG fatty acid diesters may 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, or the like, or a combination thereof. PEG fatty acid monoester / diester mixtures may include, but are not limited to, PEG caprylate / caprate, PEG mono / dicaprylate, PEG mono / dicaprate, PEG mono / dilaurate, PEG mono / dioleate, and PEG mono / distearate, or the like, or a combination thereof. PEG triglycerides of fatty acid esters may include, but are not limited to, lauroyl polyoxylglycerides, stearoyl polyoxylglycerides, oleoyl polyoxylglycerides, linoleoyl polyoxylglycerides, lauroyl polyoxylglycerides, caprylocaproyl polyoxylglycerides, and behenoyl polyoxylglycerides, or the like, or a combination thereof.

[0109] In another aspect, the polyglycerol fatty acid esters may include, but are not limited to, polyglycerol (2,3,4,6,10) oleate, polyglycerol (2,3,4,6,10) dioleate, polyglycerol (2,3,4,6,10) trioleate, polyglycerol (2,3,4,6,10) laurate, polyglycerol (2,3,4,6,10) dilaurate, polyglycerol (2,3,4,6,10) trilaurate, polyglycerol (2,3,4,6,10) stearate, polyglycerol (2,3,4,6,10) distearate, polyglycerol (2,3,4,6,10) tristearate, polyglycerol (2,3,4,6,10) mono / dioleate, polyglycerol (3,6,10) caprate, polyglyceryl (3,6,10) dicaprate, polyglyceryl (3,6,10) tricaprate, 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 / dioleate, polyglyceryl (3,6,10) caprylate, polyglyceryl (3,6,10) polycaprylate, polyglyceryl (3,6,10) caprate, polyglyceryl (3,6,10) polycaprylate and polyglyceryl (3,6,10) caprylate / caprate, etc., or combinations thereof.

[0110] On the other hand, triglycerides may include, but are not limited to, glyceryl tricaprylate, glyceryl tricaprylate / tricaprate, glyceryl tricaprylate / tricaprate / trisuccinate, glyceryl trioleate, glyceryl tristearate, glyceryl trilaurate, medium-chain natural oils, and the like, or combinations thereof.

[0111] In another aspect, hydrogenated polyoxy vegetable oil or glyceride may include, but is not limited to, castor oil or hydrogenated castor oil, or edible vegetable oil, such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil, peppermint oil, coconut oil, sunflower seed oil or almond oil, or a combination thereof. Polyoxyl groups may include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol, or a combination thereof. Examples of hydrogenated polyoxylated 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 glycerides (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 glycerides (CAPRYLCAPROYL MACROGOL GLYCERIDES), PEG-6 caprylic / capric glycerides (SOFTIGEN 767), PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (LABRAFIL M.2125CS), PEG-6 almond oil (LABRAFIL M 1966CS), PEG-6 apricot oil (LABRAFIL M1944CS), PEG-6 olive oil (LABRAFIL M 1980CS), PEG-6 peanut oil (LABRAFIL M 1969CS), PEG-6 hydrogenated palm kernel oil (LABRAFIL M2130 BS), PEG-6 palm kernel oil (LABRAFIL M 2130CS), PEG-6 triolein (LABRAFIL M 2735CS), PEG-8 corn oil (LABRAFIL WL 2609BS), PEG-20 corn glycerides (CROVOL M40) and PEG-20 almond glycerides (CROVOL A40), etc., or a combination thereof.

[0112] In one aspect, the propylene glycol fatty acid esters can include, but are not limited to, propylene glycol monolaurate (Propylene glycol monolaurate FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (MYVEROL P-06), propylene glycol dicaprylate / dicaprate (CAPTEX 200) and propylene glycol dioctanoate (CAPTEX 800), propylene glycol monocaprylate (CAPRYOL 90, NIKKOLSefsol 218), propylene glycol myristate, propylene glycol monostearate, propylene glycol ricinolate, propylene glycol isostearate, propylene glycol caprylate / caprate, propylene glycol dioleate, propylene glycol distearate, propylene glycol dilaurate, propylene glycol dicaprylate, and propylene glycol dicaprate, or the like, or combinations thereof.

[0113] On the other hand, vegetable oils can include, but are not limited to, corn oil, olive oil, peanut oil, coconut oil, peppermint oil, sunflower oil, castor oil, safflower oil, borage oil, cottonseed oil, soybean oil, palm kernel oil, almond oil, almond oil, omega-3 oils, etc., or combinations thereof.

[0114] In one aspect, sterols or derivatives thereof may include, but are not limited to, cholesterol, sitosterol, lanosterol, phytosterol, PEG derivatives thereof, etc., or combinations thereof. In various aspects, sterols or derivatives thereof may be hydrophilic or lipophilic. Examples of hydrophilic sterols include, but are not limited to, lanosterol PEG-24 cholesterol ether (e.g., SOLULAN C-24, AMERCHOL), PEG-30 soybean sterol (e.g., NIKKOL BPS-30, from Nikko), PEG-25 phytosterol (e.g., NIKKOL BPSH-25, from Nikko), PEG-30 cholesterol (e.g., NIKKOL DHC, from Nikko). Examples of lipophilic sterol surfactants are cholesterol, sitosterol, plant sterols (e.g., GENEROL series from Henkel), PEG-5 soy sterol (e.g., NIKKOL BPS-S from Nikko), PEG-10 soy sterol (e.g., NIKKOL BPS-10 from Nikko), PEG-20 soy sterol (e.g., NIKKOL BPS-20 from Nikko), etc., or combinations thereof.

[0115] In one embodiment, the additive may be a substance that can be added to the pharmaceutical preparation to enhance the release, separation or dispersion of the particles, or to enhance the dissolution and further absorption of the particles into the body. Examples of the additive may include a lipophilic additive when its HLB value is 10 or less, or a hydrophilic additive when its HLB value is greater than 10.

[0116] In one aspect, the pharmaceutically acceptable additives may include hydrophilic additives, lipophilic additives, or a combination thereof.

[0117] For example, lipophilic additives may include, but are not limited to, mono- and diglycerides of fatty acids; reaction mixtures of alcohols or polyols with various natural and / or hydrogenated 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 2125CS), PEG-6 almond oil (e.g., LABRAFIL M 1966CS), PEG-6 apricot oil (e.g., LABRAFIL M 1944CS), PEG-6 olive oil (e.g., LABRAFIL M 1980CS), PEG-6 peanut oil (e.g., LABRAFIL M 1969CS), PEG-6 hydrogenated palm kernel oil (e.g., LABRAFIL M 2130BS), PEG-6 palm kernel oil (e.g., LABRAFIL M 2130CS), PEG-6 triolein (e.g., LABRAFILM 2735CS), PEG-8 corn oil (e.g., LABRAFIL WL 2609BS), PEG-20 corn glycerides (e.g., CROVOLM40), PEG-20 almond glycerides (e.g., CROVOL A40); lipophilic polyoxyethylene-polyoxypropylene block copolymers (e.g., Pluronic L92, L101, L121, etc.), propylene glycol fatty acid esters, such as propylene glycol monolaurate (e.g., Propyleneglycol monolaurate FCC), propylene glycol ricinoleate (e.g., Propymuls), propylene glycol monooleate (e.g., MYVEROL P-06), propylene glycol dicaprylate / dicaprate (e.g., CAPTEX 200) and propylene glycol dicaprylate (e.g., CAPTEX 800), propylene glycol monocaprylate (e.g., CAPRYOL 90); propylene glycol oleate (e.g., LUTROL OP2000); 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; mixtures of propylene glycol esters with glycerol esters, such as a mixture consisting of the oleate esters of propylene glycol and glycerol (e.g., ARLACEL 186);Sterols and sterol derivatives such as cholesterol, sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soy sterol, PEG-10 soy sterol, PEG-20 soy sterol, etc.; palmitoyl stearic acid glyceryl, stearic acid glyceryl, distearic acid glyceryl, monostearic acid glyceryl, or a combination thereof; sorbitan fatty acid esters such as sorbitan monolaurate (e.g., ARLACEL 20), sorbitan monopalmitate (e.g., SPAN-40), sorbitan monooleate (e.g., SPAN-80), sorbitan monostearate and sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate, etc.; fatty acids, such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidylcholine, bile salts, etc., and mixtures thereof. It is important to note that certain lipophilic additives can also act as solubilizing agent components of the composition and oral dosage forms. In some cases, the additives used in the composition and oral dosage forms can be lipophilic surfactants. ;

[0118] In one embodiment, the pharmaceutically acceptable additive may be free of polysorbate 80. In another embodiment, the pharmaceutically acceptable additive may be free of cyclodextrin. In yet another embodiment, the pharmaceutically acceptable additive may be free of edible oil.

[0119] Pharmaceutically acceptable additives may also include hydrophilic additives. On the one hand, hydrophilic additives may include, without limitation, nonionic surfactants, ionic surfactants, zwitterionic surfactants, etc., or combinations thereof. Suitable hydrophilic surfactants may include, but are not limited to: alcohol-oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulfates, dioctyl sulfosuccinate salts; polyethylene glycol fatty acid esters; polyethylene glycol fatty acid monoesters and diester mixtures; polysorbates; polyethylene glycol derivatives of tocopherols, etc., or combinations thereof. Unless expressly specified, two or more hydrophilic additives from the same or different classes may be referred to as hydrophilic surfactants. In one aspect, non-limiting examples of hydrophilic surfactants may include PEG-8 caprylic / capric glycerides, 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 monoester and diester mixture, polysorbate 80, polysorbate 20, polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterol fatty acid esters, poloxamers, etc., or combinations thereof. In some cases, the hydrophilic additives used in the composition and oral dosage form may be hydrophilic surfactants.

[0120] Pharmaceutically acceptable additives can be combined with additives of various amount ranges or otherwise include additives of various amount ranges. For example, lipophilic additives and hydrophilic additives can be present in an amount such that the amount (wt%) of the lipophilic additive is greater than or equal to the amount (wt%) of the hydrophilic additive. On the other hand, lipophilic additives and hydrophilic additives can be present in an amount 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. On the other hand, lipophilic additives and hydrophilic additives can be present in an amount 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. On the other hand, lipophilic additives and hydrophilic additives can be present in an amount 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.

[0121] In one embodiment, the compositions and oral dosage forms may include pharmaceutically acceptable additives including at least one of alpha-tocopherol, glyceryl monocaprylate, glyceryl caprylocaprate, propylene glycol monolaurate, PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil, and combinations thereof, which, when orally administered to a subject, provide sufficient levels of 3α-OH-5β-pregnane-20-one in an amount sufficient to treat a CNS disorder.

[0122] In certain instances, the lipophilic additive may comprise from about 0.6% w / w to about 95% w / w, from about 5% w / w to about 70% w / w, from about 10% w / w to about 60% w / w, from about 15% w / w to about 55% w / w, from about 20% w / w to about 50% w / w, from about 30% w / w, from about 35% w / w, from about 40% w / w, from about 45% w / w, from about 50% w / w, from about 55% w / w, from about 60% w / w, from about 65% w / w, from about 70% w / w, from about 75% w / w, from about 80% w / w, from about 85% w / w, from about 90% w / w, or from about 95% w / w of any pharmaceutical composition described herein. In some examples, the lipophilic additive may comprise 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.

[0123] In some examples, the additive can be a surfactant. The surfactant in the present invention can be any compound containing a polar or charged hydrophilic portion and a non-polar hydrophobic (lipophilic) portion; that is, the surfactant compound must be amphiphilic. Within 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, a suitable hydrophilic surfactant will have an HLB value greater than about 10, while a suitable hydrophobic surfactant will have an HLB value less than about 10. When selecting specific hydrophobic and hydrophilic surfactants, the specific hydrophobic therapeutic agent to be used in the composition should be kept in mind, as well as the polarity range suitable for the selected therapeutic agent. Keeping these general principles in mind, a very wide range of surfactants are suitable for use in the present invention.

[0124] In one embodiment, pharmaceutically acceptable additives may optionally include at least one surfactant. When present, surfactants may account for about 0.5wt% to about 50wt% of oral solid dosage forms. In one embodiment, surfactants may account for about 2wt% to about 50wt% of oral solid dosage forms. In one embodiment, surfactants may account for about 5wt% to about 27wt% of oral solid dosage forms. In one embodiment, surfactants may be hydrophilic surfactants. Hydrophilic surfactants have surface activity characteristics and may have an HLB value of 10 or more. Hydrophilic surfactants may be anionic or nonionic surfactants. Non-limiting examples of hydrophilic surfactants that may be included in oral solid dosage forms include sodium lauryl sulfate, polysorbate, docusate sodium, polyoxy castor oil, polyoxy hydrogenated castor oil, poloxamer, lecithin or its derivatives and mixtures thereof at least one or combination.

[0125] Poloxamer stands for polyethylene-polyoxypropylene block copolymer and can be any of the following formulas: HO(C <2> H <4> O) (C<3>H<6>O) (C <2> H <4> O) H, where "a" and "b" represent the number of polyoxyethylene and polyoxypropylene units, respectively. The compounds are listed by common name with the corresponding "a" and "b" values. Poloxamers can be represented by (C <3> H <6> O) (C <2> H <4> O) H(HLB)), such as (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.

[0126] In one embodiment, the oral compositions described herein may be free of any modulators that slow the release rate of 3α-OH-5β-pregnane-20-one in aqueous media or in vivo.

[0127] In one embodiment, the composition is at least one of non-aqueous, non-liquid, and solid.

[0128] In another embodiment, the composition is a non-aqueous composition filled in a capsule or tablet dosage form.

[0129] In another embodiment, the composition is a non-aqueous liquid composition filled in a capsule dosage form.

[0130] In another embodiment, the oral solid dosage form (one or more) described herein may not have a synchronous release characteristic of 3α-OH-5β-pregnane-20-one and a solubilizer in an aqueous medium so that the dosage form can release more than 90% of 3α-OH-5β-pregnane-20-one within 4 hours after administration or in vitro testing. In other words, 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 be different from the release rate of the additive.

[0131] Other ingredients Although not always necessary, the compositions of the present invention may also include one or more additional components, i.e., functional ingredients. Classes of ingredients that may be present in the compositions include, but are not limited to, solvents, adsorbents, acids, adjuvants, anti-caking agents, glidants, anti-adhesive agents, defoamers, anticoagulants, antimicrobial agents, antioxidants, anti-inflammatory agents, astringents, disinfectants (preservatives, antiseptics), bases, adhesives, chelating agents, sequestrants, coagulants, coating agents, colorants, dyes, pigments, compatibilizers, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, drying agents, The composition includes but is not limited to: agents, dehydrating agents, diluents, dispersants, emollients, emulsifiers, encapsulating agents, enzymes, fillers, extenders, taste masking agents, flavoring agents, essences, gelling agents, curing agents, hardeners, wetting agents, lubricants, moisturizers, buffers, pH control agents, plasticizers, soothing agents, demulcents, retarder, diffusants, stabilizers, suspending agents, sweeteners, disintegrants, thickeners, consistency regulators, surfactants, opacifiers, polymers, preservatives, anti-gelling agents, rheology control agents, UV absorbers, tonicifiers and viscosity regulators. One or more ingredients from any particular category and one or more ingredients from different categories may be present in the composition. Specific examples of ingredients and their use levels are known in the art.

[0132] If present in an effective amount, other ingredients such as co-solvents can partially solubilize 3α-OH-5β-pregnane-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, butylene glycol, glycerol or its derivatives, glycerol, diglycerol, polyglycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, triacetin, trimethyl citrate, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, or a combination thereof.

[0133] In one aspect, the composition can be formulated as a solution, emulsion, liquid, semi-liquid, suspension, semi-solid, spray, emulsion, dispersion, granules, syrup, suspension, capsule, tablet, chewable or drink, etc., or a combination thereof. In one example, the composition can be diluted 10 times or 100 times with aqueous bile salts including simulated gastric or intestinal media or water (e.g., FeSSIF (see "FaSSIF / FeSSIF / FaSSGF" on the biorelevant.com website, or FeSSIF media known in the art) to form a dispersion, emulsion, solution or micellar solution. In another example, the composition can still be substantially solubilized after being diluted 10 times or 100 times with aqueous bile salts including simulated gastric or intestinal media or water. In another example, the composition can form a dispersion having an average dispersion particle size of less than 300 nm or a UV absorbance of less than 5.0 units when measured at 450 nm after being diluted 10 times or 100 times with aqueous bile salts including simulated gastric or intestinal media or water. Figure 3 Graphs showing exemplary comparative dispersibility of disclosed oral compositions including 3α-OH-5β-pregnane-20-one (Formulations #9 and #10 in Table G) after aqueous dilution (100-fold) with pH 6.8 simulated intestinal fluid according to USP 26, compared to the dispersibility of compositions including 3α-OH-5β-pregnane-20-one solubilized in medium chain triglycerides (e.g., MIGLYOL 812; Formulation #7 in Table G) and in canola oil (Formulation #8 in Table G). Figure 3 As shown, formulations #7 and #8 were not dispersed or solubilized in a 100-fold diluted aqueous medium (the oily contents on the surface were completely separated from the aqueous medium), while the disclosed inventive compositions (formulations #9 and #10) were well dispersed. Due to phase separation, the UV absorbance measured at 450 nm for formulations #7 and #8 could not be measured, while the measured values ​​of 1.3 Abs and 3.2 Abs were observed for formulations #9 and #10, respectively (for Abs, see "An Introduction to the Fundamentals of Atomic Absorption Spectroscopy (AAS)" on the agilent.com website).

[0134] In one embodiment, the 3α-OH-5β-pregnane-20-one in the composition may include a completely or partially crystalline form of a treated, 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 3α-OH-5β-pregnane-20-one active substance (active) in the additive. In another aspect, the 3α-OH-5β-pregnane-20-one of a specified weight percentage in the composition or dosage form may be in a non-crystalline form (e.g., an amorphous solid, solution, emulsion, liquid, semi-liquid, etc.). In one example, at least about 50% of the 3α-OH-5β-pregnane-20-one in the composition may be in a non-crystalline state. In another example, at least about 65% of the 3α-OH-5β-pregnane-20-one in the composition may be in a non-crystalline state. In yet another example, at least about 80% of the 3α-OH-5β-pregnane-20-one in the composition may be in a non-crystalline state. In another example, at least about 95% of the 3α-OH-5β-pregnane-20-one in the composition can be in a non-crystalline state.

[0135] In one embodiment, the oral composition of the present invention may be a crystalline solid form of 3α-OH-5β-pregnane-20-one substantially treated with at least one surfactant.

[0136] As used herein, the term "treated / processed" may be applicable to a crystalline form of an active agent or to an amorphous form of an active agent. In addition, as used herein, when applicable to a crystalline form of an active agent, the term "treated / processed" refers to a process that has been performed by processing the active agent into at least one form of an active agent that is ground, sieved, milled, micronized, or nanoscale, while when applicable to an amorphous form of an active agent, the term "treated / processed" is exemplified by processing the active agent into at least one form of an active agent that is amorphous and fully solubilized. As used herein, the term "untreated" is defined as an original ("as is") or unprocessed active agent-exemplified by not micronized or not milled. This treatment that reduces the particle size of the active agent helps to increase the release rate, dissolution rate, and bioavailability of the active agent. In one example, the initial powder of 3α-OH-5β-pregnane-20-one to be used in the composition of the present invention is treated, such as ground, sieved, milled, micronized, nanosized, amorphous or fully solubilized, before being formulated in the composition. Further, for example, the "micronization" treatment can provide a 3α-OH-5β-pregnane-20-one particle size distribution in the range of D50 = ~6 μm and D90 = ~20 μm. Still further, for example, the "nanosized" treatment can provide a 3α-OH-5β-pregnane-20-one particle size distribution in the range of 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 a specified value. D50 = 50% of the particle population in the composition has a size below a specified value. D90 = 90% of the particle population in the composition has a size below a specified value.

[0137] In one embodiment, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnane-20-one in the present invention may be in the range of D90=about 250nm to about 250μm. In one aspect, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnane-20-one in the present invention may be less than D90=about 250μm, such as any one of the following: D90=about 250nm, D90=about 300nm, D90=about 350nm, D90=about 400nm, D90=about 500nm, D90=about 750nm, D90=about 1μm, D90=about 2 In another embodiment, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnane-20-one in the present invention may be less than D90=about 75 μm.

[0138] In one embodiment, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnane-20-one in the present invention may be in the range of D50=about 150nm to about 100μm. In one aspect, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnane-20-one in the present invention may be less than D50=about 100μm, such as any one of the following: D50=about 100nm, D50=about 150nm, D50=about 200nm, D50=about 250nm, D50=about 300nm, D50=about 350nm, D50=about 400nm, D50=about 500nm, D50=about 600nm, D50=about 700nm, D50=about 800nm, D50=about 900nm, D50=about 1000nm, D50=about 15 ... In another embodiment, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnane-20-one in the present invention can be any size between D50 = about 150 nm and about 50 μm.

[0139] In one embodiment, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnan-20-one in the present invention may be in the range of D10=about 50 nm to about 50 μm. In one aspect, the particle size distribution of the treated 3α-OH-5β-pregnane-20-one crystalline form of the present invention can be less than D10=about 50 μm, such as any one of the following: 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 D10 size between the above values. In another embodiment, the particle size distribution of the treated crystalline form of 3α-OH-5β-pregnane-20-one in the present invention may be greater than D10 = about 1 μm.

[0140] In another aspect, a specified weight percentage of 3α-OH-5β-pregnane-20-one in a composition or dosage form can be solubilized. In one example, about 50% to about 100% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized. In another example, about 50% to about 65% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized. In yet another example, about 65% to about 85% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized. In another example, about 85% to about 100% of the 3α-OH-5β-pregnane-20-one in the composition can be solubilized in a variety of additives that are substantially free of SBE-β-CD.

[0141] In another embodiment, an oral pharmaceutical composition or oral dosage form may include an amount of 3α-OH-5β-pregnane-20-one that provides the desired GABAA receptor binding efficiency in a therapeutically effective amount that can treat CNS disorders when administered to a subject. For example, in one embodiment, the composition or oral dosage form may include a variety of pharmaceutically acceptable additives that maximize or otherwise accelerate the absorption of 3α-OH-5β-pregnane-20-one when administered to a subject.

[0142] 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-pregnane-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-pregnane-20-one that, when orally administered to a subject, provides greater than about 4.25 ng mL when measured using liquid chromatography or gas chromatography combined with mass spectrometry (e.g., LC-MS, LC-MSMS, or GC-MS). -1 3α-OH-5β-pregnane-20-one C max , greater than about 22.9 ng hmL -1 AUC of 3α-OH-5β-pregnane-20-one 0-t , 3α-OH-5β-pregnane-20-one C for about 1 hour or less max or about 2.5h or more than about 2.5h of 3α-OH-5β-pregnane-20-one T max .

[0143] Oral pharmaceutical compositions comprising 3α-OH-5β-pregnane-20-one can be administered as oral dosage forms (such as solid, liquid, or partially or completely solubilized oral dosage forms) conventionally intended to substantially release and deliver 3α-OH-5β-pregnane-20-one in the gastrointestinal tract other than the mouth / buccal cavity.

[0144] In certain embodiments, the oral pharmaceutical composition comprising 3α-OH-5β-pregnane-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, beads, granules, pellets, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets, and combinations thereof.

[0145] In certain embodiments, the oral pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one can be administered as a liquid (e.g., solution, suspension, drink, etc.) or partially or completely solubilized in a gelatin or non-gelatin capsule as known in the art. The gelatin capsule can be a soft gelatin capsule or a hard gelatin capsule or any other capsule. The hard gelatin capsule can be a two-piece, standard gelatin capsule, which generally includes a first bottom portion and a second top capsule portion. The soft gelatin capsule can be a two-piece capsule in which the two portions are sealed together, or it can be a one-piece, substantially airtightly sealed capsule.

[0146] In certain embodiments, the pharmaceutical composition can be administered to a subject in need of 3α-OH-5β-pregnane-20-one for CNS disorders. In specific embodiments, the amount of 3α-OH-5β-pregnane-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-pregnane-20-one.

[0147] In other embodiments, 3α-OH-5β-pregnane-20-one can be administered to a subject (e.g., males and females) in need of an oral pharmaceutical composition of the present disclosure such that the subject receives a therapeutically effective amount of 3α-OH-5β-pregnane-20-one from the oral composition. In one embodiment, the range of 3α-OH-5β-pregnane-20-one in the oral composition is from about 50 mg to about 450 mg, as well 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 350 mg, about 400 mg, about 450 mg, or any amount within the indicated range.

[0148] In one embodiment, the amount of 3α-OH-5β-pregnane-20-one in the oral pharmaceutical composition of the present invention can range from about 0.6% to about 50% by weight of the composition. In a further embodiment, an oral pharmaceutical composition having the following weight % amounts of 3α-OH-5β-pregnane-20-one can be administered to a subject in need thereof: 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 indicated values.

[0149] In certain embodiments, the oral pharmaceutical composition of the present disclosure including 3α-OH-5β-pregnane-20-one can be administered once daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated. In other embodiments, the oral pharmaceutical composition of the present disclosure can be administered twice daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated. In yet further embodiments, the oral pharmaceutical composition of the present disclosure can be administered equal to or more than three times daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated.

[0150] The compositions disclosed herein may have a daily dose of varying amounts. On the one hand, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be administered orally, once to twelve times a day. In one example, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include a daily dose of about 50 mg to about 1350 mg. In another example, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include a daily dose of about 200 mg to about 900 mg. In a further example, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include a daily dose of about 10 mg to about 450 mg. In yet another aspect, the dose of 3α-OH-5β-pregnane-20-one may be administered in a dosage form including one to four capsules or one-half to four tablets.

[0151] In one embodiment, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include any of the following daily doses: 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 indicated values.

[0152] In other aspects, 3α-OH-5β-pregnane-20-one can be administered to a subject (e.g., males and females) to provide a therapeutically effective level of 3α-OH-5β-pregnane-20-one. In one example, the total daily dose of 3α-OH-5β-pregnane-20-one in the oral composition can range from 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.

[0153] In one aspect, the number of dosage units (eg, capsules, tablets, etc.) per dose of 3α-OH-5β-pregnane-20-one can range from one-half to four units, such as one-half, one, two, three or four units.

[0154] In order to receive a therapeutic target level of 3α-OH-5β-pregnane-20-one per single dose, in some aspects, 3α-OH-5β-pregnane-20-one can be administered to a subject in an amount of 50 mg to 450 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, or any amount within the range of about 50 mg to about 450 mg.

[0155] In one aspect, the amount of 3α-OH-5β-pregnane-20-one can be orally administered once daily in any of the recited amounts until the CNS disease or condition is reduced or substantially eliminated. In one aspect, the oral composition can be administered at any time in the morning, afternoon, evening, and before bedtime. In another aspect, the oral composition can be administered at bedtime or at any time in the range of about 5 hours, about 4 hours, about 3 hours, about 2 hours, and about 1 hour before bedtime.

[0156] In other aspects, oral pharmaceutical compositions and / or oral dosage forms may be administered twice daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated. The oral composition may be administered in the morning and evening, or may be administered at intervals of 12 hours. In yet further aspects, oral pharmaceutical compositions or oral dosage forms may be administered more than or equal to three times daily in any of the described amounts until the disease or condition is reduced or substantially eliminated. On the one hand, the oral composition or dosage form may be administered once every 8 hours, every 6 hours, every 4 hours, every 3 hours, every 2 hours, or every 1 hour.

[0157] In one aspect, the 3α-OH-5β-pregnane-20-one in the composition of the present invention can be orally administered to a subject for a specified duration of about one day to about three months according to a dosage regimen. 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 reduced 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 reduced or substantially eliminated. In another aspect, the oral drug can be administered for 1 month, 2 months or 3 months until the disease or condition is reduced or substantially eliminated.

[0158] On the one hand, oral pharmaceutical compositions or dosage forms can be used with or without titration. On the one hand, oral pharmaceutical compositions can be up-titrated to 25%, 33%, 50%, 100%, 150%, 200%, 300%, 400% or 500% more than the initial (before titration) dose. On the other hand, oral pharmaceutical compositions can be down-titrated to 75%, 50% or 25% of the initial (before titration) dose. On the one hand, oral pharmaceutical compositions can be used with a fixed dose or a dose consistent with the initial dose.

[0159] In one aspect, an oral pharmaceutical composition or dosage form can be titrated to a subsequent 3α-OH-5β-pregnane-20-one dose based on the subject's pharmacokinetic or pharmacodynamic response to the initial dose. In one example, the composition or oral dosage form can be orally administered at an initial 3α-OH-5β-pregnane-20-one dose of about 50 mg to about 1400 mg and titrated to a maintenance 3α-OH-5β-pregnane-20-one dose of about 25% to about 400% of the initial dose. In one example, the 3α-OH-5β-pregnane-20-one dose can be increased or decreased from about 0.25 times the initial 3α-OH-5β-pregnane-20-one dose to about 4 times to achieve a 3α-OH-5β-pregnane-20-one maintenance dose.

[0160] On the other hand, oral pharmaceutical compositions or dosage forms can be administered with or without food (such as meals, snacks, appetizers or drinks). In one example, administration without food can be during a fasting period of the subject. Food can include various forms of food, including the following foods: fat-free and no calories; fat-free and low in calories; fat-free and medium in calories; fat-free and high in calories; low-fat and low in calories; low-fat and medium in calories; low-fat and high in calories; medium-fat and low in calories; medium-fat and medium in calories; medium-fat and high in calories; high-fat and low in calories; high-fat and medium in calories; and high-fat and high in calories. On the one hand, administration with food can be any of the following administrations: not with high-fat food; with a meal containing at least about 5% of calories from fat; with a meal containing less than about 20% of calories from fat; with a meal having a calorie content of about 20% to about 35% from fat; and with a meal having a calorie content of about 35% to about 60% from fat. The amount of fat and calories may be categorized under the food regulations of the Federal Food, Drug, and Cosmetic Act and its amendments.

[0161] In one embodiment, the composition can be formulated into an oral dosage form. The oral dosage form can be selected from: liquid, semi-liquid, semi-solid, spray, emulsion, dispersion, granule, syrup, suspension, capsule, tablet, chew, drink, etc., or a combination thereof. On the one hand, the composition can be formulated into an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnane-20-one. On the other hand, the composition can be formulated into an oral dosage form having about 50 mg to about 450 mg of 3α-OH-5β-pregnane-20-one, which, when orally administered to a subject, provides a 3α-OH-5β-pregnane-20-one C greater than about 4.25 ng / ml when measured using liquid chromatography or gas chromatography combined with mass spectrometry (e.g., LC-MS, LC-MS-MS or GC-MS). max , regardless of meal consumption.

[0162] The oral pharmaceutical composition including 3α-OH-5β-pregnane-20-one can be administered as an oral dosage form (such as a solid, liquid, or partially or completely solubilized oral dosage form) conventionally intended to release and deliver 3α-OH-5β-pregnane-20-one in large quantities in the gastrointestinal tract other than the oral cavity.

[0163] In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide a serum level of 3α-OH-5β-pregnane-20-one sufficient to treat a CNS disorder (e.g., a mean serum level of: C avg or peak serum level: C max ). In another aspect, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one in the composition can be in a form that provides a therapeutically effective serum level of 3α-OH-5β-pregnane-20-one to treat a CNS disorder in a subject after oral administration. In a further aspect, the 3α-OH-5β-pregnane-20-one in the composition disclosed herein can be in a processed form with a variety of additives, which can include at least one surfactant that provides a therapeutically effective level of 3α-OH-5β-pregnane-20-one that is effective to treat a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnane-20-one can be combined with a variety of additives that are sufficient to provide a therapeutically effective serum level of 3α-OH-5β-pregnane-20-one to treat a CNS disorder in a subject after oral administration thereof.

[0164] In another embodiment, the dosage regimens and methods of the present invention for treating CNS disorders in females include infant females, females less than 5 years old, females 5-18 years old, non-pregnant females of childbearing age (e.g., females 15-45 years old), pregnant females, females who have given birth within at least one of 1 month, 6 months and 12 months, perimenopausal females (e.g., females 45-50 years old), or postmenopausal females.

[0165] In certain embodiments, the oral pharmaceutical composition comprising 3α-OH-5β-pregnane-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, beads, granules, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets, and combinations thereof.

[0166] In certain embodiments, the oral pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one can be administered as a liquid (e.g., solution, suspension, drink, etc.) or partially or completely solubilized in a gelatin or non-gelatin capsule as known in the art. The gelatin capsule can be a soft gelatin capsule or a hard gelatin capsule or any other capsule. The hard gelatin capsule can be a two-piece, standard gelatin capsule, which generally includes a first bottom portion and a second top capsule portion. The soft gelatin capsule can be a two-piece capsule in which the two portions are sealed together, or it can be a one-piece, substantially airtightly sealed capsule.

[0167] In certain embodiments, the pharmaceutical composition can be administered to a subject in need of 3α-OH-5β-pregnane-20-one for CNS disorders. In specific embodiments, the amount of 3α-OH-5β-pregnane-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-pregnane-20-one.

[0168] In other embodiments, 3α-OH-5β-pregnane-20-one can be administered to a subject (e.g., males and females) in need of an oral pharmaceutical composition of the present disclosure such that the subject receives a therapeutically effective amount of 3α-OH-5β-pregnane-20-one from the oral composition. In one embodiment, the range of 3α-OH-5β-pregnane-20-one in the oral composition is from about 50 mg to about 600 mg, as well 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 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, or any amount within the indicated range.

[0169] In order to receive the desired therapeutic level of 3α-OH-5β-pregnane-20-one per dose, in certain embodiments, an oral pharmaceutical composition of the invention described herein may be administered to a person in need thereof, comprising 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 indicated values.

[0170] In one embodiment, the amount of 3α-OH-5β-pregnane-20-one in the oral pharmaceutical composition of the present invention can range from about 0.6% to about 50% by weight of the composition. In a further embodiment, an oral pharmaceutical composition having the following weight % amounts of 3α-OH-5β-pregnane-20-one can be administered to a subject in need thereof: 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 indicated values.

[0171] In certain embodiments, the oral pharmaceutical composition of the present disclosure including 3α-OH-5β-pregnane-20-one can be administered once daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated. In other embodiments, the oral pharmaceutical composition of the present disclosure can be administered twice daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated. In yet further embodiments, the oral pharmaceutical composition of the present disclosure can be administered equal to or more than three times daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated.

[0172] The compositions disclosed herein may have a daily dose of varying amounts. On the one hand, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may be administered orally, once to twelve times a day. In one example, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include a daily dose of about 150 mg to about 750 mg. In another example, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include a daily dose of about 200 mg to about 1400 mg. In a further example, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include a daily dose of about 50 mg to about 500 mg. In a further example, a daily dose of 3α-OH-5β-pregnane-20-one may be a fixed dose of about 50 mg to about 500 mg. In a further example, a daily dose of 3α-OH-5β-pregnane-20-one may be a fixed dose of about 50 mg to about 1400 mg. In a further example, the daily dose of 3α-OH-5β-pregnane-20-one can be a fixed dose of about 225 mg to about 900 mg. In a further example, the daily dose of 3α-OH-5β-pregnane-20-one can be a fixed dose of about 225 mg to about 450 mg. In yet another aspect, the dose of 3α-OH-5β-pregnane-20-one can be administered in a dosage form comprising one to four capsules, one-half to four tablets, or any combination thereof.

[0173] In one embodiment, a daily dose of a therapeutically effective amount of 3α-OH-5β-pregnane-20-one may include any of the following: 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 indicated values.

[0174] In other aspects, 3α-OH-5β-pregnane-20-one can be administered to a subject (e.g., males and females) to provide a therapeutically effective level of 3α-OH-5β-pregnane-20-one. In one example, the total daily dose of 3α-OH-5β-pregnane-20-one in the oral composition can range from 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.

[0175] In one aspect, the number of dosage units (eg, capsules, tablets, etc.) per dose of 3α-OH-5β-pregnane-20-one can range from one-half to four units, such as, for example, one-half, one, two, three or four units.

[0176] In order to receive a therapeutic target level of 3α-OH-5β-pregnane-20-one per single dose, in some aspects, 3α-OH-5β-pregnane-20-one can be administered to a subject in an amount 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 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.

[0177] In one aspect, the amount of 3α-OH-5β-pregnane-20-one can be orally administered once daily in any of the recited amounts until the CNS disease or condition is reduced or substantially eliminated. In one aspect, the oral composition can be administered at any time in the morning, afternoon, evening, and before bedtime. In another aspect, the oral composition can be administered at bedtime or at any time in the range of about 5 hours, about 4 hours, about 3 hours, about 2 hours, and about 1 hour before bedtime.

[0178] In other aspects, oral pharmaceutical compositions and / or oral dosage forms may be administered twice daily in any of the above indicated amounts until the disease or condition is reduced or substantially eliminated. The oral composition may be administered in the morning and evening, or may be administered at intervals of 12 hours. In yet further aspects, oral pharmaceutical compositions or oral dosage forms may be administered more than or equal to three times daily in any of the described amounts until the disease or condition is reduced or substantially eliminated. On the one hand, the oral composition or dosage form may be administered once every 8 hours, every 6 hours, every 4 hours, every 3 hours, every 2 hours, or every 1 hour.

[0179] In one aspect, the 3α-OH-5β-pregnane-20-one in the composition of the present invention can be orally administered to a subject for a specified duration of about one day to about three months according to a dosage regimen. 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 reduced 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 reduced or substantially eliminated. In another aspect, the oral drug can be administered for 1 month, 2 months or 3 months until the disease or condition is reduced or substantially eliminated.

[0180] On the one hand, oral pharmaceutical composition or dosage form can be used under the situation of titration or non-titration.On the one hand, oral pharmaceutical composition can be titrated upward to 25%, 33%, 50%, 100%, 150%, 200%, 300%, 400% or 500% more than initial (before titration) dosage.On the other hand, oral pharmaceutical composition can be titrated downward to 75%, 50% or 25% of initial (before titration) dosage.On the one hand, oral pharmaceutical composition can be used with fixed dose or the dosage consistent with predose.

[0181] In one aspect, an oral pharmaceutical composition or dosage form can be titrated to a subsequent 3α-OH-5β-pregnane-20-one dose based on the subject's pharmacokinetic or pharmacodynamic response to the initial dose. In one example, the composition or oral dosage form can be orally administered at an initial 3α-OH-5β-pregnane-20-one dose of about 50 mg to about 1400 mg and titrated to a maintenance 3α-OH-5β-pregnane-20-one dose of about 25% to about 400% of the initial dose. In one example, the 3α-OH-5β-pregnane-20-one dose can be increased or decreased from about 0.25 times the initial 3α-OH-5β-pregnane-20-one dose to about 4 times to achieve a 3α-OH-5β-pregnane-20-one maintenance dose.

[0182] On the other hand, oral pharmaceutical compositions or dosage forms can be administered with or without food (such as meals, snacks, appetizers or drinks). In one example, administration without food can be during a fasting period of the subject. Food can include various forms of food, including the following foods: fat-free and no calories; fat-free and low in calories; fat-free and medium in calories; fat-free and high in calories; low-fat and low in calories; low-fat and medium in calories; low-fat and high in calories; medium-fat and low in calories; medium-fat and medium in calories; medium-fat and high in calories; high-fat and low in calories; high-fat and medium in calories; and high-fat and high in calories. On the one hand, administration with food can be any of the following administrations: not with high-fat food; with a meal containing at least about 5% of calories from fat; with a meal containing less than about 20% of calories from fat; with a meal having a calorie content of about 20% to about 35% from fat; and with a meal having a calorie content of about 35% to about 60% from fat. The amount of fat and calories may be classified under the food regulations of the Federal Food, Drug, and Cosmetic Act and its amendments.

[0183] In one aspect, the pharmaceutically acceptable compositions and methods described herein may be refractory patients with CNS disorders (such as depression or epilepsy) or treatment-resistant patients with unresolved symptoms who are taking a stable medication (one or more) regimen to treat CNS disorders (such as anti-epileptic drugs (AEDs) or antidepressants) and who require intermittent use of 3α-OH-5β-pregnane-20-one to control increased seizure activity (acute repetitive seizures) or acute bouts of severe depressive symptoms. In another aspect, the pharmaceutically acceptable compositions and methods described herein may be patients who are undergoing background anti-epileptic or anti-depressant therapy.

[0184] In another aspect, the pharmaceutically acceptable compositions and methods described herein may be for patients suffering from various CNS disorders such as epilepsy with anxiety or depression, depression with anxiety or psychosis, or bipolar disorder.

[0185] Also provided herein are compositions and methods for treating mood disorders or mental illnesses comorbid with epilepsy, convulsions or seizures. 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 medical conditions, treatment-resistant depression, refractory depression, suicide, 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 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), women's health disorders or conditions).

[0186] Clinical depression is also known as major depression, major depressive disorder (MDD), major depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by a pervasive and persistent low mood, accompanied by low self-esteem and a loss of interest or pleasure in normally pleasurable activities. Some people with clinical depression have trouble sleeping, lose weight, and are often irritated and angry. Clinical depression affects how an individual feels, thinks, and behaves, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty carrying out daily activities, and clinical depression may make the individual feel that life is not worth living.

[0187] Perinatal depression is depression during pregnancy. Symptoms include irritability, crying spells, feeling restless, trouble sleeping, extreme tiredness (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of separation from the baby and / or fetus, and loss of interest in activities that were previously pleasurable.

[0188] Postpartum depression (PND) is also referred to as PPD, and refers to a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, loss of libido, crying attacks, anxiety, and irritability. 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 with PND also experiences depression, or symptoms of depression, during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, a subject experiencing perinatal depression experiences an increased risk of PND.

[0189] Atypical depression (AD) is characterized by mood reactivity (e.g., abnormal anhedonia) and motivation, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or hypersomnia (somnia), a sense of heaviness in the limbs, and significant social impairment due to a hypersensitivity to perceived interpersonal rejection.

[0190] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), lack of response to pleasurable stimuli, depressed mood that is more pronounced than depression of sadness or loss, excessive weight loss, or excessive guilt. Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, specifically depressive in nature, in which the individual experiences psychotic symptoms such as delusions and hallucinations. Catatonic depression refers to a major depression involving other symptoms such as motor behavior disturbances. The individual may become silent and stuporous, and either remain motionless or show purposeless or strange movements.

[0191] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual experiences a seasonal pattern of depressive episodes during the fall or winter.

[0192] Dysthymia refers to a condition associated with unipolar depression, in which the same physical and cognitive problems are evident. Such problems are less severe and tend to last longer (e.g., at least 2 years). Double depression refers to a rather depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by major depression. Depressive personality disorder (DPD) refers to a personality disorder with depressive features. Recurrent brief depression (RBD) refers to a depressive episode that occurs approximately once a month in an individual, with each episode lasting 2 weeks or less, and generally less than 2-3 days.

[0193] Minor depression or minor depression is depression that presents with at least 2 symptoms for 2 weeks. Bipolar disorder or manic-depressive disorder causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During manic phases, individuals may feel or act unusually happy, energetic, or irritable. They often make ill-considered decisions with little regard for the consequences. The need for sleep is usually reduced. During depressive phases, there may be crying spells, poor eye contact with others, and a negative outlook on life. People with this disorder have a high risk of suicide within 20 years, more than 6%, and a 30-40% risk of self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder. Depression caused by chronic medical conditions is depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, and chronic stress. Treatment-resistant depression is a condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or counseling (psychotherapy) do not relieve depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression experience improvement in symptoms, but symptoms generally recur. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics) as well as nonpharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0194] Postoperative depression refers to feelings of depression following a surgical procedure (e.g., resulting from having to deal with the death of a person). For example, an individual may have persistent feelings of sadness or emotional emptiness, a loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness. Mood disorders associated with women's health conditions or disorders refer to mood disorders (e.g., depression) that are associated with (e.g., caused by) women's health conditions or disorders (e.g., as described herein). Suicide, suicidal ideation, suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual contemplations about suicide. The range of suicidal ideation varies widely, from brief thoughts to extensive thoughts, detailed plans, role play, and incomplete attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contacts, thinking about death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing dangerous or self-destructive things, and saying goodbye to people as if they will never be seen again. Symptoms of depression include persistent anxious or sad moods, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, physical challenges, loss of interest in pleasurable activities or hobbies, difficulty concentrating, loss of energy, poor self-esteem, lack of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., through a mental status examination).

[0195] Anxiety disorders :Compositions and methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive compulsive disorder, phobia, post-traumatic stress disorder) are provided herein. Anxiety disorders are a blanket term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0196] Generalized anxiety disorder is a common, chronic disorder characterized by persistent anxiety that is not centered on any one object or situation. Those suffering from generalized anxiety experience nonspecific, persistent fears and worries and become overly concerned with everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0197] In panic disorder, a person experiences brief attacks of intense terror and paranoia, often characterized by shaking, trembling, confusion, dizziness, nausea, and difficulty breathing. The APA defines such panic attacks as fear or discomfort that begins suddenly and peaks in less than ten minutes, can last for hours, and can be triggered by stress, fear, or even exercise; although the specific cause is not always obvious. In addition to repeated unexpected panic attacks, a diagnosis of panic disorder requires that the attacks have chronic consequences, namely: either worry about the potential effects of the attack, persistent fear of future attacks, or significant changes in behavior associated with the attack. Therefore, those with panic disorder will experience symptoms even outside of specific panic attacks. Often, people with panic disorder will notice normal changes in their heartbeat and think that there is something wrong with their heart or that they are about to have another panic disorder attack. In some cases, there is a heightened awareness of bodily functions (hypervigilance) during a panic attack, in which any perceived physiological changes are interpreted as potentially life-threatening (i.e., extreme hypochondriasis).

[0198] Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (the urge to perform specific behaviors or rituals). The OCD thought pattern can be likened to a superstition because it involves the belief in cause and effect relationships that, in reality, do not exist. Often the process is completely illogical; for example, the compulsion to walk in a certain pattern may be used to relieve an obsession with impending harm. In many cases, the compulsions are completely unexplained and are simply a stress-triggered urge to complete a ritual. In a few cases, people with OCD may experience only obsessions without overt compulsions, and a much smaller number of people experience only compulsions.

[0199] The largest category of anxiety disorders is phobias, which include all situations in which fear and anxiety are triggered by a specific stimulus or situation. The sufferer generally anticipates that encountering the object of their fear will have dire consequences, which could be anything from an animal to a place to a bodily fluid.

[0200] Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by a traumatic experience. PTSD can develop in extreme situations, such as fights, rape, hostage situations, or even serious accidents. It can also be the result of long-term (chronic) exposure to a severe stressor, such as soldiers who endure individual combat but cannot cope with sustained combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0201] In one embodiment, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative disorders in a subject comprises orally administering to the subject an effective amount of any of 3α-OH-5β-pregnane-20-one, its pharmaceutically acceptable salts, its isomers, and combinations thereof. On the other hand, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative disorders in a subject comprises orally administering to the subject a composition comprising any amount of 3α-OH-5β-pregnane-20-one, its pharmaceutically acceptable salts, its isomers, and combinations thereof, which may be greater than about any of 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and 15% bioavailability relative to an equivalent dose of 3α-OH-5β-pregnane-20-one administered by IV infusion.

[0202] In another embodiment, the disclosed method of treating a CNS disorder may comprise orally administering to a subject sufficient GABA to achieve A The receptor binding is such that the CNS disorder in the subject is substantially reduced or eliminated in an amount of 3α-OH-5β-pregnane-20-one.

[0203] In one embodiment of the invention, the disclosed method comprises orally administering to a subject a composition having orally bioavailable 3α-OH-5β-pregnane-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 dosage regimen may range from at least once a day for a specified duration of about one day to about three months, or for more than three months or for an unspecified duration.

[0204] In one embodiment of the invention, a subject in need of an oral composition comprising orally bioavailable 3α-OH-5β-pregnane-20-one may suffer from a CNS disorder, such as depression (e.g., PPD, postpartum substance addiction disorder, major depressive disorder, treatment-resistant depression, peripartum depression, perimenopausal or postmenopausal depression).

[0205] In one embodiment of the invention, the disclosed compositions can be used to treat, reduce or eliminate conditions, symptoms or diseases associated with male or female CNS disorders. On the one hand, the subject can be an adolescent male or an adult male. In a further aspect, the subject can be an adolescent female or an adult female. Adult females can be in childbearing age, premenopausal, perinatal, postpartum, pregnancy, perimenopausal or postmenopausal. In yet another aspect, the CNS disorder of the subject can be asymptomatic and it can also suffer from a disease associated with a CNS disorder as described herein.

[0206] Clinical CNS activity can be assessed by monitoring some of these CNS vital signs, such as composite memory, verbal memory, visual memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, executive function, nonverbal reasoning, social acuity, sustained attention, working memory, simple motor speed. Optionally, CNS activity can also be assessed by monitoring the occurrence of drowsiness, dry mouth, loss of consciousness, dizziness, somnolence, fatigue, hot flashes, pulse oximetry monitoring and eye saccadic speed measurement.

[0207] In one embodiment, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative disorders in a subject comprises orally administering to the subject an effective amount of any of 3α-OH-5β-pregnane-20-one, its pharmaceutically acceptable salts, its isomers, and combinations thereof. On the other hand, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative disorders in a subject comprises orally administering to the subject a composition comprising any amount of 3α-OH-5β-pregnane-20-one, its pharmaceutically acceptable salts, its isomers, and combinations thereof, which may be greater than about any of 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and 15% bioavailability relative to an equivalent dose of 3α-OH-5β-pregnane-20-one administered by IV infusion.

[0208] In one embodiment, a method of treating a CNS disorder comprises orally administering to a subject a pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one and a plurality of additives to provide an elevated serum C level of 3α-OH-5β-pregnane-20-one in the subject. max Levels, elevated serum C avg level, or both, wherein the increase is greater than a similar increase obtained by administering to a subject substantially equivalent amounts of at least one of a composition of 3α-OH-5β-pregnane-20-one in a SBE-β-CD solution (cyclodextrin administration), a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of medium chain triglycerides (MCTs) (MCT administration), a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of a polysorbate 80 suspension (polysorbate 80), and a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of canola oil or peanut oil (edible oil administration).

[0209] In another aspect, 3α-OH-5β-pregnane-20-one can be in a form that increases the serum level of 3α-OH-5β-pregnane-20-one in a subject, wherein the increased serum level is greater than the serum level obtained by administering to the subject substantially equal amounts of at least one of the following: a composition of 3α-OH-5β-pregnane-20-one in a SBE-β cyclodextrin solution (cyclodextrin administration), a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of medium chain triglycerides (MCTs) (MCT administration), a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of a polysorbate 80 suspension (polysorbate 80), and a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of canola oil or peanut oil (edible oil administration). In one example, the elevated serum level of 3α-OH-5β-pregnane-20-one can be elevated by at least about 1.2-fold compared to the serum level obtained by administering to a subject substantially equivalent amounts of a composition of 3α-OH-5β-pregnane-20-one in a SBE-β cyclodextrin solution (cyclodextrin administration), a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of medium chain triglycerides (MCTs) (MCT administration), a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of a polysorbate 80 suspension (polysorbate 80), and a composition of 3α-OH-5β-pregnane-20-one in a solution consisting essentially of canola oil or peanut oil (edible oil administration).

[0210] In one aspect, the CNS disorder can be any one or more of the following: sleep disorders (e.g., insomnia), mood disorders (e.g., depression, such as PND, major depressive disorder, PPD, essential tremor, treatment-resistant depression or perinatal depression), dysthymic disorder (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 disorders (e.g., obsessive-compulsive disorder, OCD), schizophrenia spectrum disorders (e.g., schizophrenia spectrum disorders ... disorders) (e.g., schizophrenia, schizoaffective disorder), convulsive disorders (e.g., epilepsy, status epilepticus (SE), seizures), memory and / or cognitive disorders (e.g., attention disorders, attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, 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 disorders (ASD) (e.g., autism, monogenic causes of autism such as synaptopathy, Rett syndrome, fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., opiate, cocaine and / or alcohol addiction), tinnitus, and combinations thereof.

[0211] In another embodiment, the disclosed method of treating a CNS disorder may comprise orally administering to a subject sufficient GABA to achieve A The receptor binding is such that the CNS disorder in the subject is substantially reduced or eliminated in an amount of 3α-OH-5β-pregnane-20-one.

[0212] In one embodiment of the invention, the disclosed method comprises orally administering to a subject a composition having orally bioavailable 3α-OH-5β-pregnane-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 dosage regimen may range from at least once a day for a specified duration of about one day to about three months, or for more than three months or for an unspecified duration.

[0213] In one embodiment of the invention, a subject in need of an oral composition comprising orally bioavailable 3α-OH-5β-pregnane-20-one may suffer from a CNS disorder, such as depression (e.g., PPD, postpartum substance addiction disorder, major depressive disorder, treatment-resistant depression, peripartum depression, perimenopausal or postmenopausal depression).

[0214] In general, 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, to manage epilepsy in women of childbearing age during menstruation, pregnancy, or the perinatal and postpartum periods, and to manage epilepsy in postmenopausal or perimenopausal women.

[0215] 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, neuropathic pain syndrome, trigeminal neuralgia, etc.) and to treat or manage epilepsy in adult males with epilepsy, juvenile males with epilepsy, and juvenile females with epilepsy.

[0216] In one embodiment of the invention, the disclosed compositions can be used to treat, reduce or eliminate conditions, symptoms or diseases associated with male or female CNS disorders. On the one hand, the subject can be an adolescent male or an adult male. In a further aspect, the subject can be an adolescent female or an adult female. Adult females can be in childbearing age, premenopausal, perinatal, postpartum, pregnancy, perimenopausal or postmenopausal. In yet another aspect, the CNS disorder of the subject can be asymptomatic and it can also suffer from a disease associated with a CNS disorder as described herein.

[0217] Exemplary diagnosis of a clinical CNS disorder such as depression can be made, for example, by evaluating / performing at least one of the following rating scales / questionnaires or similar measures that include measuring the severity of depression in an individual:

[0218] a. 17-item Hamilton Rating Scale for Depression (HAM-D)

[0219] The HAM-D is a 17-item questionnaire used to diagnose depression and as a guide for assessing recovery and remission.

[0220] The HAM-D is the most commonly used instrument for assessing depressive symptoms and is administered by trained physicians.

[0221] b. Montgomery-Asberg Depression Rating Scale for Depression (MADRS)

[0222] MADRS is a clinician-rated scale used to examine the severity of depressive episodes in patients with mood disorders. It consists of a 10-item clinical interview that progresses from broad questions to more detailed questions.

[0223] c. Columbia-Suicide Severity Rating Scale (C-SSRS)

[0224] The C-SSRS is a suicidal ideation and behavior rating scale used to assess suicidal tendencies. The C-SSRS consists of a baseline assessment, which assesses the subject's lifetime experience with suicidal ideation and / or behavior, and a post-baseline assessment, which focuses on suicide risk since the last visit.

[0225] d. Clinical Global Impression Scales for Severity (CGI-S) and Clinical Global Impression Scales for Improvement (CGI-I)

[0226] The Clinical Global Outcome Rating Scale is a validated measure used in clinical research. It allows clinicians to integrate several sources of information into a single rating of a subject's condition.

[0227] e.CGI-S

[0228] The CGI-S is an objective measure of the severity of a patient's illness at the time of the assessment relative to the clinician's past experience with patients with the same diagnosis.

[0229] f.CGI-I

[0230] The CGI-I is a 7-item measure that evaluates the overall improvement in a patient's disease relative to the subject's baseline condition.

[0231] g.Hamilton Rating Scale for Anxiety (HAM-A)

[0232] The HAM-A is a clinician-rated scale used to assess the severity of anxiety symptoms. The HAM-A consists of 14 items, each defined by a series of mental and physical anxiety symptoms.

[0233] h. Edinburgh Postnatal Depression Scale (EPDS)

[0234] The EPDS is a self-report questionnaire used to identify PPD in the clinic, home visiting settings, or at the 6-8 week postpartum check-up. The EPDS consists of 10 items assessing depressive symptoms such as guilt, low energy, anhedonia, insomnia, and suicidal ideation.

[0235] i. Maternal Postnatal Attachment Scale (MPAS)

[0236] The MPAS is a self-report questionnaire used to assess mother-infant attachment. The MPAS consists of 19 items that assess the emotional bond between mother and infant.

[0237] j. The Center for Epidemiologic Studies Depression Scale (CES-D)

[0238] The CES-D is a 20-item measure that asks caregivers to rate how often they experienced depression-related symptoms, such as disturbed sleep, loss of appetite, and loneliness, in the past week. The CES-D also provides cutoff scores (e.g., 16 or higher) that help identify individuals at risk for clinical depression, has good sensitivity and specificity, and high internal consistency.

[0239] k. The Beck Depression Inventory (BDI)

[0240] The BDI is a 21-item self-report rating scale that measures characteristic attitudes and symptoms of depression.

[0241] Clinical CNS activity can be assessed by monitoring some of these CNS vital signs, such as composite memory, verbal memory, visual memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, executive function, nonverbal reasoning, social acuity, sustained attention, working memory, simple motor speed. Optionally, CNS activity can also be assessed by monitoring drowsiness, dry mouth, loss of consciousness, dizziness, somnolence, fatigue, occurrence of hot flashes, pulse oximetry monitoring and eye saccadic speed measurement.

[0242] Women's health disorders: Provided herein are compositions and methods for treating conditions or disorders related to women's health. 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, and issues related to women's overall health and well-being (e.g., menopause). Gynecological health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and such disorders as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0243] Premenstrual syndrome (PMS) refers to the physical and mental symptoms that a woman experiences one to two weeks before her menstrual period. Symptoms vary, but may include bleeding, mood swings, breast tenderness, food cravings, fatigue, irritability, acne, and depression.

[0244] 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 may interfere with work, social activities, and relationships. PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, significant anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feelings of being out of control or overwhelmed, sleep problems, and physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

[0245] Pregnancy issues include anteconception and antenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and premature birth, sudden infant death syndrome (SID), breastfeeding, and birth defects.

[0246] Abortion is the intentional termination of a pregnancy and can be performed within the first 28 weeks of pregnancy.

[0247] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis and primary ovarian insufficiency. Polycystic ovary syndrome (PCOS) refers to endocrine disorders that occur in women of childbearing age. PCOS is a group of symptoms caused by elevated levels of male hormones in a woman's body. Most women with PCOS develop many small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstruation, heavy menstrual bleeding, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant and thick, dark, velvety patches on the skin. PCOS can be associated with conditions such as type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders and endometrial cancer. Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome and ovarian and cervical cancer. Issues related to women's overall health and well-being include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health and menopause.

[0248] Menopause is the 12 months after a woman's last menstrual period and marks the end of menstrual cycles. Menopause generally occurs in women in their 40s or 50s. Physical symptoms, such as hot flashes, and emotional symptoms of menopause may disrupt sleep, reduce energy, or trigger anxiety or feelings of sadness or loss. Menopause includes neutral menopause and surgical menopause, which is a type of menopause induced by surgery (e.g., hysterectomy, oophorectomy; and cancer). Menopause is induced when the ovaries are severely damaged, such as by radiation, chemotherapy, or other medications.

[0249] The methods described herein can be used to treat neuropsychiatric (see Wikipedia neuropsychiatric entry) or neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders associated with progressive loss of neuronal structure or function or neuronal death. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including symptoms associated with mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); hypoxic-ischemic injury; ataxia and convulsions (including for the treatment and prevention of epileptic seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS) (see the latest webpage neuroacanthocytosis entry); closed brain injury; coma; contusive injury (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; disturbance of consciousness (disturbances ofconsciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (e.g., antipsychotic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and loss; Huntington's chorea; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders, including akinesia and akinetic (rigid) syndromes (including basal ganglia calcifications, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex muscle spasms and disorders associated with muscle spasticity or weakness, including chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballism, Huntington's disease, neuroacanthocytosis, Sydenham's disease, and symptomatic chorea), dyskinesia (including tics, such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal myoclonus), tremor (such as resting tremor, postural tremor, and intention tremor), and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonias such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage, including eye damage, retinal disease, or macular degeneration of the eye;Neurotoxic injury after stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; epileptic seizure; status epilepticus; stroke; tinnitus; tubular sclerosis and viral infection-induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury after stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. ;

[0250] Epileptic seizures (see "Clonic Seizures" on epilepsy.com) are physical findings or behavioral changes that occur 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 a rapid, uncontrolled shaking of a person's body. During a convulsion, a person's muscles contract and relax repeatedly. Seizures can be divided into two main categories based on the type of behavior and brain activity: generalized and partial (also called localized or focal). The classification of seizure types helps doctors diagnose whether a person has epilepsy. Generalized seizures are produced by electrical impulses that travel throughout the brain, while partial seizures are produced (at least initially) by electrical impulses in a relatively small subpart of the brain. The part of the brain where the seizure occurs is sometimes called the focal point. There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also known as a grand mal (generalized tonic-clonic). In this type of seizure, the person loses consciousness and usually collapses. After the loss of consciousness, there is generalized stiffness of the body (called the "tonic" phase of the seizure) for 30 to 60 seconds, followed by violent convulsions (the "clonic" phase) for 30 to 60 seconds, after which the person falls into a deep sleep (the "postictal" or postictal phase). During a grand mal seizure, injuries and accidents, such as tongue biting and urinary incontinence, can occur. Absence seizures (petit mal) cause a brief loss of consciousness (only a few seconds) with few or no symptoms. The person (more often a child) typically interrupts activity and stares blankly. These seizures begin and end suddenly and may occur several times a day. The person is usually unaware that they are having a seizure, but they may be aware that they have lost time. Myoclonic seizures consist of sporadic convulsions, usually on both sides of the body. The person sometimes describes the convulsions as brief electric shocks. When violent, these seizures can cause objects to be dropped or thrown involuntarily.

[0251] Clonic seizures are repetitive, rhythmic twitches that affect both sides of the body at the same time. Tonic seizures are characterized by muscle rigidity. Atonic seizures consist of a sudden and general loss of muscle tone, especially in the arms and legs, often leading to falls. The epileptic seizures described herein with or without epilepsy may include epileptic seizures, acute repetitive seizures, cluster seizures, and continuous seizures; uninterrupted seizures, prolonged seizures, recurrent seizures, status epilepticus seizures, refractory convulsive status epilepticus seizures, nonconvulsive status epilepticus seizures, 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), atonic seizures, benign motor seizures, febrile seizures, emotional seizures, focal seizures, gelastic seizures, generalized onset seizures, infantile spasms, Jackson seizures, massive bilateral monooclonus seizures, multifocal seizures, neonatal onset seizures Seizures, nocturnal seizures, occipital lobe seizures, post-traumatic seizures, subtle seizures, Sylvan seizures, visual reflex seizures, or withdrawal 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 female childhood epilepsy. Juvenile myoclonic epilepsy (JME) is the most common systemic epilepsy syndrome.

[0252] Typically, epilepsy patients need to take seizure medications throughout their lives as monotherapy or polytherapy with multiple agents to treat, prevent, reduce or control seizures and epilepsy.

[0253] In one embodiment, the method of treating or preventing a neurodegenerative disease by orally administering an oral composition comprising orally bioavailable 3α-OH-5β-pregnane-20-one also includes treating or preventing the loss of neuronal function characteristic of a neurodegenerative disorder 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 epileptic discharges, and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and may include 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 the persistence of status epilepticus seizures despite treatment with first-line therapy and the administration of second-line therapy. Refractory status epilepticus is characterized by the persistence of status epilepticus seizures despite treatment with first-line therapy and second-line therapy. Refractory status epilepticus is often treated with general anesthetics. Super-refractory status epilepticus is characterized by the persistence of status epilepticus seizures despite treatment with first-line therapy, second-line therapy, and general anesthetics for more than 24 hours.

[0254] Nonconvulsive status epilepticus may include focal nonconvulsive status epilepticus, complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, imperceptible nonconvulsive status epilepticus; generalized nonconvulsive status epilepticus, late onset absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0255] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as a monotherapy to a subject suffering from at least one of the following to treat, prevent, reduce or ameliorate seizures or epilepsy: 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, seizure clusters, acute repetitive seizures, generalized periodic epileptiform discharges, and periodic lateralized epileptiform discharges.

[0256] In another embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as a monotherapy to a subject suffering from at least one of the four classified epilepsy to treat, prevent, reduce or ameliorate epileptic seizures or epilepsy, including focal epilepsy (such as frontal lobe epilepsy), generalized epilepsy, generalized and focal epilepsy, simple or complex partial onset epilepsy, and unknown epilepsy (including neonatal and infantile epilepsy) classified by the International League Against Epilepsy (ILAE) in 2017.

[0257] In one aspect, the compositions and methods disclosed herein can be used to treat, prevent, reduce or ameliorate at least one of the following generalized epilepsy: generalized tonic-clonic seizures (symptoms: loss of consciousness, followed by body rigidity, and then violent convulsions after entering 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, rhythmic jerking movements occurring simultaneously on both sides of the body), tonic seizures (symptoms: muscle rigidity and stiffness) and atonic seizures (symptoms: sudden and complete loss of muscle tone in the arms and legs).

[0258] In another aspect, the compositions and methods disclosed herein can be used to treat, prevent, reduce or ameliorate at least one of the following focal epilepsy: focal retained awareness seizures (motor / sensory / autonomic / psychological), focal impairedawareness seizures, focal motor seizures, focal non-motor seizures, focal to bilateral tonic-clonic seizures.

[0259] In a further aspect, the compositions and methods disclosed herein can be used to treat, prevent, reduce or ameliorate at least one of the following unknown (or idiopathic) epilepsy: unknown motor seizures, unknown non-motor seizures, and unclassified seizures including neonatal and infantile seizures. An unknown seizure is defined as a seizure that occurs during sleep or in an indescribable situation because the patient is alone or witnesses cannot describe it. When a clinician determines that the event is an epileptic seizure, but cannot describe it due to incomplete information, it is designated as an unclassified seizure.

[0260] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as an adjunctive therapy to a subject suffering from at least one of the following to treat, prevent, reduce or ameliorate seizures or epilepsy: 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 epileptic discharges.

[0261] In another embodiment, the pharmaceutically acceptable compositions and methods described herein may be administered as an adjunctive therapy to treat, prevent, reduce, or ameliorate seizures or epilepsy in a subject suffering from at least one of the four classified epilepsy types: focal epilepsy, generalized epilepsy, generalized combined focal epilepsy, and unknown epilepsy.

[0262] In one aspect, the pharmaceutically acceptable compositions and methods described herein can be used as adjunctive therapy with anti-epileptic agents such as bromides, phenobarbital, mephobarbital, phenytoin, acetazolamide, trimethadione, mephenytoin, paramethadione, corticosteroids, adrenocorticotropic hormone (ACTH), phenylacetamide, phensuximide, primidone, methsuximide, ethotoin, ethosuximide, chlordiazepoxide, sulthiazine, diazepam, carbamazepine, valproate, clonazepam, clobazam, flusaldiamide, vigabatrin, zonisamide, lamotrigine, oxcarbazepine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin, stiripentol, rufinamide, lacosamide, eslicarbazepine acetate, At least one of valproate acetate, retigabine (ezogabine), perampanel, imepitoin, brivaracetam, everolimus, valproic acid, eslicarbazepine, cenobamate, fenfluramine, midazolam and alprazolam is administered together to treat, prevent, reduce or ameliorate seizures or epilepsy in a subject in need of treatment.

[0263] Studies have shown that the incidence of epilepsy and unprovoked (or reflex) seizures is slightly lower in women than in men. This difference is generally attributed to the fact that men are more exposed to risk factors for lesional epilepsy and acute symptomatic seizures. Idiopathic generalized epilepsy (IGE) accounts for approximately 15-20% of all epilepsy and is more common in women. In addition, the behavior of some common epilepsy syndromes (such as mesial temporal sclerosis) can differ between the sexes, with isolated auras being more common in women and secondary seizures being more likely to spread in men. For example, epilepsy trends between sexes show that the incidence of status epilepticus, the incidence of sudden unexpected death in epilepsy (SUDEP), prognosis, and mortality are more common in men. Another example is that boys with epilepsy with myoclonic-astatic seizures (Doose syndrome) are about twice as frequent as girls. In addition, focal seizures with hyperautomatism are about twice as prevalent in men as in women.

[0264] More women than men were diagnosed with idiopathic generalized epilepsy. No sex differences were found in location-related epilepsy, but location-related symptomatic epilepsy was more frequent in men, whereas cryptogenic location-related epilepsy was more frequent in women.

[0265] Some epilepsy syndromes are more common in women, including childhood absence epilepsy, typical early onset absence epilepsy, photosensitive epilepsy, juvenile myoclonic epilepsy, and catamenial epilepsy.

[0266] Subjects for whom the disclosed compositions and methods may be needed and for whom the disclosed compositions and methods may be useful include women of childbearing age (e.g., 12-49, 15-49, or 18-45 years old). More specifically, the disclosed compositions and methods may be particularly useful for such women who are capable of nulliparous or multiparous (>1 year postpartum or prior birth), planned or unplanned pregnancy, more particularly in the pre-pregnancy, pregnancy, labor, perinatal, and postpartum periods.

[0267] Perimenopausal women are defined as women who are around the time of menopause, ranging in age from about 39 to about 50 years old (eg, perimenopausal age may be 40 to 50 years old).

[0268] Before the age of 10 years (including infant and childhood ages), pseudo-epileptic paroxysms are equally common in boys and girls. After 10 years (up to age 18 years), pseudo-epileptic paroxysms are more common in girls. In adulthood (18 to about 70 years), 60-80% of epilepsy cases occur in women. Epilepsy is more common in women than in men during adolescence and up to age 30 and over 70 years. During adolescence, young men are more likely to work in their free time, and this work may result in insufficient sleep and trigger epileptic seizures.

[0269] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to male or female children aged 5 to 17 years who have at least one of the following to treat, prevent, ameliorate or control seizures or epilepsy (including breakthrough seizures) in such subjects: 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.

[0270] In another embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to male or female children aged 5 to 17 years with at least one of the four classified epilepsy types, including focal epilepsy, generalized epilepsy, generalized and focal epilepsy, and unknown epilepsy, as classified by the International League Against Epilepsy (ILAE) in 2017, to treat epileptic seizures or epilepsy in such subjects.

[0271] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to a male suffering from at least one of the following to treat seizures or epilepsy: 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.

[0272] In another embodiment, the pharmaceutically acceptable compositions and methods described herein may be administered to males suffering from at least one of the four classified epilepsy types, including focal epilepsy, generalized epilepsy, generalized and focal epilepsy, and unknown epilepsy as classified by the International League Against Epilepsy (ILAE) in 2017, to treat seizures or epilepsy.

[0273] In adult males, epilepsy or AEDs can cause dysfunction at all levels of the hypothalamus-pituitary-sex system, leading to sexual dysfunction. Epileptic seizures are often associated with hormonal disorders, causing the release of hypothalamic and pituitary hormones. In addition, some AEDs may also change sex hormone levels and induce their effects. Prolactin interictal increases have been observed in men and women with epilepsy, regardless of whether anti-epileptic therapy is administered. Epileptic seizures can cause prolactin levels to rise, reaching a maximum value within a short period of time (about 1 hour) after the onset. On the one hand, pharmaceutically acceptable compositions and methods as described herein can be applied to men with symptoms of sexual dysfunction with epilepsy 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 reduced free testosterone.

[0274] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to a female suffering from at least one of the following to treat seizures or epilepsy: 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.

[0275] In another embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to a female suffering from at least one of the four classified epilepsy types to treat epileptic seizures or epilepsy, including focal epilepsy (such as frontal lobe epilepsy), generalized epilepsy, generalized combined focal epilepsy, and unknown epilepsy as classified by the International League Against Epilepsy (ILAE) in 2017.

[0276] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to menopausal or perimenopausal women with epilepsy or active epilepsy (controlled or uncontrolled seizures within the previous 6-12 months prior to initiation of other AED(s) or monotherapy or adjunct to other AED(s) or monotherapy) to improve, control, prevent, prevent an increase (including breakthrough seizures), or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0277] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to menopausal or perimenopausal women with a history of catamenial epilepsy or active epilepsy (controlled or uncontrolled seizures within the previous 6-12 months prior to the initiation of other AED(s) or monotherapy or as an adjunct to other AED(s) or monotherapy) to improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0278] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to menopausal or perimenopausal women with epilepsy or active epilepsy (controlled or uncontrolled seizures within the previous 6-12 months prior to initiation of other AED(s) or monotherapy or adjunct to other AED(s) or monotherapy) and with endogenous positive allosteric neuroactive steroid deficiency to improve, control, prevent, prevent increase, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0279] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to menopausal or perimenopausal women or women of childbearing age who are receiving hormone replacement therapy, have epilepsy or active epilepsy (controlled or uncontrolled seizures within the previous 6-12 months prior to the initiation of other AED(s) or monotherapy or prior to adjunct to other AED(s) or monotherapy) and have an endogenous positive allosteric modulator neuroactive steroid deficiency to improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0280] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to menopausal or perimenopausal women or women of childbearing age who have epilepsy or active epilepsy (controlled or uncontrolled seizures within the previous 6-12 months prior to initiation of other AED(s) or monotherapy or adjunct to other AED(s) or monotherapy) and are at risk for compromised bone health to improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0281] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to menopausal or perimenopausal women or women of childbearing age with epilepsy who have at least 3 or more seizures per month just prior to the initiation of other AED(s) or monotherapy or prior to adjunct to other AED(s) or monotherapy to improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0282] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to menopausal or perimenopausal women or women of childbearing age with epilepsy who have no more than 25 seizure-free days in the last two months prior to the initiation of other AED(s) or monotherapy or as an adjunct to other AED(s) or monotherapy to improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0283] In one embodiment, the pharmaceutically acceptable compositions and methods described herein may be administered to females of childbearing age with epilepsy or active epilepsy to 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, just prior to the initiation of other AED(s) or monotherapy or as an adjunct to other AED(s) or monotherapy.

[0284] In one embodiment, the pharmaceutically acceptable compositions and methods described herein may be administered to females of childbearing age who have epilepsy or active epilepsy and have endogenous progesterone or positive allosteric modulator neuroactive steroid deficiency or high testosterone or estrogen levels to improve, control, prevent, prevent increase, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders, regardless of the use of oral hormonal contraceptives, just prior to the initiation of other AED(s) or monotherapy or as an adjunct to other AED(s) or monotherapy.

[0285] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to females of childbearing age with epilepsy or active epilepsy to improve, control, prevent, prevent an increase in, or treat seizures or epilepsy, and / or mood disorders, and / or sleep disorders without regard to drug-drug interactions (DDIs) that compromise the contraceptive or seizure control efficacy of the co-administered drugs.

[0286] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age who suffer from epilepsy or active epilepsy and menstrual disorders (such as premenstrual syndrome, premenstrual dysphoric disorder (PMDD) and ovulation disorders) to improve, control, prevent, prevent an increase in or treat epileptic seizures or epilepsy, and / or mood disorders, and / or sleep disorders.

[0287] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age with epilepsy as an adjunct to other AED(s) to prevent breakthrough seizures or maintain seizure control while adjusting the AED dose in women planning pregnancy.

[0288] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age with epilepsy as an adjunct therapy or monotherapy to other AED(s) to replace all or a substantial amount of such AED(s) with teratogenic risk in women planning pregnancy.

[0289] In one embodiment, the pharmaceutically acceptable compositions and methods described herein may be administered to women of childbearing age with epilepsy as an adjunct to other AED(s) or monotherapy to reduce or eliminate polypharmacy dependence on such AED(s) to achieve seizure control dosages in women planning pregnancy.

[0290] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to women of childbearing age with epilepsy as an adjunct to other AED(s) or monotherapy to reduce or eliminate polypharmacy dependence on such AED(s) to achieve seizure control dosages in women planning pregnancy by providing physiological levels of endogenous neuroactive steroids.

[0291] In one embodiment, the pharmaceutically acceptable compositions and methods described herein may be administered as an adjunct to other AED(s) or monotherapy to improve, control, prevent, prevent increase, or treat at least one of seizure management, depression, anxiety, sleep impairment, and suicidal ideation in females of childbearing age with epilepsy or active epilepsy who are pregnant, planning pregnancy, or at risk of becoming pregnant.

[0292] In one embodiment, the pharmaceutically acceptable compositions and methods described herein may be administered as an adjunct to other AED(s) without increasing the dosage of the AED or as monotherapy to improve, control, prevent, prevent increase, or treat at least one of seizure management, depression, anxiety, sleep disturbance, and suicidal ideation in pregnant women of childbearing age.

[0293] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered as an adjunct to other AED(s) or monotherapy to improve, control, prevent, prevent an increase, prevent an increase, or treat at least one of seizure management and related comorbid conditions such as depression, anxiety, sleep disturbances, and suicidal ideation in women of childbearing age with epilepsy or active epilepsy who are pregnant, planning pregnancy, or at risk of becoming pregnant.

[0294] On the one hand, the pharmaceutically acceptable compositions and methods described herein can be applied to women of childbearing age who suffer from at least one of childhood absence epilepsy, typical early-onset absence epilepsy, photosensitive epilepsy, juvenile myoclonic epilepsy, acute repetitive epileptic seizures, and catamenial epilepsy to treat epileptic seizures, epilepsy, or related symptoms. On the other hand, the pharmaceutically acceptable compositions and methods described herein can be applied to women of childbearing age who suffer from catamenial epilepsy, including 1) the anticonvulsant effect of withdrawing endogenous neuroactive steroids during the premenstrual period (the anticonvulsant effect is through the endogenous neuroactive steroids on GABA A receptors) and GABA A Epilepsy related to changes in receptor subunits and subsequent changes in neuronal inhibition, 2) estrogen peaks on the day before ovulation, and 3) increased frequency of anovulatory cycles caused by dysregulation of the hypothalamic-pituitary-gonadal axis and subsequent low progesterone luteal phase to treat epileptic seizures or epilepsy. Menstrual epilepsy patterns can be divided into three types according to the time period in the menstrual cycle, namely: 1) Perimenstrual pattern (C1 pattern: related to a drop in progesterone, day 25 to day 3), 2) Periovulatory pattern (C2 pattern: related to a sudden increase in estrogen, day 10 to day 15), and 3) Luteal pattern (C3 pattern: related to insufficient luteal phase cycles due to low progesterone levels, resulting in anovulatory cycles, day 10 of one cycle to day 3 of the next cycle). Premenstrual (or perimenstrual) pattern or C1 pattern epilepsy is the most common type of epilepsy in female subjects of childbearing age with menstrual epilepsy.

[0295] In one aspect, the pharmaceutically acceptable compositions and methods described herein can be administered to females of childbearing age suffering from at least one of perimenstrual pattern catamenial epilepsy, periovulatory pattern catamenial epilepsy, and luteal pattern catamenial epilepsy to treat seizures or epilepsy.

[0296] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to postmenopausal or perimenopausal women suffering from epilepsy associated with low estrogen and progesterone levels (a focal epilepsy), epilepsy not related to hormone levels (a generalized epilepsy), and unknown epilepsy to treat seizures or epilepsy.

[0297] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be applied to pregnant women suffering from epilepsy, including focal epilepsy, generalized epilepsy, generalized combined focal epilepsy and unknown epilepsy, to treat epileptic seizures or epilepsy. For some pregnant women, particularly pregnant women who are sleep deprived or do not take medication as prescribed, pregnancy can increase the frequency of epileptic seizures. On the one hand, the pharmaceutically acceptable compositions and methods described herein can be applied to pregnant women suffering from epilepsy to treat symptoms or diseases caused by epilepsy during pregnancy, such as slowing of fetal heart rate, fetal hypoxia, fetal injury, premature separation of placenta from uterus (placental abruption), abortion caused by trauma (e.g., falling during epileptic seizures), pre-determined birth, sudden infant death syndrome, breastfeeding difficulties, birth defects and premature birth.

[0298] In one embodiment, the pharmaceutically acceptable compositions and methods described herein can be administered to perinatal (late pregnancy and after delivery) women with epilepsy or epilepsy including three types of seizures, namely: 1) exacerbation of a known pre-existing seizure disorder (primarily epilepsy), 2) new onset of seizures not caused by pregnancy-related problems, and 3) seizures associated with pregnancy conditions to treat seizures or epilepsy. There are two types of pregnancy-related seizures, namely: i) focus on eclampsia, and ii) new onset of pregnancy-related epilepsy, including at least one of osterior reversible encephalopathy syndrome, reversible cerebral vasoconstriction syndrome, cerebral venous sinus thrombosis, thrombotic thrombocytopenic purpura, amniotic fluid embolism, and air embolism.

[0299] Also described herein are methods and compositions for treating movement disorders. As used herein, the term "movement disorder" refers to a variety of diseases and disorders associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and Parkinson's syndrome (particularly defined by bradykinesia), dystonia, chorea and Huntington's chorea, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette's syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0300] The methods and compositions described herein can be used to treat tremors such as cerebellar or intention tremors, dystonic tremors, essential tremors, orthostatic tremors, Parkinsonian tremors, physiological tremors, psychogenic tremors, and rubral tremors. Tremors include hereditary, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively. Tremors can be caused by or associated with: metabolic diseases (e.g., thyroid-parathyroid, liver, and hypoglycemia); peripheral neuropathy (associated with Shiller-Marinus syndrome); Figure 3 Disease, Rolls-Roche-Levy disease, diabetes, complex regional pain syndrome (complexregional pain syndrome); toxins (e.g., nicotine, mercury, lead, CO, manganese, arsenic, and toluene); selected drugs (e.g., narcoleptics, tricyclics, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, and vincristine); and psychiatric disorders. Clinical tremor can be classified as physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neurogenic tremor, toxic or drug-induced tremor, and psychogenic tremor. A tremor is an involuntary, sometimes rhythmic contraction and relaxation of muscles that may involve oscillations or twitches of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds (voice cords), trunk, and legs). Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum, such as tumors, stroke, or disease (e.g., multiple sclerosis, an inherited degenerative disease). Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or pain and abnormal posture or position. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is often relieved by complete rest. Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, or slowly progressive, starting on one side of the body but affecting both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be affected. Tremor frequency may decrease as a person ages, but tremor severity may increase. Tremors may be triggered and / or made more severe by emotional excitement, stress, fever, physical exhaustion, or low blood sugar. These symptoms often evolve over time and may be both visible and persistent after onset.

[0301] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. The thighs and legs may feel cramped, and the patient may rock uncontrollably when asked to stand in one position. People with essential tremor may develop orthostatic tremor.

[0302] Parkinson's tremor is caused by damage to structures in the brain that control movement. Parkinson's tremor is often a precursor to Parkinson's disease and is generally seen in "pill-rolling" movements of the hands, which may also affect the jaw, lips, legs, and trunk. The onset of Parkinson's tremor generally begins after age 60. The movements begin in one limb or side of the body and may progress to include the other side.

[0303] Physiologic tremor occurs in normal people and has no clinical significance. It is felt in all voluntary muscle groups. Physiologic tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including an overactive thyroid gland and hypoglycemia. The frequency of a physiologic tremor is usually about 10 Hz.

[0304] Psychogenic or hysterical tremors may occur at rest or during postural or motor movements. People with psychogenic tremors may have conversion disorders or other psychiatric disorders. Rubral tremor is characterized by a coarse, slow tremor that may occur at rest, during posture, and during intentional movement. Rubral tremor is associated with conditions that affect the red nucleus of the midbrain and is typically associated with unusual strokes.

[0305] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism is the same as the symptoms found in Parkinson's disease, but it is a syndrome rather than a progressive neurodegenerative disease. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that result in abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, or trembling. Dystonia is often triggered or exacerbated by voluntary actions and is associated with overflow muscle activation.

[0306] Chorea is a neurological disorder characterized by involuntary jerking movements that generally affect the shoulders, hips, and face. Huntington's chorea is a genetic disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's chorea can impede walking, speaking, and swallowing. Ataxia is the loss of complete control of body movements and can affect the fingers, hands, arms, legs, body, speech, and eye movements. Myoclonus and startle are responses to sudden and unexpected stimuli, which can be auditory, tactile, visual, or vestibular.

[0307] A tic is an involuntary movement that is usually sudden, brief, repetitive but not rhythmic, generally mimics normal behavior and often occurs outside the context of normal activities. Tics can be classified as motor or vocal. Motor tics are associated with movement, while vocal tics are associated with sound. Tics can be classified as simple or complex. For example, simple motor tics involve only a few muscles localized to a specific body part. Tourette syndrome is an inherited neuropsychiatric and neurodegenerative disorder that begins in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0308] Restless legs syndrome is a neurological sensorimotor disorder characterized by a strong urge to move the legs while at rest. Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle rigidity, typically involving the lower back and legs. Stiff-person syndrome generally presents with a stiff-legged gait with exaggerated lumbar lordosis. Characteristic abnormalities on EMG recordings with continuous motor unit activity of the paraspinal axial muscles are also commonly observed. Variants include "stiff-limb syndrome" - producing focal stiffness that typically affects the distal leg and foot.

[0309] Gait disorders refer to abnormalities in the pattern or manner of walking caused by neuromuscular, arthritic, or other physical changes. Gaits are classified according to the system causing the abnormal movement and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, chorea-like gait, ataxic gait, and sensory gait.

[0310] Also provided herein are compositions and methods for treating mood disorders. 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 depression, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicide, 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 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), women's health disorders or conditions).

[0311] Clinical depression is also known as major depression, major depressive disorder (MDD), major depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by a pervasive and persistent low mood, accompanied by low self-esteem and a loss of interest or pleasure in normally pleasurable activities. Some people with clinical depression have trouble sleeping, lose weight, and are often irritated and angry. Clinical depression affects how an individual feels, thinks, and behaves, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty carrying out daily activities, and clinical depression may make the individual feel that life is not worth living.

[0312] Perinatal depression is depression during pregnancy. Symptoms include irritability, crying spells, feeling restless, trouble sleeping, extreme tiredness (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of separation from the baby and / or fetus, and loss of interest in activities that were previously pleasurable.

[0313] Postpartum depression (PND) is also referred to as PPD, and refers to a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, loss of libido, crying attacks, anxiety, and irritability. 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 with PND also experiences depression, or symptoms of depression, during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, a subject experiencing perinatal depression experiences an increased risk of PND.

[0314] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and motivation, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or hypersomnia (somnia), a sense of heaviness in the limbs, and significant social impairment due to a hypersensitive response to perceived interpersonal rejection.

[0315] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), lack of response to pleasurable stimuli, depressed mood that is more pronounced than depression due to sadness or loss, excessive weight loss, or excessive guilt. Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode that is depressive in nature, in which the individual experiences psychotic symptoms such as delusions and hallucinations. Catatonic depression refers to a major depression that involves other symptoms such as disturbances in motor behavior. The individual may become silent and stuporous, and either remain motionless or exhibit purposeless or strange movements.

[0316] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual experiences a seasonal pattern of depressive episodes during the fall or winter.

[0317] Dysthymia refers to a condition associated with unipolar depression, in which the same physical and cognitive problems are evident. Such problems are less severe and tend to last longer (e.g., at least 2 years). Double depression refers to a rather depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by major depression. Depressive personality disorder (DPD) refers to a personality disorder with depressive features. Recurrent brief depression (RBD) refers to a depressive episode that occurs approximately once a month in an individual, with each episode lasting 2 weeks or less, and generally less than 2-3 days.

[0318] Minor depression or minor depression is depression that presents with at least 2 symptoms for 2 weeks. Bipolar disorder or manic-depressive disorder causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During manic phases, individuals may feel or act unusually happy, energetic, or irritable. They often make ill-considered decisions with little regard for the consequences. The need for sleep is usually reduced. During depressive phases, there may be crying spells, poor eye contact with others, and a negative outlook on life. People with this disorder have a high risk of suicide within 20 years, more than 6%, and a 30-40% risk of self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder. Depression caused by chronic medical conditions is depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, and chronic stress. Treatment-resistant depression is a condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or counseling (psychotherapy) do not relieve depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression experience improvement in symptoms, but symptoms generally recur. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics) as well as nonpharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0319] Postoperative depression refers to feelings of depression following a surgical procedure (e.g., resulting from having to deal with the death of a person). For example, an individual may continue to feel sad or emotionally empty, lose pleasure or interest in hobbies and activities that they normally enjoy, or continue to feel worthless or hopeless. Mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a women's health condition or disorder (e.g., as described herein). Suicide, suicidal ideation, suicidal behavior refers to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual contemplations about suicide. The range of suicidal ideation varies greatly, such as from brief thoughts to extensive ideas, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contacts, thinking about death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing dangerous or self-destructive things, and saying goodbye to people as if they will never be seen again. Symptoms of depression include persistent anxious or sad moods, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, physical challenges, loss of interest in pleasurable activities or hobbies, difficulty concentrating, loss of energy, poor self-esteem, lack of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., through a mental status examination).

[0320] Anxiety disorders : 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 disorder is an umbrella term that covers several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0321] Generalized anxiety disorder is a common, chronic disorder characterized by persistent anxiety that is not centered on any one object or situation. Those suffering from generalized anxiety experience nonspecific, persistent fears and worries and become overly concerned with everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0322] In panic disorder, a person experiences brief attacks of intense terror and paranoia, often characterized by shaking, trembling, confusion, dizziness, nausea, and difficulty breathing. The APA defines such panic attacks as fear or discomfort that begins suddenly and peaks in less than ten minutes, can last for hours, and can be triggered by stress, fear, or even exercise; although the specific cause is not always obvious. In addition to repeated unexpected panic attacks, a diagnosis of panic disorder requires that the attacks have chronic consequences, namely: either worry about the potential effects of the attack, persistent fear of future attacks, or significant changes in behavior associated with the attack. Therefore, those with panic disorder will experience symptoms even outside of specific panic attacks. Often, people with panic disorder will notice normal changes in their heartbeat and think that there is something wrong with their heart or that they are about to have another panic disorder attack. In some cases, there is a heightened awareness of bodily functions (hypervigilance) during a panic attack, in which any perceived physiological changes are interpreted as potentially life-threatening (i.e., extreme hypochondriasis).

[0323] Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (the urge to perform specific behaviors or rituals). The OCD thought pattern can be likened to a superstition because it involves the belief in cause and effect relationships that, in reality, do not exist. Often the process is completely illogical; for example, the compulsion to walk in a certain pattern may be used to relieve an obsession with impending harm. In many cases, the compulsions are completely unexplained and are simply a stress-triggered urge to complete a ritual. In a few cases, people with OCD may experience only obsessions without overt compulsions, and a much smaller number of people experience only compulsions.

[0324] The largest category of anxiety disorders is phobias, which include all situations in which fear and anxiety are triggered by a specific stimulus or situation. The sufferer generally anticipates that encountering the object of their fear will have dire consequences, which could be anything from an animal to a place to a bodily fluid.

[0325] Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by a traumatic experience. PTSD can develop in extreme situations, such as fights, rape, hostage situations, or even serious accidents. It can also be caused by long-term (chronic) exposure to severe stressors, such as soldiers who endure individual combat but cannot cope with sustained combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0326] 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 following ordered steps: identifying a subject suffering from or predisposed to epilepsy (e.g., such as being identified as being genetically susceptible to epilepsy), and orally administering an anti-epileptic drug (AED) to the subject. Administration may, for example, include an administration regimen, which includes a predetermined amount of AED (e.g., such as one or more AED capsules) at a predetermined frequency (e.g., such as once or more times a day) and for a predetermined duration (e.g., such as a single administration or daily administration for multiple days). The subject preferably includes epileptic women (WWE), more particularly WWE of childbearing age. The composition preferably includes a neuroactive steroid (NAS), more particularly endogenous NAS (ENAS), and even more particularly, the composition preferably includes 3α-OH-5β-pregnane-20-one. The method preferably results in the prevention or reduction of the frequency or amplitude of epileptic seizures.

[0327] In some aspects, the compositions and methods disclosed herein for oral administration are intended to treat CNS disorders including at least one of the following: sleep disorders (e.g., insomnia), mood disorders (e.g., depression in women of childbearing age with or without active epilepsy, such as PND, major depressive disorder, postpartum depression (PPD), essential tremor, treatment-resistant depression or perinatal depression, antenatal anxiety and / or depression), anhedonia, dysthymic disorder (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 (e.g., obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), convulsive disorders (e.g., epilepsy, absence seizures, status epilepticus (SE)), epileptic seizures, acute repetitive epilepsy, The present invention relates to a variety of disorders including, but not limited to, attention deficit hyperactivity disorder (ADHD), dementia (e.g., Alzheimer's disease, dementia with Lewy bodies, 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 disorders (ASD) (e.g., autism, monogenic causes of autism such as synaptopathy (see Wikipedia entry "Synaptopathy"), Rett syndrome, fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., opiate, cocaine and / or alcohol addiction), and tinnitus.

[0328] In one aspect, oral compositions and methods disclosed herein are formulated to treat 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).

[0329] In one aspect, the oral compositions and methods disclosed herein are designed to treat CNS disorders (e.g., suicidal ideation, depression, anxiety) in women of childbearing age with epilepsy, manage epilepsy during menstruation, manage epilepsy during pregnancy, manage perinatal and postpartum epilepsy, or manage epilepsy in postmenopausal or perimenopausal women.

[0330] In one embodiment, 3α-OH-5β-pregnane-20-one compositions and oral dosage forms can be formulated to provide a therapeutically effective amount or peak level of 3α-OH-5β-pregnane-20-one to treat CNS disorders when orally administered to a subject. For example, in one aspect, the compositions and oral dosage forms can include a variety of pharmaceutically acceptable additives that, when orally administered to a subject, provide serum 3α-OH-5β-pregnane-20-one levels in an amount sufficient to treat CNS disorders.

[0331] In one embodiment, the present invention is an oral pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one and a plurality of additives, wherein oral administration of the composition to a subject suffering from at least one neuropsychiatric and neurodegenerative disorder results in a serum level of said 3α-OH-5β-pregnane-20-one in the subject such that at least one of the neuropsychiatric and neurodegenerative disorders is substantially eliminated, improved or reduced.

[0332] In one embodiment, the present invention is an oral pharmaceutical composition comprising: a rapid release form of 3α-OH-5β-pregnane-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 level of 3α-OH-5β-pregnane-20-one in the subject as compared to the level of 3α-OH-5β-pregnane-20-one provided by a composition comprising an equal amount of 3α-OH-5β-pregnane-20-one but lacking a solubilizer and / or dispersant.

[0333] In another embodiment, the disclosed oral pharmaceutical composition comprises a fast-release form of 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives. When the composition is administered with a meal, the composition provides a serum level that is higher than the serum level produced by administration of a comparable cyclodextrin solution. In yet a further embodiment, the disclosed oral pharmaceutical composition comprises a fast-disintegrating form of 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives.

[0334] In one embodiment, the 3α-OH-5β-pregnane-20-one composition or oral dosage form can be formulated to effectively provide a therapeutically effective amount of 3α-OH-5β-pregnane-20-one when orally administered to a subject to treat CNS disorders. On the other hand, the 3α-OH-5β-pregnane-20-one in the composition can be in a form that can provide an effective level of 3α-OH-5β-pregnane-20-one when orally administered to a subject. On the other hand, the 3α-OH-5β-pregnane-20-one can be in a form that increases the level of 3α-OH-5β-pregnane-20-one in a subject when orally administered to a subject. On the other hand, the composition of the present invention is expected to increase the level of 3α-OH-5β-pregnane-20-one in a subject when orally administered to a subject compared to a composition comprising an equal amount of micronized or non-micronized (e.g., crystals) 3α-OH-5β-pregnane-20-one suspended in an edible oil and orally administered to a subject.

[0335] In yet another embodiment, dosage regimens and methods 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-pregnane-20-one.

[0336] In one embodiment, the compositions and oral dosage forms may include a variety of pharmaceutically acceptable additives including at least one of alpha-tocopherol, glyceryl monocaprylate, glyceryl monocaprylocaprate, propylene glycol monolaurate, PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil, and combinations thereof, which, when orally administered to a subject, provide therapeutically effective levels of 3α-OH-5β-pregnane-20-one in an amount sufficient to treat a CNS disorder.

[0337] In one aspect, the amount of 3α-OH-5β-pregnane-20-one in the composition can provide a therapeutically effective level (e.g., mean serum level C ) of 3α-OH-5β-pregnane-20-one sufficient to treat a CNS disorder. avg or peak serum level C max ). In another aspect, the 3α-OH-5β-pregnane-20-one in the composition can be in a rapid release form that provides therapeutically effective levels of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. In another aspect, the 3α-OH-5β-pregnane-20-one in the composition can be in a solubilized or amorphous form that provides therapeutically effective levels of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. In another aspect, the 3α-OH-5β-pregnane-20-one in the composition disclosed herein can be in a form treated with a plurality of additives that can include at least one surfactant that provides therapeutically effective levels of 3α-OH-5β-pregnane-20-one that is effective for treating a CNS disorder in a subject. In yet another aspect, the 3α-OH-5β-pregnane-20-one can be formulated with a plurality of additives that provide therapeutically effective levels of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject.

[0338] Figure 4 is a schematic representation of a PK curve showing the plasma concentration of a single dose of a drug administered orally as a function of time. A PK curve can be used to characterize the absorption / bioavailability of 3α-OH-5β-pregnane-20-one in a subject's blood over time. The most common PK parameter is C max 、T max and area under the curve (AUC). The plasma concentration of a single dose of the drug is observed to increase until it reaches a peak concentration C max ,like Figure 4 As shown. Figure 4 As shown, reaching C max The time required is called T max . refer to Figure 4 , an exemplary AUC for drug concentration 0-24 (AUC from time 0 to 24 hours) is the integrated area under the curve of observed plasma concentration vs. time. AUC 0-24 It represents the exposure of a drug in the systemic circulation over a period of time. Unless otherwise stated, the measured pharmacokinetic parameters are the average reported values ​​of a group of subjects. The parameter T max It is not the average reported value, but the median value reported from a group of subjects.

[0339] Although AUC 0-24 It refers to the area under the curve from 0 to 24 hours, but the PK curve parameters for treatments beyond 24 hours can be calculated by AUC 0-t (AUC from 0 to the end of the treatment observation / sampling period) or by AUC 0-∞ Further expanded to the total drug exposure observed in plasma. 0-∞ is the total exposure and is derived from AUC 0-t +C t / k el Extracted from. t is the drug concentration observed in plasma at time t, and k el is the drug clearance rate. In addition, max Similarly, another PK parameter that can provide insight into the minimum effective dose required for treatment is C min,t , which is the minimum concentration that can be observed at t. By knowing the minimum effective plasma concentration for subject treatment, the minimum dose concentration that must be used can be determined. Unless otherwise stated, the AUC reported in this disclosure and used to describe 0-t or C min,t The time is the time after the initial application, expressed in hours.

[0340] It may not be possible to use the pharmaceutical composition itself to determine a subject's serum drug blood level. As an example, reference is now made to Figure 5 , which is a schematic diagram of two simulated single-dose PK curves of a first oral administration composition, the first oral administration composition includes treated (e.g., micronized - i.e., labeled as "microdifferentiated" - black solid line) 3α-OH-5β-pregnane-20-one and untreated (e.g., unmicronized - i.e., labeled as "unmicronized" - gray dashed line) 3α-OH-5β-pregnane-20-one, the first oral administration composition including the treated 3α-OH-5β-pregnane-20-one providing superior blood levels (C max and AUC 0-t higher). Although Figure 5 Schematic representations of treated and untreated embodiments of the active form are shown, but multiple adjustments can provide similar effects on serum drug blood levels. As an additional example, similar effects were observed when a pharmaceutical composition (e.g., a 300 mg tablet dosage form) was treated and its composition included at least 7.5% surfactant (e.g., poloxamer 407; w / w %), while a second pharmaceutical composition was substantially similar except that it had no or less than 0.5% surfactant. Serum drug blood levels of samples containing 7.5% surfactant and no surfactant were compared Figure 5 The serum drug blood levels observed between the micronized and non-micronized examples were substantially similar. Therefore, in order to achieve the target blood level (C max and AUC 0-t ) and biological sensitivity, all conditions for preparing the stated amounts must be followed.

[0341] Therefore, the 3α-OH-5β-pregnane-20-one in the oral pharmaceutical composition may preferably be in a processed form. More preferably, in an oral solid composition (e.g., a 225 or 450 mg tablet dosage form) comprising 3α-OH-5β-pregnane-20-one, 3α-OH-5β-pregnane-20-one may be in a processed form. The active drug that is at least partially crystalline in the solid form of the oral pharmaceutical composition may further include at least one polymorph of the active drug. In some embodiments, the active drug 3α-OH-5β-pregnane-20-one is substantially crystalline. In some embodiments, 3α-OH-5β-pregnane-20-one may be processed as described above.

[0342] Thus, there remains an unmet need for compositions and methods that can produce higher, faster, more reliable and sufficient serum levels of 3α-OH-5β-pregnane-20-one in a biologically acceptable manner to treat various CNS disorders, thereby enabling the desired release and subsequent effective absorption of 3α-OH-5β-pregnane-20-one to treat subjects in need of 3α-OH-5β-pregnane-20-one for the treatment of CNS disorders. In some aspects, we surprisingly found that the oral compositions and methods of the present invention can effectively produce the desired or required levels of effectiveness of 3α-OH-5β-pregnane-20-one without high sensitivity to food / meal effects.

[0343] In addition, the pharmacodynamic effectiveness of treatment for subjects with at least one epilepsy classification can be identified by monitoring the photoparoxysmal response range (PPR) in individuals with photosensitive epilepsy. Photosensitivity describes the ability to produce epileptiform reactions by light stimulation. This EEG pattern is called photoparoxysmal response (PPR). In the photosensitivity verification of the principle model, patients with PPR in response to flickering diffuse white light are used as subjects. The photosensitivity range of each subject can be determined by deriving the upper and lower limits of sensitivity to intermittent photic stimulation (IPS). This photosensitivity range, defined as the difference between the highest and lowest flash rates that continuously induce PPR, can be used as a quantitative measure of photosensitivity and therefore also as a quantitative measure of epileptogenicity. In photosensitivity studies, the photosensitivity range is repeatedly measured (up to 8 times) over the course of a day. After a single dose of ASM, the reduction in the photosensitivity range can be easily quantified. This reduction has been used as evidence of the anti-epileptic effect of many ASMs currently on the market or in development, most notably levetiracetam, lamotrigine, brivaracetam, carisbamate, ceramide and valproate. If the PPR decreases by at least 2 points compared to placebo or compared to the pre-dose value, the therapy for resolving epilepsy can be considered to be effective. In another embodiment, the PPR may be reduced 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. If the PPR decreases by at least 2 points, the therapy for resolving epilepsy can be considered to be effective. In another embodiment, the PPR may be reduced 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 may be reduced by more in a group orally administered 3α-OH-5β-pregnane-20 than in a group administered placebo. In another embodiment, the PPR may be reduced to zero (complete response).

[0344] Example

[0345] The following examples are provided to facilitate a clearer understanding of certain embodiments of the present invention and are in no way intended to be limiting thereof.

[0346] Example 1. Oral pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one

[0347] The following oral pharmaceutical composition examples are provided to facilitate a clear understanding of certain embodiments of the present invention relating to the treatment of subjects (females and / or males) in need of CNS disorder therapy and are in no way intended to be limiting thereof.

[0348] The following tables (Table A-Table C8) present oral compositions or dosage forms comprising 3α-OH-5β-pregnane-20-one in a form that includes at least one of the following: solubilized, partially solubilized, dissolved, partially dissolved, an amorphous solid, a solid dispersion, a solid solution, and a eutectic mixture.

[0349] Table A. Oral compositions comprising 3α-OH-5β-pregnane-20-one

[0350]

[0351] *Other ingredients may include, but are not limited to, co-solvents, antioxidants, penetration enhancers, stabilizers, plasticizers, curing agents, preservatives, etc. Hereinafter, this applies to all embodiments.

[0352] Table B. Oral compositions comprising 3α-OH-5β-pregnane-20-one and at least one lipophilic additive and one hydrophilic additive

[0353]

[0354] Table C1. Oral compositions comprising tocopherol

[0355]

[0356] The lipophilic or hydrophilic additive may be selected from at least one or a combination of the ingredients shown in the table, but is not limited thereto. Hereinafter, it applies to all embodiments.

[0357] Table C2. Oral compositions containing fatty acids

[0358]

[0359] Table C3. Oral compositions containing glycerol fatty acid esters

[0360]

[0361] Table C4. Oral compositions of PEG glycerides containing fatty acid esters

[0362]

[0363] Table C5. Oral compositions containing polyglycerol fatty acid esters

[0364]

[0365] Table C6. Oral compositions containing triglycerides

[0366]

[0367] Table C7. Oral compositions containing propylene glycol fatty acid esters

[0368]

[0369] Table C8. Oral compositions containing edible oils

[0370]

[0371] The oral pharmaceutical compositions described herein including 3α-OH-5β-pregnane-20-one can be formulated in liquids (e.g., solutions, suspensions, emulsions, beverages, etc.) or in encapsulated gelatin or non-gelatin capsule dosage forms known to those skilled in the art. The capsule can be a soft gelatin or non-gelatin capsule, or a hard gelatin or non-gelatin capsule. The hard capsule can be a two-piece, standard capsule, which generally includes a bottom first capsule portion and a top second capsule portion. The soft capsule can be a two-piece capsule in which the two portions are sealed together, or it can be a one-piece, airtight sealed cap.

[0372] As shown in Table D and Table E below, the oral compositions or dosage forms of the present invention may include a fully solubilized or non-crystalline form (e.g., amorphous) of 3α-OH-5β-pregnane-20-one. The oral compositions of the present disclosure may be formulated to provide a % release rate that may produce enhanced therapeutic levels of 3α-OH-5β-pregnane-20-one for the treatment of depression. The in vitro release percentage of 3α-OH-5β-pregnane-20-one from these oral compositions may be obtained by measuring the release percentage of 3α-OH-5β-pregnane-20-one using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium dodecyl sulfate and using an HPLC method during a 4-hour exposure period of the composition.

[0373] Table D. Oral compositions comprising a non-crystalline form of 3α-OH-5β-pregnane-20-one

[0374]

[0375] Table E. Oral dosage forms comprising an amorphous form of 3α-OH-5β-pregnane-20-one

[0376]

[0377] *5α3βP is 3α-OH-5β-pregnane-20-one.

[0378] As shown in Table E, the oral dosage forms disclosed herein can provide a ratio of 3α-OH-5β-pregnane-20-one to α-tocopherol of less than 1.3, such as 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.

[0379] In one example, the oral dosage form can provide a ratio of 3α-OH-5β-pregnane-20-one to medium chain monoglycerides of less than or equal to about 0.4, about 0.3, about 0.2, about 0.15, such as 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.

[0380] In another example, the oral dosage form can provide a ratio of alpha-tocopherol to hydrophilic additive of about 0.05 to about 4.2, such as any one of 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.

[0381] Table F1. Oral drink dosage form composition including 3α-OH-5β-pregnane-20-one

[0382]

[0383] * The components in the beverage composition may include optional other ingredients, including but not limited to at least one of flavoring agents, sweeteners, antimicrobial agents, preservatives, antioxidants and edible fats.

[0384] Table F2. Drink dosage forms including 3α-OH-5β-pregnane-20-one

[0385]

[0386] * The components in the beverage composition may include optional other ingredients, including but not limited to at least one of flavoring agents, sweeteners, antimicrobial agents, preservatives, antioxidants and edible fats.

[0387] Table F3. Drink dosage forms including 3α-OH-5β-pregnane-20-one

[0388]

[0389] * The components in the beverage composition may include optional other ingredients, including but not limited to at least one of flavoring agents, sweeteners, antimicrobial agents, preservatives, antioxidants and edible fats.

[0390] In one embodiment, the oral solid dosage form of the present disclosure may be formulated to include about 50 mg to about 600 mg of treated 3α-OH-5β-pregnane-20-one, and a variety of additives including at least one surfactant. In another embodiment, the oral solid dosage form may include about 150 mg to about 500 mg of treated 3α-OH-5β-pregnane-20-one, and a variety of additives including at least one surfactant. In yet another embodiment, the oral solid dosage form may include about 50 mg to about 450 mg of treated 3α-OH-5β-pregnane-20-one, and a variety of additives including at least one surfactant. In another embodiment, the oral solid dosage form may include about 225 mg to about 450 mg of treated 3α-OH-5β-pregnane-20-one, and a variety of additives including at least one surfactant. In yet another embodiment, the oral solid dosage form may include about 300 mg to about 450 mg of treated 3α-OH-5β-pregnane-20-one, and a variety of additives including at least one surfactant.

[0391] The solid form of 3α-OH-5β-pregnane-20-one in the composition may account for about 5wt% to about 60wt% of the oral solid dosage form described herein. In one embodiment, 3α-OH-5β-pregnane-20-one may account for about 10wt% to about 45wt% of the oral solid dosage form. In the compositions and forms of the present invention, 3α-OH-5β-pregnane-20-one can be processed as needed. In another embodiment, the oral solid dosage form may include a combination of these forms. In another embodiment, 3α-OH-5β-pregnane-20-one may exist as a processed form (such as an amorphous, micronized, nanoscale, milled, sieved form, or a combination thereof) or be added to an oral solid dosage form comprising at least one surfactant. 3α-OH-5β-pregnane-20-one may be dispersed in the oral solid dosage form. The dispersed portion of 3α-OH-5β-pregnane-20-one may be partially or completely micronized, nanoscale, milled, sieved, amorphous form, or a combination thereof.

[0392] 3α-OH-5β-pregnane-20-one in the oral solid dosage form of the present invention may be partially or completely in a high-energy solid form, which significantly increases the release rate in an aqueous medium compared to its untreated crystalline form (low-energy form). Examples of high-energy solid forms of 3α-OH-5β-pregnane-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-pregnane-20-one in the present invention can be physicochemically stable for at least one month. In another embodiment, the high-energy form of 3α-OH-5β-pregnane-20-one can be physically and / or chemically associated with at least one of the following additional substances: for example, alcohols, pyrrolidone, cellulose, poloxamer, polyols, polyethylene glycol, dextrin, cyclodextrin, etc. Several methods known in the art can be used to produce the high-energy form of 3α-OH-5β-pregnane-20-one in the present invention; for example, coprecipitation, solid-solution, co-melting, co-grinding, hot-melt extrusion, hot-melt spraying, spray drying with a co-solvent, controlled precipitation from a supersaturated solution, a solidified supersaturated solution, and combinations thereof.

[0393] The oral solid dosage form of the present disclosure may include one or more pharmaceutically acceptable additives. Pharmaceutically acceptable additives may be selected from a wide range of compounds and compound classes. Pharmaceutically acceptable additives may account for 40wt% to about 99.5wt% of the oral solid dosage form. In one embodiment, pharmaceutically acceptable additives may account for about 50wt% to 90wt% of the oral dosage form. In one embodiment, pharmaceutically acceptable additives may account for about 50wt% to 85wt% of the oral solid dosage form. In another embodiment, pharmaceutically acceptable additives may account for about 50wt% to 70wt% of the oral solid dosage form.

[0394] Non-limiting examples of compounds that can be used as at least a portion of the pharmaceutically acceptable additive include, but are not limited to, cellulose; dextrins, gums, carbomers, methacrylates, sugars, lactose, inorganic carbonates, oxides, chlorides, sulfates; calcium salts; magnesium salts; fatty acid salts; inorganic and organic acids, bases and salts; propylene glycol; glycerol; fatty acids; fatty alcohols; fatty acid esters; glycerides; mono-, di- or triglycerides; edible oils; omega oils; vegetable oils, hydrogenated vegetable oils; partially or fully hydrogenated vegetable oils; glycerides of fatty acids; waxes; alcohols; gelatin; polyethylene glycol; polyethylene oxide copolymers; silicates; antioxidants, tocopherols, sugar stearates, starches, shellac, resins, proteins, acrylates; methyl copolymers; polyvinyl alcohol; starch; phthalates; and combinations thereof.

[0395] It is important to note that the additives used in the compositions of the present invention can serve a variety of functional purposes in the oral solid dosage form. For example, the additive can also act as a filler, binder, diluent, disintegrant, lubricant, glidant, preservative, sweetener, flavor, coating agent, colorant, antioxidant or release modifier.

[0396] Oral solid dosage form (one or more) is not limited in size, shape or overall configuration, and can be formulated into various dosage forms, including but not limited to two-piece hard gelatin capsules, soft gelatin capsules, pearls, beads, granules, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets and combinations thereof. Other oral solid dosage forms known to those of ordinary skill in the art can also be used. On the one hand, 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.

[0397] The coating can be applied by conventional techniques, such as by pan coaters, rotary granulators and fluidized bed coaters such as top-spray, tangential-spray or bottom-spray (Wurster coating), and most preferably by the latter. A preferred coating solution consists of about 40 wt% EUDRAGIT L30-D55 and 2.5 wt% triethyl citrate in about 57.5 wt% water. The enteric coating solution can be applied to the core of the oral dosage form using a pan coater. The enteric coating materials listed above can be used to granulate the mixture containing 3α-OH-5β-pregnane-20-one. The resulting granulates can be filled into capsules or compressed to form tablets or caplets. The release of 3α-OH-5β-pregnane-20-one from the oral dosage form of the present disclosure or the components of the dosage form (e.g., granules) can be controlled or delayed.

[0398] Several oral dosage forms including 3α-OH-5β-pregnane-20-one in solid form were prepared using the components listed in Table H and Table I. Examples of 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 uniform powder blend. In another aspect, the amount of surfactant in the composition may be greater than 0.5% (w / w) of the composition. The powder blend can be compressed to form tablets by direct compression or after a dry or wet granulation process step. In the case of wet granulation, a binder (e.g., PVP K30) solution can be used for granulation. When a surfactant is present in the dosage form, the binder solution may optionally include a portion (or all) of the amount of at least one surfactant. After granulation, the resulting product can be dried, sieved, and compressed into tablets.

[0399] The solid dosage form of 3α-OH-5β-pregnane-20-one may include a crystalline or amorphous solid form of 3α-OH-5β-pregnane-20-one. The final form of 3α-OH-5β-pregnane-20-one in the dosage form may be the result of the processing technology used (such as size reduction, coating, spraying, drying, hot melt extrusion, etc.). The final form of 3α-OH-5β-pregnane-20-one in the solid dosage form may be milled, micronized, nanoscale, amorphous, a solid solution or dispersion or a eutectic mixture. The solid dosage form may be in the form of a capsule, tablet, or powder, or granules, or pellets.

[0400] The oral compositions of the present disclosure including solid forms of 3α-OH-5β-pregnane-20-one can be formulated to provide a % release rate that can produce an enhanced therapeutic effect of 3α-OH-5β-pregnane-20-one for treating CNS disorders. The in vitro release percentage of 3α-OH-5β-pregnane-20-one from these oral compositions can be obtained by inserting the oral composition into a USPII type dissolution apparatus at about 75-100 rpm, 37° C. and measuring the release percentage of 3α-OH-5β-pregnane-20-one in an aqueous medium with sink conditions for at least 4 hours using an HPLC method.

[0401] In one aspect, the treated solid form oral composition of the present invention comprising 3α-OH-5β-pregnane-20-one can disintegrate in an aqueous medium for less than 25 min. In another aspect, the treated solid form oral composition of the present invention comprising 3α-OH-5β-pregnane-20-one can disintegrate in an aqueous medium for less than 20 min. In a further aspect, the treated solid form oral composition of the present invention comprising 3α-OH-5β-pregnane-20-one can disintegrate in an aqueous medium for less than 20 min, such as less than 19 min, 18 min, 16 min, 15 min, 14 min, 13 min, 12 min, 11 min, 10 min, 9 min, 8 min, 7 min, 6 min, 5 min, 4 min, 3 min, 2 min and 1 min.

[0402] In one aspect, the oral dosage form disclosed herein can be prepared with 3α-OH-5β-pregnane-20-one obtained by treating the original powder of 3α-OH-5β-pregnane-20-one. For example, the treated 3α-OH-5β-pregnane-20-one in the present invention is a micronized powder of 3α-OH-5β-pregnane-20-one, which may have a particle size distribution of D90<20μm. For example, one of the treated 3α-OH-5β-pregnane-20-ones in the present invention is a micronized powder of 3α-OH-5β-pregnane-20-one, which has a particle size distribution of D90=16μm. In addition, as another example, another one of the treated 3α-OH-5β-pregnane-20-ones in the present invention is a micronized powder of 3α-OH-5β-pregnane-20-one, which has a particle size distribution of D90=13μm. On the other hand, an oral dosage form can be prepared to achieve immediate release to improve bioavailability, which includes a processing aid and at least one surfactant and treated 3α-OH-5β-pregnane-20-one to form a uniform powder blend. Table G shows some exemplary oral solid compositions of the present invention, which include 3α-OH-5β-pregnane-20-one in a solid form treated to achieve immediate release and any surfactant.

[0403] Table G. Oral compositions comprising processed 3α-OH-5β-pregnane-20-one

[0404]

[0405] *Processing aids may include but are not limited to fillers, binders, diluents, disintegrants, lubricants, glidants, preservatives, sweeteners, flavors, coating agents, colorants, antioxidants, release modifiers, water, etc.

[0406] Processed is defined as ground, sieved, micronized or nanosized, milled, amorphous, or fully solubilized.

[0407] In another example, Table H shows some preferred oral compositions of the present invention, which include 3α-OH-5β-pregnane-20-one in a solid form for achieving immediate release and optionally a surfactant.

[0408] Table H. Preferred oral compositions comprising treated solid forms of 3α-OH-5β-pregnane-20-one

[0409]

[0410] Processed is defined in this table as ground, sieved, micronized or nanosized, milled or amorphous.

[0411] *Binders may also include, but are not limited to, povidone, copovidone, crospovidone, polyvinylpyrrolidone, starch, sucrose, polyethylene glycol, cellulose, lactose, croscarmellose sodium, and gelatin.

[0412] **Surfactants may also include, but are not limited to, sodium lauryl sulfate, TPGS, cyclodextrin, polysorbate, sodium lauryl ethoxy sulfate, sodium lauryl sulfate, sodium docusate, and hydrogenated polyoxyl castor oil.

[0413] ***Glidants may also include, but are not limited to, magnesium carbonate, glyceryl distearate, glyceryl palmitostearate, ascorbyl palmitate, calcium palmitate, starch, and talc.

[0414] **** Lubricants may also include, but are not limited to, stearic acid, stearin, glyceryl dibehenate, sodium stearyl fumarate, glyceryl distearate, glyceryl palmitostearate, PEG, boric acid, and waxes.

[0415] In addition to the functional components shown in the table, processing aids may also be added with, but are not limited to, release modifiers, disintegrants, preservatives, sweeteners, flavors, coating agents, colorants, antioxidants and water.

[0416] Example 2. Oral Dosage Formulations Including 3α-OH-5β-Pregnane-20-One

[0417] Solubility, dispersibility and dissolution testing were performed and compared with various exemplary oral dosage form formulations in solid, liquid and suspension forms including 3α-OH-5β-pregnane-20-one. Table 1 shows various exemplary oral dosage form formulations including 3α-OH-5β-pregnane-20-one to evaluate the effects of formulation on solubility, dispersibility and dissolution, which may affect the bioavailability (or in vivo absorption) of 3α-OH-5β-pregnane-20-one to subjects in need of 3α-OH-5β-pregnane-20-one therapy.

[0418] Table I. Oral Dosage Formulations Including 3α-OH-5β-Pregnane-20-One

[0419]

[0420] The release rate of 3α-OH-5β-pregnane-20-one was obtained from each of the composition formulations #1, #2 and #3 by exposing one gram of each composition to 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate in a USPI II dissolution apparatus at 37°C and 75 rpm. The results were compared with the release rate of a composition consisting of a conventional tablet formulation without surfactant (Formulation #4), a suspension formulation of crystalline 3α-OH-5β-pregnane-20-one in canola oil (Formulation #5), and a suspension formulation of crystalline 3α-OH-5β-pregnane-20-one in polysorbate 80 (Formulation #6). Figure 2 The dosage amounts per unit of 3α-OH-5β-pregnane-20-one released in the test are shown as Formulation #1: 52 mg / g, Formulation #2: 65 mg / g, Formulation #3: 85 mg / g, Formulation #4: 93 mg / g, Formulation #5: 30 mg / g, Formulation #6: 30 mg / g.

[0421] The dispersibility of the disclosed oral compositions comprising 3α-OH-5β-pregnane-20-one (Formulations #9 and #10) was conducted in aqueous dilution (100-fold) of simulated intestinal fluid, pH 6.8, according to USP 26. The dispersibility results were compared to the dispersibility of compositions comprising solubilized 3α-OH-5β-pregnane-20-one in medium chain triglycerides (e.g., MIGLYOL 812, Formulation #7) and in canola oil (Formulation #8).

[0422] Figure 2 Release performance results in

[0423] Figure 2 A graph showing the release rates of 3α-OH-5β-pregnane-20-one obtained for Formulations #1, #2 and #3 compared to the conventional compositions of Formulations #4, #5 and #6. Figure 2 The dosage amounts of 3α-OH-5β-pregnane-20-one per unit of the release test are respectively Formulation #1: 52 mg / g, Formulation #2: 65 mg / g, Formulation #3: 85 mg / g, Formulation #4: 93 mg / g, Formulation #5: 30 mg / g, Formulation #6: 30 mg / g. In these formulations, 3α-OH-5β-pregnane-20-one is processed (e.g., micronized) before formulating the composition.

[0424] In one example, if Figure 2 As shown, when measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium dodecyl sulfate, the composition of the present invention can release at least 45 mg of 3α-OH-5β-pregnane-20-one after 30 minutes.

[0425] In another example, Figure 2 As shown, when measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium dodecyl sulfate, the composition of the present invention can release at least 70% of 3α-OH-5β-pregnane-20-one after 30 minutes.

[0426] In a further example, if Figure 2 As shown, when measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate, the composition of the present invention can release greater than about 35 mg of 3α-OH-5β-pregnane-20-one after 15 minutes.

[0427] In yet a further example, if Figure 2 As shown, when measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium dodecyl sulfate, the composition of the present invention can release at least 50% of 3α-OH-5β-pregnane-20-one after 15 minutes.

[0428] In yet a further example, if Figure 2 As shown, when measured using a USPII type II dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate, the composition of the present invention can release at least 25% more 3α-OH-5β-pregnane-20-one after 30 minutes compared to a composition mainly consisting of a conventional tablet formulation without a surfactant (Formulation #4), a suspension formulation of crystalline 3α-OH-5β-pregnane-20-one in canola oil (Formulation #5), and a suspension formulation of crystalline 3α-OH-5β-pregnane-20-one in polysorbate 80 (Formulation #6).

[0429] In not shown Figure 2 In one example, when measured using a USPII type II dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate, the composition of the present invention can release at least 20% more 3α-OH-5β-pregnane-20-one after 30 minutes compared to a tablet formulation (formulation #12) composition containing less than 0.5% (w / w) of the composition. In another example, the composition of the present invention has a faster disintegration time (e.g., less than 25 min) than a tablet form (formulations #4 and #12) comprising less than 0.5% (w / w) of the composition.

[0430] In yet a further example, if Figure 2 As shown, a conventional solid dosage form composition (e.g., Formulation #4) without a surfactant can release less than about 45 mg of 3α-OH-5β-pregnane-20-one after 30 minutes when measured using a USPII type dissolution apparatus at 37°C, 75 rpm in 900 mL of deionized water containing 0.5% (w / v) sodium lauryl sulfate.

[0431] In yet another embodiment, in a method of using a composition disclosed herein, the composition comprises a 30-minute initial release rate of 3α-OH-5β-pregnane-20-one, the 30-minute initial release rate of 3α-OH-5β-pregnane-20-one comprising at least one of: A) at least one of 10%, 15%, 20%, and 25% greater than the 3α-OH-5β-pregnane-20-one release rate 30 minutes after the start of the in vitro test of a first comparative composition consisting primarily of treated 3α-OH-5β-pregnane-20-one suspended in Tween 80, B) at least one of 10%, 15%, 20%, and 25% greater than the 3α-OH-5β-pregnane-20-one release rate 30 minutes after the start of the in vitro test of a first comparative composition consisting primarily of treated 3α-OH-5β-pregnane-20-one suspended in Tween 80, and B) at least one of 10%, 15%, 20%, and 25% greater than the 3α-OH-5β-pregnane-20-one release rate 30 minutes after the start of the in vitro test of a first comparative composition consisting primarily of treated 3α-OH-5β- The invention relates to a second comparative composition comprising pregnane-20-one, wherein the release rate of 3α-OH-5β-pregnane-20-one is at least 10%, 15%, 20% and 25% greater than the release rate of 3α-OH-5β-pregnane-20-one 30 minutes after the start of the in vitro test, and C) is at least 10%, 15%, 20% and 25% greater than the release rate of 3α-OH-5β-pregnane-20-one 30 minutes after the start of the in vitro test of a third comparative composition comprising treated crystalline 3α-OH-5β-pregnane-20-one and multiple additives, wherein the additives include a surfactant in an amount not exceeding 0.5wt% of the 3α-OH-5β-pregnane-20-one of the third comparative composition.

[0432] Figure 3 Dispersion evaluation after SIF dilution

[0433] Figure 3 Shown are images of the comparative dispersibility of disclosed oral compositions comprising a non-crystalline 3α-OH-5β-pregnane-20-one form exposed to aqueous dilution (100-fold) of simulated intestinal fluid according to USP 26, pH 6.8, compared to the dispersibility of compositions comprising 3α-OH-5β-pregnane-20-one solubilized in medium chain triglycerides (e.g., MIGLYOL 812, Formulation #7) and in canola oil (Formulation #8).

[0434] like Figure 3 As shown, formulations #7 and #8 (comprising 3α-OH-5β-pregnane-20-one solubilized in MIGLYOL 812 and canola oil, respectively) were not dispersed or solubilized (the oily content at the surface was completely separated from the aqueous medium) in a 100-fold diluted pH 6.8 simulated intestinal fluid according to USP 26, while the compositions of the disclosed invention (formulations #9 and #10) dispersed well. The UV absorbance measured at 450 nm for formulations #7 and #8 was not measurable, while formulations #9 and #10 measured 1.3 Abs and 3.2 Abs, respectively.

[0435] Example 3. Oral Dosage Formulations Comprising Untreated 3α-OH-5β-Pregnane-20-One

[0436] The oral composition comprising untreated 3α-OH-5β-pregnane-20-one in crystalline form is expected to have a slower release rate of 3α-OH-5β-pregnane-20-one, which may be due to the particle size distribution of 3α-OH-5β-pregnane-20-one in the composition. Table J shows various exemplary oral dosage form formulations comprising untreated 3α-OH-5β-pregnane-20-one, and its expected release rate is measured using a USPII type dissolution apparatus at 75 rpm in 900 mL of aqueous medium at 37°C, with the sink condition of the 3α-OH-5β-pregnane-20-one.

[0437] Table J

[0438]

[0439] *Untreated D10>20 μm and D50=55 μm.

[0440] Example 4.3 PK Value of Oral Composition of α-OH-5β-Pregnane-20-one

[0441] Exemplary non-aqueous oral dosage forms I2 (e.g., Formulation 2 in Table I) and H8 (e.g., Formulation 8 in Table H) were prepared and single doses of varying dosage concentrations were administered to subjects while monitoring serum drug blood levels over a 24-hour period. Composition I2 can be prepared, for example, as D1 and D2 doses including 3α-OH-5β-pregnane-20-one in a manner substantially similar to the methods described for composition I2 in Table I. Composition I2 can be prepared to have 6.5% 3α-OH-5β-pregnane-20-one (% w / w). Composition I2 can be administered in the fed meal state as D1 and D2 doses, and the D2 dose can also be administered in the fasted meal state. Composition H4 can be prepared as dose D3 in a manner substantially similar to the methods described for composition 4 in Table H. Composition H4 can be prepared to have 16.9% 3α-OH-5β-pregnane-20-one (% w / w). Composition H4 can be administered as dose D3 in the fasted meal state. Composition H8 can be prepared as a dose D4 in a manner substantially similar to that described with respect to Composition 8 in Table H. Composition H8 can be prepared to have 40% 3α-OH-5β-pregnane-20-one (% w / w). Composition H8 can be administered as a dose D4 in the fasted fed state, and the D4 dose can also be administered in the fed fed state. A comparison of exemplary single-dose oral pharmaceutical compositions is shown in Table K below. This table identifies the formulation, the administered dose of 3α-OH-5β-pregnane-20-one, the fed state, the average PK parameter C max and AUC 0-t .

[0442] Table K

[0443]

[0444] Referring to Table K, the PK parameters of formulations I2, H4 and H8 were calculated to compare the PK parameter AUC 0-t (AUC is the area under the curve measured from time 0 hours to the end of treatment observation. 0-t / 剂量 , C max , C max / 剂量 and T max Composition I2 is a non-aqueous, cyclodextrin-free encapsulated liquid form of 3α-OH-5β-pregnane-20-one, while compositions H4 and H8 are solid dosage forms (also non-aqueous and cyclodextrin-free) comprising treated 3α-OH-5β-pregnane-20-one.

[0445] On the other hand, allowing for timed release of drug exposure (e.g., fast release, intermediate release, or slow release) can further benefit drug administration efficacy. max 2.5 hours or less) may be preferred for treatment of disorders requiring a fast onset (such as ARS), while other treatments will benefit from allowing for an intermediate release (e.g., T max 2 hours or between 2 hours and 8 hours) of prolonged drug exposure, such as generalized epilepsy. For example, various embodiments of the present disclosure can be used to extend the T of drug treatment max The T of the drug treatment is controlled to be less than or about 2 hours, greater than 2 hours, or less than or about 8 hours. As another example, the T of the drug treatment max It may be greater than or equal to about 1 hour, greater than or equal to about 2.5 hours, greater than or equal to about 3 hours, greater than or equal to about 3.5 hours, greater than or equal to about 6 hours, or greater than or equal to about 8 hours.

[0446] As an example, various exemplary embodiments of the present disclosure may be used to control PK exposure. max Can be equal to or greater than 4.25 ng mL -1 , equal to or greater than 6.32ng mL -1 , equal to or greater than 11.0ng mL -1 , equal to or greater than 40.0ng mL -1 , equal to or greater than 17.9 ng mL -1 , equal to or greater than 48.5ng mL -1 , equal to or greater than 53.6ng mL -1 or equal to or greater than 48.6 ng mL -1 As another example, AUC 0-t Can be equal to or greater than about 22.9 ng h mL -1 , equal to or greater than about 54.8ngh mL -1 , equal to or greater than about 72.0 ng h mL -1 , equal to or greater than about 86.4 ng h mL -1 , equal to or greater than about 73.5 ng hmL -1 , equal to or greater than about 171.7 ng h mL -1 , equal to or greater than about 226.5 ng h mL -1 or equal to or greater than about 243.8ngh mL -1 .

[0447] In another aspect, the compositions disclosed herein including 3α-OH-5β-pregnane-20-one can be in a form that provides a therapeutically effective amount / blood level of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnane-20-one can be combined with a variety of additives, including at least one lipophilic additive, sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. In another aspect, 3α-OH-5β-pregnane-20-one can be combined with a variety of additives, including at least one surfactant, sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. In another aspect, 3α-OH-5β-pregnane-20-one can be combined with a variety 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-pregnane-20-one for treating a CNS disorder in a subject. In one aspect, the composition is a solid dosage form or a non-liquid dosage form. In another aspect, in the composition of the starting form of the 3α-OH-5β-pregnane-20-one composition, the 3α-OH-5β-pregnane-20-one form is a solid form or a solid crystalline form or a non-completely solubilized form.

[0448] In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide sufficient or adequate or required CNS max and / or AUC 0-t .

[0449] In another aspect, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide a minimum C of 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 of 3α-OH-5β-pregnane-20-one. max .

[0450] In addition, in yet another embodiment, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide about 0.06 ngmL -1 mg -1 , about 0.07ng mL -1 mg -1 , about 0.09ng mL -1 mg -1 , about 0.11ng mL -1 mg -1 , about 0.12ng mL -1 mg -1 , about 0.16ng mL -1 mg -1 and about 0.27 ng mL -1 mg -1 The dose-normalized maximum C max In another aspect, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide a minimum C of at least about 4.25 ng / mL of 3α-OH-5β-pregnane-20-one. max , and / or about 0.27 ng mL -1 mg -1 At least one of the dose-normalized maximum C max On the one hand, C max and / or dose normalized C max The minimum threshold of is achieved by the compositions and methods of the present invention, wherein the composition is a solid dosage form or a non-liquid dosage form or an encapsulated liquid dosage form or a liquid dosage form without cyclodextrin or a non-aqueous liquid dosage form or a dosage form comprising less than 250 mg / ml or mg / g cyclodextrin. On the other hand, C max and / or dose-normalized AUC 0-t The minimum threshold of C is achieved by including a composition in the form of 3α-OH-5β-pregnane-20-one in the composition, wherein the starting form of 3α-OH-5β-pregnane-20-one used for formulation or processing or post-formulation / processing is substantially in solid form or solid crystalline form or encapsulated fully solubilized form or substantially non-aqueous solubilized form or aqueous solubilized form without cyclodextrin or solid / solubilized form containing less than 250 mg / ml or mg / g cyclodextrin. On the other hand, C is achieved by oral administration of the composition regardless of food / meal or in the fasting state. max and / or dose normalized C max The minimum threshold value.

[0451] In another embodiment, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide a minimum AUC of 3α-OH-5β-pregnane-20-one. 0-t At least 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. In addition, in another embodiment, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide a dose-normalized minimum AUC of at least one 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 aspect, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide a minimum AUC of 3α-OH-5β-pregnane-20-one of at least about 20 ng*h / mL. 0-t , and / or a dose-normalized minimum AUC of at least one of about 0.46 h / L 0-t On the one hand, AUC 0-t and / or dose-normalized AUC 0-t The minimum threshold is achieved by the compositions and methods of the present invention, wherein the composition is a solid dosage form or a non-liquid dosage form or an encapsulated liquid dosage form or a liquid dosage form without cyclodextrin or a non-aqueous liquid dosage form or a dosage form comprising less than 250 mg / ml or mg / g cyclodextrin.

[0452] On the other hand, AUC 0-t and / or dose-normalized AUC 0-t The minimum threshold of AUC is achieved by including a composition in the form of 3α-OH-5β-pregnane-20-one in the composition, wherein the starting form of 3α-OH-5β-pregnane-20-one used for formulation or processing or post-formulation / processing is substantially a solid form or a solid crystalline form or an encapsulated fully solubilized form or a substantially non-aqueous solubilized form or an aqueous solubilized form without cyclodextrin or a solid / solubilized form containing less than 250 mg / ml or mg / g cyclodextrin. On the other hand, regardless of food / meal, AUC is achieved by oral administration of the composition 0-t and / or dose-normalized AUC 0-t The minimum threshold value.

[0453] On the other hand, the composition disclosed herein including 3α-OH-5β-pregnane-20-one can be in a form that provides a therapeutically effective amount / blood level of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnane-20-one can be combined with a variety of additives, including at least one lipophilic additive, sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. On the other hand, 3α-OH-5β-pregnane-20-one can be combined with a variety of additives, including at least one surfactant, sufficient to provide a therapeutically effective amount / blood level of 3α-OH-5β-pregnane-20-one for treating a CNS disorder in a subject. In one aspect, the composition is a solid dosage form or a non-liquid dosage form. On the other hand, in the composition of the starting form of the 3α-OH-5β-pregnane-20-one composition, the 3α-OH-5β-pregnane-20-one form is in a solid form or a solid crystalline form or a non-completely solubilized form.

[0454] Furthermore, 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, wherein the composition is a solid dosage form or a non-liquid dosage form or an encapsulated liquid form or a cyclodextrin-free liquid form or a non-aqueous liquid form. On the other hand, C max and / or dose-normalized AUC 0-t The minimum threshold of C is achieved by including a composition in the form of 3α-OH-5β-pregnane-20-one in the composition, wherein the starting form of 3α-OH-5β-pregnane-20-one used for formulation or processing or post-formulation / processing is substantially in solid form or solid crystalline form or encapsulated fully solubilized form or substantially non-aqueous solubilized form or aqueous solubilized form free of cyclodextrin. On the other hand, C is achieved by oral administration of the composition regardless of food / meal or in the fasting state. max and / or dose normalized C max The minimum threshold value.

[0455] On the other hand, AUC 0-t and / or dose-normalized AUC 0-t The minimum threshold of AUC is achieved by including a composition in the form of 3α-OH-5β-pregnane-20-one in the composition, wherein the starting form of 3α-OH-5β-pregnane-20-one used for formulation or processing or post-formulation / processing is substantially in solid form or solid crystalline form or encapsulated fully solubilized form or substantially non-aqueous solubilized form or aqueous solubilized form free of cyclodextrin. On the other hand, AUC is achieved by oral administration of the composition regardless of food / meal 0-t and / or dose-normalized AUC 0-t The minimum threshold value.

[0456] In one embodiment, 3α-OH-5β-pregnane-20-one compositions and oral dosage forms can be formulated to provide a blood level or peak blood level of 3α-OH-5β-pregnane-20-one that is therapeutically effective for treating a CNS disorder when orally administered to a subject. For example, in one aspect, the compositions and oral dosage forms can include a variety of pharmaceutically acceptable additives that provide serum 3α-OH-5β-pregnane-20-one in an amount / level sufficient to treat a CNS disorder when orally administered to a subject.

[0457] In one embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of additives, wherein oral administration of the composition to a subject suffering from at least one neuropsychiatric and neurodegenerative disorder results in a serum level of 3α-OH-5β-pregnane-20-one in the subject such that the at least one neuropsychiatric and neurodegenerative disorder is substantially eliminated, improved or reduced.

[0458] In one embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of an aqueous solution of non-encapsulated SBE-β-CD (administration of a cyclodextrin solution). max Serum C levels and 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0459] In one embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject in the fasting state, the composition provides a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of an aqueous solution of non-encapsulated SBE-β-CD (administered in a cyclodextrin solution). max or dose-normalized C max Serum C level and / or 3α-OH-5β-pregnane-20-one avg or dose-normalized C avg At least one of the levels.

[0460] In one embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject with food, the composition provides a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of an aqueous solution of non-encapsulated SBE-β-CD (administered in a cyclodextrin solution). max or dose-normalized C max Serum C level and / or 3α-OH-5β-pregnane-20-one avg or dose-normalized C avg At least one of the levels.

[0461] In one embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject without regard to meals / food, the composition provides a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of an aqueous solution of non-encapsulated SBE-β-CD (administered in a cyclodextrin solution). max Level or dose normalization C max and / or 3α-OH-5β-pregnane-20-one serum C avg or dose-normalized C avg At least one of the levels.

[0462] In another embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition provides a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of a medium chain triglyceride solution (MCT administration). max Serum C levels and 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0463] In yet another embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition is intended to provide a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of a polysorbate-80 suspension (polysorbate 80 administration). max Levels, serum C of 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0464] In yet another embodiment, an oral pharmaceutical composition comprises 3α-OH-5β-pregnane-20-one and a plurality of pharmaceutically acceptable additives, wherein when the composition is orally administered to a subject, the composition is expected to provide a serum C level of 3α-OH-5β-pregnane-20-one in the subject that is greater than the serum level provided by administration of a substantially equivalent amount of 3α-OH-5β-pregnane-20-one in a composition consisting essentially of a canola oil or peanut oil solution (edible oil administration). max Levels, serum C of 3α-OH-5β-pregnane-20-one avg At least one of the levels.

[0465] In one embodiment, the 3α-OH-5β-pregnane-20-one composition or oral dosage form or method can be formulated to effectively provide an expected serum level of 3α-OH-5β-pregnane-20-one when orally administered to a subject, which is therapeutically effective for treating CNS disorders. On the other hand, when orally administered to a subject, 3α-OH-5β-pregnane-20-one can be in a form that maximizes the serum level of 3α-OH-5β-pregnane-20-one. On the other hand, 3α-OH-5β-pregnane-20-one can be in a form that increases the serum level of 3α-OH-5β-pregnane-20-one when orally administered to a subject. On the other hand, the compositions and methods of the present invention, when orally administered to a subject, increase the serum level of 3α-OH-5β-pregnane-20-one compared to a composition comprising an equal amount of a processed crystalline (micronized) form of 3α-OH-5β-pregnane-20-one mainly composed of 3α-OH-5β-pregnane-20-one suspended in an edible oil when administered orally.

[0466] In yet another embodiment, dosage regimens and methods 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-pregnane-20-one.

[0467] In one embodiment, the compositions and oral dosage forms may include a plurality of pharmaceutically acceptable additives, wherein the additives include at least one of alpha-tocopherol, sterols, glyceryl monocaprylate, propylene glycol monolaurate, PEG-35 hydrogenated castor oil, PEG-40 hydrogenated castor oil, poloxamers, and combinations thereof, which, when orally administered to a subject, provide sufficient levels of 3α-OH-5β-pregnane-20-one in an amount sufficient to treat a CNS disorder.

[0468] In one aspect, a therapeutically effective amount of 3α-OH-5β-pregnane-20-one can provide a serum level of 3α-OH-5β-pregnane-20-one sufficient to treat a CNS disorder (e.g., a mean serum level of: C avg or peak serum level: C max ). In another aspect, the therapeutically effective amount of 3α-OH-5β-pregnane-20-one in the composition can be in a form that provides a therapeutically effective serum level of 3α-OH-5β-pregnane-20-one to treat a CNS disorder in a subject after oral administration. In a further aspect, the 3α-OH-5β-pregnane-20-one in the composition disclosed herein can be in a processed form with a variety of additives, which can include at least one surfactant that provides a therapeutically effective level of 3α-OH-5β-pregnane-20-one that is effective to treat a CNS disorder in a subject. In yet another aspect, 3α-OH-5β-pregnane-20-one can be combined with a variety of additives that are sufficient to provide a therapeutically effective serum level of 3α-OH-5β-pregnane-20-one to treat a CNS disorder in a subject after oral administration thereof.

[0469] In another embodiment, the dosage regimens and methods of the present invention for treating CNS disorders in females include infant females, females less than 5 years old, females 5-18 years old, non-pregnant females of childbearing age (e.g., females 15-45 years old), pregnant females, females who have given birth within at least one of 1 month, 6 months and 12 months, perimenopausal females (e.g., females 45-50 years old), or postmenopausal females.

[0470] In one embodiment, the oral composition described herein may not contain any modulators that slow down the release rate of 3α-OH-5β-pregnane-20-one in aqueous media or in vivo. In one embodiment, the composition may be non-aqueous. In another more specific embodiment, the composition may be encapsulated.

[0471] In another embodiment, the composition may include less than 250 mg / ml or mg / g of SBE-β-CD. In another more specific embodiment, the composition may be substantially free of SBE-β-CD.

[0472] In another embodiment, the composition is a non-aqueous composition filled in a capsule or tablet dosage form.

[0473] In another embodiment, the oral solid dosage form (one or more) described herein may not have a synchronous release characteristic of 3α-OH-5β-pregnane-20-one and a solubilizer in an aqueous medium so that the dosage form can release more than 90% of 3α-OH-5β-pregnane-20-one within 4 hours after administration or in vitro testing. In other words, 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 be different from the release rate of the additive.

[0474] 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-pregnane-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-pregnane-20-one, which, when orally administered to a subject, is expected to provide a 3α-OH-5β-pregnane-20-one C of greater than about 4.25 ng / ml when measured using LC-MS or GC-MS. max , regardless of meal consumption.

[0475] The oral pharmaceutical composition including 3α-OH-5β-pregnane-20-one can be administered as an oral dosage form (such as a solid, liquid, or partially or completely solubilized oral dosage form) conventionally intended to release and deliver 3α-OH-5β-pregnane-20-one in large quantities in the gastrointestinal tract other than the oral cavity.

[0476] In certain embodiments, the oral pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one can be administered as a solid dosage form known to those of ordinary skill in the art. Examples of solid dosage forms include, but are not limited to, two-piece hard gelatin capsules, soft gelatin capsules, beads, beads, granules, pellets, pellets, microcapsules, microspheres, nanospheres, nanocapsules, tablets, and combinations thereof.

[0477] In certain embodiments, the oral pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one can be administered as a liquid (e.g., solution, suspension, drink, etc.) or partially or completely solubilized in a gelatin or non-gelatin capsule as known to those skilled in the art. The gelatin capsule can be a soft gelatin capsule or a hard gelatin capsule or any other capsule. The hard gelatin capsule can be a two-piece, standard gelatin capsule, which generally includes a first bottom capsule portion and a second top capsule portion. The soft gelatin capsule can be a two-piece capsule in which the two portions are sealed together, or it can be a one-piece, airtightly sealed capsule.

[0478] In one embodiment, a method for improving symptoms of CNS or neuropsychiatric and neurodegenerative disorders in a subject comprises orally administering to the subject an effective amount of 3α-OH-5β-pregnane-20-one or a pharmaceutically acceptable salt or polymorph thereof or a combination thereof. On the other hand, a method for improving symptoms of CNS, neuropsychiatric and neurodegenerative disorders in a subject comprises orally administering to the subject a composition comprising an effective amount of oral 3α-OH-5β-pregnane-20-one, a pharmaceutically acceptable salt thereof, a polymorph thereof, and a combination thereof. In one aspect, a method for improving symptoms of a CNS or neuropsychiatric and neurodegenerative disorder in a subject comprises, when administered to a subject, an amount of any of oral 3α-OH-5β-pregnane-20-one, a pharmaceutically acceptable salt thereof, a polymorph thereof, and a combination thereof, which, when compared to an equivalent dose of 3α-OH-5β-pregnane-20-one orally administered with a composition comprising an oral aqueous non-encapsulated cyclodextrin, can be greater than any of about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% and 15% of the blood level obtained.

[0479] In one embodiment, a method of treating a CNS disorder comprising orally administering to a subject a pharmaceutical composition comprising 3α-OH-5β-pregnane-20-one and a plurality of additives is contemplated to provide an elevated serum C level of 3α-OH-5β-pregnane-20-one in the subject. max Levels and elevated serum C avg The invention relates to at least one of the following: an increase in the level of 3α-OH-5β-pregnane-20-one in a non-encapsulated SBE-β-CD aqueous solution comprising at least 250 mg / ml of SBE-β-CD (cyclodextrin administration), 3α-OH-5β-pregnane-20-one in a medium chain triglyceride (MCT) solution (MCT administration), 3α-OH-5β-pregnane-20-one in a polysorbate 80 suspension (polysorbate 80 administration), and 3α-OH-5β-pregnane-20-one in canola oil or peanut oil (edible oil administration) to a subject.

[0480] On the other hand, the 3α-OH-5β-pregnane-20-one in the current composition of the present invention can be in a form that increases the serum level of 3α-OH-5β-pregnane-20-one, wherein the increase is greater than a similar increase obtained by administering to a subject substantially equal amounts of at least one of the following: cyclodextrin administration, MCT administration, polysorbate 80 administration, and edible oil administration. In one example, the serum level of 3α-OH-5β-pregnane-20-one can be increased by at least about 20% compared to the serum level obtained by administering to a subject substantially equal amounts of cyclodextrin administration, MCT administration, polysorbate 80 administration, and edible oil administration.

[0481] In one embodiment, when the subject is in a fasting state, administering the composition to the subject results in a T of 3α-OH-5β-pregnane-20-one in the subject after administration. max At least one of less than about 1.5 hours, less than about 2 hours, and less than about 3 hours.

[0482] In one embodiment, when the composition is administered to a subject without regard to meals, the subject causes a T of 3α-OH-5β-pregnane-20-one in the subject after administration. max 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.

[0483] In one embodiment, when a non-solid or liquid composition is administered to a subject without regard to meals, the subject causes a T of 3α-OH-5β-pregnane-20-one in the subject after administration. max 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.

[0484] In one embodiment, when the composition is administered to a subject without regard to meals, wherein the 3α-OH-5β-pregnane-20-one is solubilized or in a non-crystalline form or in a crystalline micronized or nanosized form, the subject results in a T of 3α-OH-5β-pregnane-20-one in the subject after administration. max 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.

[0485] In one embodiment, administering the composition to a subject while the subject is in a fed state results in a T of 3α-OH-5β-pregnane-20-one in the subject after administration. max At least one of greater than or about 3 hours, greater than or about 6 hours, and greater than or about 8 hours.

[0486] In one embodiment, the administered dose includes at least one of a QD dose, a BID dose, a TID dose, a QID dose, and more than a QID dose.

[0487] In one embodiment, the duration of treatment may be at least one of a minimum of 1 day, 2 days, 2.5 days, 3 days, 5 days, 7 days, and 14 days.

[0488] In another embodiment, the disclosed method of treating a CNS disorder may comprise orally administering to a subject sufficient GABA to achieve A The receptor binding is such that the CNS disorder in the subject is substantially reduced or eliminated in an amount of 3α-OH-5β-pregnane-20-one.

[0489] In one embodiment of the invention, the disclosed method comprises orally administering to a subject a composition having orally bioavailable 3α-OH-5β-pregnane-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 dosage regimen may range from at least once a day for a specified duration of about one day to about three months, or for more than three months.

[0490] In one embodiment of the invention, the disclosed method comprises orally administering to a subject a composition having orally bioavailable 3α-OH-5β-pregnane-20-one therein, wherein the subject has at least one of the following: an acute CNS disorder, an episodic CNS disorder, an intermittent CNS disorder, a subchronic CNS disorder, a chronic CNS disorder, and combinations thereof. The duration of treatment may range from at least once a day or as needed for episodic treatment for a specified duration of about one day to about three months, or for more than three months or for an unspecified duration.

[0491] In one embodiment, a subject in need of an oral composition comprising orally bioavailable 3α-OH-5β-pregnane-20-one as described herein may suffer from a CNS disorder, such as depression (e.g., postpartum depression, postpartum substance addiction disorder, major depressive disorder, treatment-resistant depression, peripartum depression, perimenopausal or postmenopausal depression).

[0492] In some embodiments, oral compositions can be used to treat, reduce or improve conditions, symptoms or diseases associated with CNS disorders described herein in men or women. In one aspect, the subject can be an adolescent male or an adult male. In a further aspect, the subject can be a teenager, an adult, a female of childbearing age, a premenopausal, perinatal, postpartum, pregnancy, perimenopausal or postmenopausal female. In yet another aspect, the subject may not show symptoms of CNS disorders, but may suffer from a disease associated with or caused by a CNS disorder described herein.

Claims

1. A method of treating, ameliorating or managing a condition associated with at least one of seizures, convulsions and epilepsy, the method comprising orally administering a 3α-OH-5β-pregnane-20-one composition to a subject suffering from or susceptible to said condition, wherein in response to said administration, at least one of the following results is achieved, the results comprising: Object C max The minimum threshold is 4.25 ng mL -1 , Object T max In no more than about 2.5 hours, Object T max In no more than about 2.0 hours, Object T max In no more than about 1.5 hours, Object AUC 0-t The minimum threshold is 22.9 ng h mL -1 ,as well as The subject's PPR drops by at least 2 points.

2. The method of claim 1, wherein the result is achieved regardless of the subject's fed or fasted state.

3. The method of claim 1, wherein the composition comprises at least one of a capsule and a tablet.

4. The method according to claim 3, wherein the 3α-OH-5β-pregnane-20-one comprises at least one of crystalline 3α-OH-5β-pregnane-20-one and amorphous 3α-OH-5β-pregnane-20-one or is prepared from the same.

5. The method of claim 1, wherein the composition comprises a surfactant in an amount of at least about 0.5% of the composition.

6. The method of claim 1, wherein the 3α-OH-5β-pregnane-20-one comprises solubilized 3α-OH-5β-pregnane-20-one.

7. The method of claim 1, wherein the treatment, improvement or management comprises at least one of the following: There is no recurrence of the epileptic seizure for at least one of about 2 hours, about 4 hours, about 6 hours, and about 8 hours after said administering, and During a post-administration period of about 28 days, the subject's seizure rate is reduced by at least one of about 10%, about 20%, about 30%, about 40%, and about 50% relative to the subject's baseline seizure rate.

8. The method of claim 1, wherein the epilepsy comprises focal onset epilepsy (FOE), and wherein the epileptic seizure comprises ARS.

9. The method of claim 8, wherein the ARS comprises at least one of clustered seizures, intermittent seizures, crescendo seizures, interictal seizures, recurrent seizures, and periodic seizures.

10. The method of claim 1, wherein the object has at least one of the following: the need for treatment of the condition, Various CNS disorders, History of anti-epileptic treatment, History of antidepressant treatment, Unresolved epileptic symptoms, Unresolved depressive symptoms, anxiety, Depression, and Mental illness.

11. The method of claim 1, wherein the subject comprises a WWE of childbearing age.

12. A method of treating, ameliorating or managing a condition associated with at least one of seizures, convulsions and epilepsy, the method comprising orally administering a 3α-OH-5β-pregnane-20-one composition to a subject suffering from or susceptible to said condition, wherein in response to said administration, regardless of the fed or fasted state of said subject, at least one of the following results is achieved, said results comprising: Object C max The minimum threshold is 4.25 ng mL -1 , Object T max In no more than about 2.5 hours, Object T max In no more than about 2.0 hours, Object T max In no more than about 1.5 hours, Object AUC 0-t The minimum threshold is 22.9 ng h mL -1 ,as well as The subject's PPR drops by at least 2 points.

13. The method of claim 12, wherein the composition comprises at least one of a capsule and a tablet.

14. The method according to claim 13, wherein the 3α-OH-5β-pregnane-20-one comprises at least one of crystalline 3α-OH-5β-pregnane-20-one and amorphous 3α-OH-5β-pregnane-20-one or is prepared from the same.

15. The method of claim 12, wherein the composition comprises a surfactant in an amount of at least about 0.5% of the composition.

16. The method of claim 12, wherein the 3α-OH-5β-pregnane-20-one comprises solubilized 3α-OH-5β-pregnane-20-one.

17. The method of claim 12, wherein the treatment, improvement or management comprises at least one of the following: There is no recurrence of the epileptic seizure for at least one of about 2 hours, about 4 hours, about 6 hours, and about 8 hours after said administering, and During a post-administration period of about 28 days, the subject's seizure rate is reduced by at least one of about 10%, about 20%, about 30%, about 40%, and about 50% relative to the subject's baseline seizure rate.

18. The method of claim 12, wherein the epilepsy comprises FOE, and wherein the epileptic seizure comprises ARS.

19. The method of claim 18, wherein the ARS comprises at least one of clustered seizures, intermittent seizures, crescendo seizures, interictal seizures, recurrent seizures, and periodic seizures.

20. The method of claim 12, wherein the subject has at least one of the following: the need for treatment of the condition, Various CNS disorders, History of anti-epileptic treatment, History of antidepressant treatment, Unresolved epileptic symptoms, Unresolved depressive symptoms, anxiety, Depression, and Mental illness.

21. The method of claim 12, wherein the subject comprises a WWE of childbearing age.

22. A method of treating, ameliorating or managing a condition associated with at least one of seizures, convulsions and epilepsy, the method comprising orally administering a 3α-OH-5β-pregnane-20-one composition to a subject suffering from or susceptible to said condition, wherein in response to said administration, the condition is treated, ameliorated or managed regardless of the fed or fasted state of said subject.

23. The method of claim 22, wherein said treating, improving or managing comprises achieving at least one of the following: Object C max The minimum threshold is 4.25 ng mL -1 , Object T max In no more than about 2.5 hours, Object T max In no more than about 2.0 hours, Object T max In no more than about 1.5 hours, Object AUC 0-t The minimum threshold is 22.9 ng h mL -1 ,as well as The subject's PPR drops by at least 2 points.

24. The method of claim 22, wherein the composition comprises at least one of a capsule and a tablet.

25. The method according to claim 24, wherein the 3α-OH-5β-pregnane-20-one comprises or is prepared from at least one of crystalline 3α-OH-5β-pregnane-20-one and non-crystalline 3α-OH-5β-pregnane-20-one.

26. The method of claim 22, wherein the composition comprises a surfactant in an amount of at least about 0.5% of the composition.

27. The method of claim 22, wherein the 3α-OH-5β-pregnane-20-one comprises solubilized 3α-OH-5β-pregnane-20-one.

28. The method of claim 22, wherein the treating, ameliorating or managing comprises at least one of the following: There is no recurrence of the epileptic seizure for at least one of about 2 hours, about 4 hours, about 6 hours, and about 8 hours after said administering, and During a post-administration period of about 28 days, the subject's seizure rate is reduced by at least one of about 10%, about 20%, about 30%, about 40%, and about 50% relative to the subject's baseline seizure rate.

29. The method of claim 22, wherein the epilepsy comprises FOE, and wherein the epileptic seizure comprises ARS.

30. The method of claim 29, wherein the ARS comprises at least one of clustered seizures, intermittent seizures, crescendo seizures, interictal seizures, recurrent seizures, and periodic seizures.

31. The method of claim 22, wherein the subject has at least one of the following: the need for treatment of the condition, Various CNS disorders, History of anti-epileptic treatment, History of antidepressant treatment, Unresolved epileptic symptoms, Unresolved depressive symptoms, anxiety, Depression, and Mental illness.

32. The method of claim 22, wherein the subject comprises a WWE of childbearing age.

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