Compositions for the treatment of neurodegenerative conditions

Abstract

Disclosed herein are pharmaceutical compositions comprising solid state forms of 17-ethynyl-10R,13S-dimethyl-2,3,4,7,8R,9S,10,11,12,13,14S,15,16,17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3R,7R,17S-triol. Further disclosed herein are methods for using the solid state forms for the treatment of conditions associated with neurodegenerative conditions, including Parkinson's disease.

Description

[Technical field]

[0001] Incorporation by reference to any priority application Any and all applications for which a foreign or domestic priority claim is recognized as being filed with this application in a PCT application are hereby incorporated by reference.

[0002] Background technology Field of the Disclosure The present disclosure relates generally to a compound, 17-ethynyl-10R,13S-dimethyl-2,3,4,7,8R,9S,10,11,12,13,14S,15,16,17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3R,7R,17S-triol, solid state forms of the compound, and methods for using the compound and the solid state forms.

[0003] The present disclosure relates to pharmaceutical compositions of compounds and solid state forms, including polymorphic and pseudopolymorphic forms, and methods for using the compounds and solid state forms in preparing solid and liquid formulations.

[0004] The present disclosure relates to compounds, solid state forms, pharmaceutical compositions, and methods for using solid and liquid formulations for the treatment of conditions associated with neurodegenerative conditions, including Parkinson's disease. [Background technology]

[0005] Description of the Prior Art Levodopa (L-3,4-dihydroxyphenylalanine), also known as L-dopa, is the most effective treatment for alleviating motor symptoms caused by Parkinson's disease (PD), but does not slow disease progression. Levodopa treatment relies on active transport of exogenous levodopa by large neutral amino acid transporters into the central nervous system (CNS), where levodopa is decarboxylated by aromatic L-amino acid decarboxylase to produce dopamine. Crucially, dopamine cannot cross the blood-brain barrier into the CNS, and metabolism of exogenous levodopa in the periphery creates unusable dopamine in the bloodstream. Due to the short half-life of exogenous levodopa, approximately 90 min, and the limited storage capacity of dopamine at dopaminergic terminals in the CNS, levodopa must be administered frequently to be effective in alleviating motor symptoms of PD.

[0006] When levodopa treatment is first initiated, PD patients typically respond smoothly and sustainably, with no motor symptoms and few side effects. However, as PD progresses, degeneration of dopaminergic neurons makes levodopa less efficient to store and release, and the beneficial effects begin to wane 3-4 hours after dosing. Such a reduction in efficacy before the next scheduled dose is called "wearing off." As larger doses of levodopa are administered, various side effects, such as motor complications, become more frequent over time. Motor complications associated with levodopa treatment occur in 30-40 percent of patients during the first 5 years of use and in at least 60 percent of patients by 10 years.

[0007] In levodopa combination therapy, a second medication is administered that slows the peripheral metabolism of levodopa, allowing for the administration of smaller doses of levodopa, with the benefit of delaying the onset of motor complications. One class of medications used for levodopa combination therapy are decarboxylase inhibitors that cannot cross the blood-brain barrier, such as carbidopa (L-alpha-(3,4-dihydroxybenzyl)-alpha-hydrazinopropionic acid). However, levodopa-carbidopa combination therapy involves a number of side effects that may include dizziness, loss of appetite, diarrhea, dry mouth, sore mouth and throat, constipation, altered taste, amnesia, or confusion.

[0008] It has been suggested that levodopa metabolism increases oxidative stress in dopaminergic neurons, which increases the rate of PD progression. However, recent publications indicate that there is no conclusive evidence of levodopa-induced disease acceleration. In the majority of Parkinson's disease patients, chronic pulsatile levodopa exposure produces adaptive responses in dopaminergic and serotonergic neurons, as well as other adaptations that result in hypersensitivity to dopamine and abnormal involuntary movements called levodopa-induced dyskinesia (LID). The pathophysiology of LID is complex, and symptoms may vary between patients compared to levodopa pharmacodynamics. Increased LID severity over time is common, and LID development can be as problematic for patients as Parkinson's disease itself. Inflammatory extracellular signal-regulated kinases 1 and 2 (ERK1 / 2, ERK) have been linked to LID development in animal models, but the specific mechanisms linking inflammation to LID have not been fully elucidated. Anti-inflammatory strategies have been reported to reduce LID in rodent models, but similar publications in non-human primate models are lacking.

[0009] A variety of dopamine receptor agonists and inhibitors of dopamine metabolism (monoamine oxidase inhibitors, MAOIs) have been developed that provide exercise treatments that are less likely to promote LID. These levodopa substitutes provide an important option for patients to delay the initiation of levodopa, which for most patients begins a predictable course that leads to LID, although recent peer reviews have cast doubt on the association between levodopa exposure and time to LID. Unfortunately, many dopamine receptor agonists have undesirable side effects or less stimulatory activity than levodopa, whereas the stimulatory activity of MAOIs makes them useful as monotherapy only early in the disease.

[0010] Efforts to develop treatments for LID are largely based on selective dopamine receptor antagonism and non-pulsatile levodopa administration strategies. Neuropharmacologists working with medicinal chemists have developed highly selective dopamine receptor antagonists that reduce LID expression, but these treatments also generally reduce facilitatory dopaminergic signaling. Strategies to reduce the pulsatility of oral levodopa administration include slow and continuous release oral formulations and L-dopa continuous jejunal infusion, with the latter having the greatest utility in patients with significantly higher LID susceptibility. Despite these treatment options, for the majority of PD patients, LID remains an unsolved problem in the general treatment paradigm. The high likelihood that levodopa treatment induces LID provides a rationale for the development of non-dopaminergic therapeutic alternatives to levodopa. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent No. 8,252,947 Summary of the Invention [Problem to be solved by the invention]

[0012] There is a need for non-dopaminergic therapeutic compositions for the treatment of PD. There is also a need for non-dopaminergic therapeutic compositions for use in levodopa combination therapy that can reduce motor symptoms, delay the onset of motor complications, and exhibit fewer side effects. There is a need for non-dopaminergic therapeutic compositions for the treatment of LID. [Means for solving the problem]

[0013] Disclosed herein is a method for treating a neurodegenerative condition, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising 17α-ethynylandrost-5-ene-3β,7β,17β-triol and at least one pharma- ceutical acceptable excipient. In some embodiments, the neurodegenerative condition is Parkinson's disease.

[0014] In some embodiments, the method further comprises administering to the patient at least one additional medicament. In some embodiments, the additional medicament comprises at least one dopamine agonist. In some embodiments, the additional medicament comprises at least one dopamine precursor. In some embodiments, the additional medicament comprises L-dopa.

[0015] In some embodiments, the additional medicament is administered at a delay after the first administration of the composition. In some embodiments, the delay is 2 years or more. In some embodiments, the delay is 2, 3, or 4 years. In some embodiments, the delay is 5 years. In some embodiments, the delay is more than 5 years.

[0016] In some embodiments, at least one motor symptom develops in the patient. In some embodiments, the motor symptom is selected from tremors and / or tremors in the limbs, slowing of movement (bradykinesia), muscle stiffness, rigidity, immobility (freezing), muscle spasms, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing ability, motor fluctuations, dystonia, and any combination of the foregoing.

[0017] In some embodiments, at least one motor complication develops in the patient. In some embodiments, the motor complication is selected from wearing off, underdosing, onset of dose deterioration, rebound after stopping dosing, unpredictable off-phases, freezing of gait, poor on-phases, acute akinesia, dyskinesia, and any combination of the foregoing.

[0018] In some embodiments, the motor symptoms develop 2, 2.5, 3, 3.5, 4, 4.5, or 5 or more times after the additional medication is administered.

[0019] In some embodiments, the motor complication develops 2, 2.5, 3, 3.5, 4, 4.5, or 5 or more times after the additional medication is administered.

[0020] In some embodiments, 17α-ethynylandrost-5-ene-3β,7β,17β-triol is a solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol is a crystalline solvate of 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is crystalline methanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is crystalline ethanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is crystalline hydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is Form III 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is Form IV 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is Form V 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol is amorphous 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

[0021] In some embodiments, the pharmaceutical compositions contain less than about 3% by weight of impurities.

[0022] In some embodiments, the patient is a human or mammal.

[0023] Further disclosed herein is a pharmaceutical composition comprising 17α-ethynylandrost-5-ene-3β,7β,17β-triol for use in treating a neurodegenerative condition. In some embodiments, the pharmaceutical composition comprises at least one pharma- ceutically acceptable excipient. In some embodiments, the neurodegenerative condition is Parkinson's disease.

[0024] Further disclosed herein is a use of a pharmaceutical composition comprising 17α-ethynylandrost-5-ene-3β,7β,17β-triol for treating a neurodegenerative condition. In some embodiments, the use comprises at least one pharma- ceutically acceptable excipient. In some embodiments, the neurodegenerative condition is Parkinson's disease.

[0025] Further disclosed herein is the use of 17α-ethynylandrost-5-ene-3β,7β,17β-triol in the manufacture of a medicament for treating a neurodegenerative condition. In some embodiments, the medicament comprises at least one pharma- ceutically acceptable excipient. In some embodiments, the neurodegenerative condition is Parkinson's disease. [Brief description of the drawings]

[0026] [Figure 1] 1 shows immobility scores for test subjects treated with a pharmaceutical composition according to an embodiment of the present disclosure. [Diagram 2] 1 shows abnormal involuntary movement scores for test subjects treated with pharmaceutical compositions according to embodiments of the present disclosure. [Diagram 3] 1 shows the percentage of remaining neurons in test subjects treated with a pharmaceutical composition according to an embodiment of the present disclosure. [Figure 4] 1 shows the body weight of test subjects treated with a pharmaceutical composition according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The following description provides context and examples, but should not be construed to limit the scope of the disclosure, which is encompassed by the claims set forth herein below or in any other application claiming priority hereto. No single component or collection of components is essential or required. For example, in some embodiments, one or more variables, such as Y or Y and Q, may be omitted. Any feature, structure, component, material, step, or method described and / or illustrated in any embodiment herein can be used with or in place of any feature, structure, component, material, step, or method described and / or illustrated in any other embodiment herein.

[0028] definition The term "dopamine agonist" as used herein is a substance or drug that can mimic the action of dopamine when ingested. These substances can improve symptoms associated with insufficient levels of dopamine in a subject.

[0029] As used herein, the term "dopamine precursors" refers to substances or drugs that are converted to dopamine in the body. These substances can enter the brain and restore depleted dopamine levels.

[0030] As used herein, "subject," "host," "patient," and "individual" are used interchangeably and are given their ordinary meaning in the art and refer to an organism that has cancer and / or leukemia, including mammals, such as humans, non-human primates, ungulates, canines, felines, equines, mice, and rats. The term "mammal" includes both human and non-human mammals.

[0031] The terms "therapeutically effective amount" and "effective amount" refer to the amount of an active pharmaceutical ingredient required to provide the desired pharmacological result. In practice, the therapeutically effective amount will vary widely depending on the severity of the disease state, the age of the subject, and the desired therapeutic effect.

[0032] The terms "treatment", "treating" and "treat" are to be given their ordinary meanings and are to be included herein to refer generally to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in terms of completely or partially preventing the disease or condition, and / or therapeutic, in terms of partial or complete stabilization, or curing the disease and / or adverse effects attributable to the disease. The term "treatment" as used herein is to be given its ordinary meaning and is to be included in any treatment of a disease in a mammal, particularly a human, including (a) preventing a disease or condition from occurring in a subject who may be predisposed to the disease or condition, but has not yet been diagnosed as having it, (b) inhibiting a disease symptom, e.g., arresting its onset, and / or (c) relieving a disease symptom, e.g., causing regression of the disease or condition.

[0033] All literature and similar materials mentioned in this application, including but not limited to patents, patent applications, papers, books, articles, and Internet web pages, are expressly incorporated by reference in their entirety for any purpose. In the event that the definition of a term in a cited reference appears to differ from the definition provided in the present teachings, the definition provided in the present teachings shall govern. It will be recognized that there is an implied "about" preceding the temperatures, concentrations, times, etc. discussed in the present teachings, such that very small minor deviations are within the scope of the teachings herein. In this application, the use of the singular includes the plural, unless specifically stated otherwise. Also, the use of "comprise", "comprises", "comprising", "contain", "contains", "containing", "include", "includes", and "including" are not intended to be limiting. It is to be understood that both the general description and the following detailed description are exemplary and explanatory only and not restrictive. The term "and / or" indicates that the offered possibilities can be used together or in the alternative. Thus, the term "and / or" indicates that both options are present with respect to a set of possibilities.

[0034] Terms and phrases used in this application, particularly in the appended claims, and variations thereof, unless expressly stated otherwise, should be construed as open-ended as opposed to limiting. For the foregoing examples, the term "including" should be interpreted to mean "including but not limited to" or "including but not limited to" and the like; the term "comprising" as used herein is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least"; the term "includes" should be interpreted as "including but not limited to"; the term "examples" is used to provide illustrative examples of the items discussed, rather than an exhaustive or exclusive enumeration thereof; the use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood as suggesting that a particular feature is critical, essential, or even crucial to the structure or function of the invention, but instead is merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present disclosure. Additionally, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.Similarly, a group of items joined by the conjunction "and" should not be read as requiring the presence of every single one of those items in the grouping, but rather, unless expressly stated otherwise, should be read as "and / or." Similarly, a group of items joined by the conjunction "or" should not be read as requiring mutual exclusivity among the group, but rather, unless expressly stated otherwise, should be read as "and / or."

[0035] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art may convert from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0036] Treatment methods The embodiments of the present disclosure relate to a method for treating a neurodegenerative condition. In some embodiments, the method comprises administering an effective amount of a pharmaceutical composition to a patient in need thereof. In some embodiments, the pharmaceutical composition comprises 17-ethynyl-10R,13S-dimethyl-2,3,4,7,8R,9S,10,11,12,13,14S,15,16,17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3R,7R,17S-triol represented by formula 1. Hereinafter, the compound of formula 1 is also referred to as compound 1 or 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

[0037] [ka]

[0038] In some embodiments, the neurodegenerative condition is Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis. In some embodiments, the neurodegenerative condition is Parkinson's disease, parkinsonism, parkinsonian syndrome, or any combination of the foregoing. In some embodiments, the neurodegenerative condition includes idiopathic Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and vascular parkinsonism, or any combination of the foregoing. In some embodiments, the neurodegenerative condition is Parkinson's disease.

[0039] In some embodiments, the patient is a human or mammal. In some embodiments, the patient is a human.

[0040] In some embodiments, the methods delay administering one or more dopamine agonists to the patient, hi some embodiments, the methods delay administering L-dopa to the patient.

[0041] In some embodiments, the method delays the onset of motor complications in a patient caused by one or more dopamine agonists, hi some embodiments, the method delays the onset of motor complications in a patient caused by L-dopa.

[0042] In some embodiments, the method includes administering at least one additional medicament to the patient. In some embodiments, the additional medicament includes at least one dopamine agonist. In some embodiments, the additional medicament includes an ergoline dopamine agonist, a non-ergoline dopamine agonist, or any combination of the foregoing. Non-limiting examples of suitable dopamine agonists include bromocriptine, cabergoline, apomorphine, pramipexole, ropinirole, rotigotine, APOKYN, KYNMOBI, MIRAPEX, NEUPRO, PARLODEL, and REQUIP. In some embodiments, the additional medicament includes at least one dopamine precursor. Non-limiting examples of suitable dopamine precursors include carbidopa, L-dopa (i.e., levodopa), entacapone, COMTAN, DUOPA, INBRIJA, RYTARY, SINEMET, SINEMET CR, and STALEVO. In some embodiments, the additional medication comprises L-dopa.

[0043] In some embodiments, the additional pharmaceutical agent is administered with a delay time after the first administration of the composition. In some embodiments, the first administration may be administered using a dosing schedule that is daily, weekly, monthly, or any combination of the foregoing. In some embodiments, the first administration schedule may include 1, 2, 3 or more daily doses of the composition. In some embodiments, the first administration schedule may include 1, 2, 3 or more weekly doses of the composition. In some embodiments, the first administration schedule may include 1, 2, 3 or more monthly doses of the composition. In some embodiments, the delay time is about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or more, or a range including and / or spanning the values ​​set forth above. In some embodiments, the delay time is 2 years or more. In some embodiments, the delay time is zero and the additional pharmaceutical agent is administered simultaneously with the first administration of the composition. In some embodiments, the additional pharmaceutical agent is administered using a dosing regimen that is daily, weekly, monthly, or any combination of the foregoing. In some embodiments, the dosing regimen of the additional pharmaceutical agent may include one, two, three or more daily doses of the composition. In some embodiments, the dosing regimen of the additional pharmaceutical agent may include one, two, three or more weekly doses of the composition. In some embodiments, the dosing regimen of the additional pharmaceutical agent may include one, two, three or more monthly doses of the composition.

[0044] In some embodiments, at least one motor symptom develops in the patient.The term "motor symptom" as used herein is one or more of the following: tremor and / or trembling in limbs, slowing of movement (bradykinesia), muscle rigidity, rigidity, immobility (freezing), muscle spasms, posture and / or balance disorder, falling, dizziness, loss of automatic movements such as blinking or smiling, change in speech and / or writing ability, motor fluctuations, and dystonia.The term "dystonia" as used herein is a dystonic state that leads to muscle spasms and abnormal posture.

[0045] In some embodiments, at least one motor complication develops in the patient. The term "motor complication" as used herein may be a repetition of on-phase and off-phase. The term "on-phase" as used herein is a state of positive response to the composition, additional medication, or combination thereof. The on-phase is characterized by the absence or reduction of symptoms associated with Parkinson's disease, parkinsonism, parkinsonian syndrome, or any combination of the foregoing. The term "off-phase" as used herein is a state of no response to the composition, additional medication, or combination thereof. The off-phase is characterized by the presence of symptoms associated with Parkinson's disease, parkinsonism, parkinsonian syndrome, or any combination of the foregoing. In some embodiments, symptoms associated with Parkinson's disease, parkinsonism, and / or parkinsonian syndrome may include at least one motor symptom, as described elsewhere herein.

[0046] In some embodiments, the motor complications may include wearing off, underdosing, onset of dose deterioration, rebound after stopping dosing, unpredictable off-phases, freezing of gait, poor on-phases, acute akinesia, or a combination of the foregoing. The term "wearing off" as used herein is the recurrence of symptoms associated with Parkinson's disease that occurs when metabolism of the composition, additional medication, or combinations thereof is completed. The term "unpredictable off-phases" is an off-phase that does not correlate with administration of the composition, additional medication, or combinations thereof. The term "freezing of gait" as used herein is a state in which progress stops or is significantly reduced. The term "poor on-phases" as used herein is the absence of on-phases following administration of the composition, additional medication, or combinations thereof. The term "acute akinesia" as used herein is a sudden and / or significant increase in symptoms associated with Parkinson's disease, including immobility that lasts for several days and is unresponsive to administration of the composition, additional medication, or combinations thereof.

[0047] In some embodiments, the motor complication may include dyskinesia. The term "dyskinesia" as used herein is an abnormality or disorder of voluntary movement and / or posture. In some embodiments, the motor complication includes dyskinesia selected from L-dopa-induced dyskinesia, chorea, dystonia, ballismus, myoclonus, peak-dose dyskinesia, biphasic dyskinesia, wearing-off dyskinesia, wearing-off dystonia, or a combination of the foregoing. The term "peak-dose dyskinesia" as used herein appears during the on-phase and begins about 30-90 minutes after administration of the composition, additional pharmaceutical agent, or combination thereof. The term "biphasic dyskinesia" as used herein includes two separate periods of involuntary movement after administration of the composition, additional pharmaceutical agent, or combination thereof. The first occurs at the onset of the on-phase and the second occurs at the onset of the off-phase. The term "wearing-off dyskinesia" as used herein is less common and may be characterized by large amplitude movements. The term "wearing-off dystonia" as used herein refers to dystonia during the off phase, usually involving the limbs, but may involve the face, neck, or trunk. In some embodiments, the dyskinesia occurs at different times in relation to administration of the composition, additional medicament, or combination thereof.

[0048] In some embodiments, motor symptoms occur when the composition, the additional pharmaceutical agent, or a combination thereof is completely metabolized. In some embodiments, motor symptoms occur when the composition is completely metabolized. In some embodiments, motor symptoms occur when the additional pharmaceutical agent is completely metabolized. In some embodiments, motor symptoms occur when the dopamine agonist is completely metabolized. In some embodiments, motor symptoms occur when the dopamine precursor is completely metabolized. In some embodiments, motor symptoms occur when L-dopa is completely metabolized.

[0049] In some embodiments, motor complications occur when the composition, the additional pharmaceutical agent, or a combination thereof is completely metabolized. In some embodiments, motor complications occur when the composition is completely metabolized. In some embodiments, motor complications occur when the additional pharmaceutical agent is completely metabolized. In some embodiments, motor complications occur when the dopamine agonist is completely metabolized. In some embodiments, motor complications occur when the dopamine precursor is completely metabolized. In some embodiments, motor complications occur when L-dopa is completely metabolized.

[0050] In some embodiments, the motor symptoms develop about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after the composition is administered. In some embodiments, the motor symptoms develop about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after the additional pharmaceutical agent is administered. In some embodiments, the motor symptoms develop about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after the dopamine precursor is administered. In some embodiments, the motor symptoms develop about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after L-dopa is administered.

[0051] In some embodiments, the motor complication develops about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after the composition is administered. In some embodiments, the motor complication develops about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after the additional pharmaceutical agent is administered. In some embodiments, the motor complications develop about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after the dopamine precursor is administered. In some embodiments, the motor complications develop about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 or more years after L-dopa is administered.

[0052] In some embodiments, the pharmaceutical composition comprises a solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the solid state form is crystalline 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the solid state form is crystalline 17α-ethynylandrost-5-ene-3β,7β,17β-triol that is substantially free of amorphous form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

[0053] In some embodiments, the solid state form is crystalline solvate 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is crystalline methanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is crystalline ethanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is crystalline hydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

[0054] In some embodiments, the crystalline solvate is Form III 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is Form IV 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the crystalline solvate is Form V 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

[0055] In some embodiments, the solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol is amorphous 17α-ethynylandrost-5-ene-3β,7β,17β-triol. In some embodiments, the amorphous 17α-ethynylandrost-5-ene-3β,7β,17β-triol is substantially free of the solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

[0056] In some embodiments, the pharmaceutical composition comprises at least one pharma- ceutically acceptable excipient.Non-limiting examples of pharma-ceutically acceptable excipients suitable for use in the composition include fillers, diluents, disintegrants, binders, glidants, and / or lubricants.Other pharma-ceutically acceptable excipients suitable for use in the composition include absorption enhancers, acidifiers, sustained-release agents, alkalizing agents, antioxidants, buffers, chelating agents, colorants, complexing agents, emulsifiers, flavoring agents, moisturizers, humidity regulators, pH adjusters, preservatives, solubilizers, stabilizers, surfactants, suspending agents, sweeteners, flavoring agents, and wetting agents.

[0057] Non-limiting examples of fillers suitable for use in the compositions include lactose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose polymers, hydroxyethyl cellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethyl cellulose, and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrin, maltodextrin, starch, or modified starch (including potato starch, corn starch, and rice starch), calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, and collagen.

[0058] Non-limiting examples of diluents suitable for use in the compositions include, for example, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, glucose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, and sugar.

[0059] Non-limiting examples of disintegrants suitable for use in the compositions include alginic acid or alginates, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, and carboxymethyl starch.

[0060] Non-limiting examples of binders suitable for use in the compositions include acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, polyethylene oxide, povidone, and pregelatinized starch.

[0061] Non-limiting examples of glidants and / or lubricants suitable for use in the compositions include stearic acid, magnesium stearate, calcium stearate, or other metallic stearates, talc, waxes, and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycol, alkyl sulfates, sodium benzoate, and sodium acetate.

[0062] Non-limiting examples of antioxidants suitable for use in the compositions include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, and derivatives of tocopherol.

[0063] In some embodiments, the pharma- ceutically acceptable excipient is selected from sodium dodecyl sulfate, microcrystalline cellulose, magnesium stearate, and any combination of the foregoing, hi some embodiments, the pharma-ceutically acceptable excipient is sodium dodecyl sulfate.

[0064] In some embodiments, the pharmaceutical composition is formulated into an oral dosage form. In some embodiments, the dosage form may include capsules and tablets. In some embodiments, the dosage form may include one or more different types of delayed release layers selected from sealants and / or enteric layers. For example, delayed release layers with different release rate characteristics can provide a dosage form with different overall drug release characteristics. In some such embodiments, the pharma- ceutical acceptable excipient is a surfactant. In some embodiments, the surfactant is present in an amount sufficient to provide 90% dissolution of the pharmaceutical composition in water after 30 min at room temperature. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the pharmaceutical composition is a capsule or tablet.

[0065] In some embodiments, the pharmaceutical compositions contain less than about 3% by weight of impurities.

[0066] In some embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable formulation of 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

[0067] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising 17α-ethynylandrost-5-ene-3β,7β,17β-triol for use in treating neurodegenerative conditions. In some embodiments, the neurodegenerative condition is Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis. In some embodiments, the neurodegenerative condition is Parkinson's disease, parkinsonism, parkinsonian syndrome, or any combination of the foregoing. In some embodiments, the neurodegenerative condition includes idiopathic Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and vascular parkinsonism, or any combination of the foregoing. In some embodiments, the neurodegenerative condition is Parkinson's disease. In some embodiments, the pharmaceutical composition comprises at least one pharma- ceutically acceptable excipient.

[0068] In some embodiments, the pharmaceutical composition is used with at least one additional medicament. In some embodiments, the additional medicament comprises at least one dopamine agonist, as described elsewhere herein. In some embodiments, the additional medicament comprises at least one dopamine precursor, as described elsewhere herein. In some embodiments, the additional medicament comprises L-dopa. In some embodiments, the additional medicament is used at a delay time after use of the pharmaceutical composition begins. In some embodiments, the delay time is 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or more, or a range including and / or spanning the values ​​listed above. In some embodiments, the delay time is 2 years or more.

[0069] In some embodiments, at least one motor symptom may develop during the use of the pharmaceutical composition. Such motor symptoms are described elsewhere herein. In some embodiments, the motor symptoms develop 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years, or ranges including and / or ranging from the above values, after the use of the pharmaceutical composition begins. In some embodiments, the motor symptoms develop 2 years or more after the use of the pharmaceutical composition begins. In some embodiments, the motor symptoms develop 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years, or ranges including and / or ranging from the above values, after the use of additional medication begins. In some embodiments, the motor symptoms develop more than two years after the additional medication is initiated.

[0070] In some embodiments, at least one motor complication may develop during the use of the pharmaceutical composition. Such motor complications are described elsewhere herein. In some embodiments, the motor complication develops 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging from the above values ​​after the use of the pharmaceutical composition begins. In some embodiments, the motor complication develops 2 years or more after the use of the pharmaceutical composition begins. In some embodiments, the motor complication develops 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging from the above values ​​after the use of additional medicine begins. In some embodiments, the motor complications develop more than two years after the use of the additional medication begins.

[0071] Some embodiments of the present disclosure relate to the use of a pharmaceutical composition comprising 17α-ethynylandrost-5-ene-3β,7β,17β-triol for treating a neurodegenerative condition. In some embodiments, the neurodegenerative condition is Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis. In some embodiments, the neurodegenerative condition is Parkinson's disease, parkinsonism, parkinsonian syndrome, or any combination of the above. In some embodiments, the neurodegenerative condition includes idiopathic Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and vascular parkinsonism, or any combination of the above. In some embodiments, the neurodegenerative condition is Parkinson's disease. In some embodiments, the pharmaceutical composition comprises at least one pharma- ceutical acceptable excipient.

[0072] In some embodiments, the use is concurrent with the use of at least one additional medicament. In some embodiments, the additional medicament comprises at least one dopamine agonist, as described elsewhere herein. In some embodiments, the additional medicament comprises at least one dopamine precursor, as described elsewhere herein. In some embodiments, the additional medicament comprises L-dopa. In some embodiments, the use of at least one additional medicament comprises a lag time after the use of the pharmaceutical composition begins. In some embodiments, the lag time is 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or more, or a range including and / or spanning the values ​​described above. In some embodiments, the lag time is 2 years or more. In some embodiments, the use comprises the development of at least one motor complication. Such motor complications are described elsewhere herein. In some embodiments, the motor complication develops 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging from the above values ​​after the use of the pharmaceutical composition begins. In some embodiments, the motor complication develops 2 years or more after the use of the pharmaceutical composition begins. In some embodiments, the motor complication develops 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging from the above values ​​after the use of the additional medication begins. In some embodiments, the motor complication develops 2 years or more after the use of the additional medication begins.

[0073] Some embodiments of the present disclosure relate to the use of 17α-ethynylandrost-5-ene-3β,7β,17β-triol in the manufacture of a medicament for treating a neurodegenerative condition. In some embodiments, the neurodegenerative condition is Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis. In some embodiments, the neurodegenerative condition is Parkinson's disease, parkinsonism, parkinsonian syndrome, or any combination of the above. In some embodiments, the neurodegenerative condition includes idiopathic Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and vascular parkinsonism, or any combination of the above. In some embodiments, the neurodegenerative condition is Parkinson's disease. In some embodiments, the medicament comprises at least one pharma- ceutically acceptable excipient.

[0074] In some embodiments, the medicament comprises at least one additional medicament. In some embodiments, the additional medicament comprises at least one dopamine agonist, as described elsewhere herein. In some embodiments, the additional medicament comprises at least one dopamine precursor, as described elsewhere herein. In some embodiments, the additional medicament comprises L-dopa.

[0075] In some embodiments, the use includes a lag time after use of the medicament begins. In some embodiments, the lag time is 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or more, or a range including and / or spanning the values ​​set forth above. In some embodiments, the lag time is 2 years or more.

[0076] In some embodiments, the use includes the onset of at least one motor symptom. Such motor symptoms are described elsewhere herein. In some embodiments, the motor symptoms are 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging from the above values ​​after the use of the medicine is started. In some embodiments, the motor symptoms are 2 years or more after the use of the medicine is started. In some embodiments, the motor symptoms are 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging from the above values ​​after the use of the additional medicine is started. In some embodiments, the motor symptoms develop more than two years after the additional medication is initiated.

[0077] In some embodiments, the use includes the onset of at least one motor complication. Such motor complications are described elsewhere herein. In some embodiments, the motor complication develops 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging between the values ​​mentioned above after the use of the medicament is started. In some embodiments, the motor complication develops 2 years or more after the use of the medicament is started. In some embodiments, the motor complication develops 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years or ranges including and / or ranging between the values ​​mentioned above after the use of the additional medicament is started. In some embodiments, the motor complications develop more than two years after the use of the additional medication begins.

[0078] The subject matter of this application includes features discussed in U.S. Patent No. 8,252,947, issued Aug. 28, 2012, which is incorporated herein by reference in its entirety for all purposes. EXAMPLES

[0079] Example 1. Inflammatory pathways of neurodegenerative mechanisms implicated in PD progression The majority of Parkinson's disease (PD) cases are characterized as idiopathic, with a minority having a known genetic basis, most frequently linked to mutations in genes associated with the neuronal protein, alpha-synuclein (SNCA), and mitochondrial homeostasis. Overproduction, misfolding, and aggregation of SNCA are major contributors to neurooxidative stress and energy dyshomeostasis. Misfolded SNCA is thought to act as a prion and participate in disease spread within the central nervous system (CNS), with evidence of transmission from the gastrointestinal tract to the CNS as a possible disease initiation vehicle. A widely held view is that the motor symptoms of the disease result primarily from low levels of the neurotransmitter, dopamine, and secondarily from loss of dopaminergic neurons in the substantia nigra. This dopamine-centric view tends to downplay the crucial contribution of inflammation to disease expression. Although a threshold of 50%-80% reduction in dopamine levels is generally assumed to be necessary to elicit motor symptoms, parkinsonian behaviors with significantly less neurodegeneration can be observed in animal models of PD initiated with neuroinflammatory agents. Furthermore, reducing neuroinflammation and oxidative stress without dopaminergic treatment can improve mobility and reduce clinical signs of the disease in animal models and humans. Critical to the concept of anti-inflammatory treatment of PD is pharmacologic acceptability, which spans the safety of drug candidates for chronic use, blood-brain barrier permeability, and mechanisms of action that target crucial aspects of the inflammatory process that drives disease expression and progression.

[0080] Inflammation and oxidative stress are mutually inductive and drive pathophysiology in neurodegenerative diseases. In PD, misfolded, overexpressed, and aggregated SNCA interacts with molecular pattern receptors, toll-like receptor 4 (TLR4), and receptor for advanced glycation end products (RAGE) to activate inflammatory signaling cascades controlled by specific extracellular signal-regulated kinase-nuclear factor kappa B (ERK-NFkB)-containing scaffolds that mediate tumor necrosis factor (TNF), interleukin-1b (IL-1b), interleukin-6 (IL-6), and other inflammatory cytokine production. These inflammatory signaling mechanisms are independent of the NFkB-ERK homeostasis signaling pathways (Ras / Raf / MEK / ERK, etc.) that control cell proliferation, long-term potentiation, and insulin signaling.

[0081] Activation of inflammatory pathways leads to the synthesis of inducible nitric oxide synthase (iNOS), which promotes the formation of reactive nitrogen and oxygen species, which affect mitochondrial cytochrome efficiency to decrease energy production, increase calcium currents, and generate more reactive oxygen species. These oxidative species activate NFkB and calmodulin kinase in a cycle that tends to feed forward, creating a state of chronic inflammation and oxidative stress. Mitochondrial dysfunction in its various forms is a major driver of PD pathophysiology. Activated microglia and astrocytes play a prominent role in PD pathology and progression by maintaining an inflammatory environment. Accumulating evidence indicates that reactive oxygen species (ROS) and pro-inflammatory cytokines produced by microglia are involved in the induction and perpetuation of the neurodegenerative process in PD.

[0082] Dopaminergic neurons have high energy requirements, making them particularly vulnerable to the deleterious effects of mitochondrial dysfunction. Maintenance of protein homeostasis is an energy-intensive process. When cells do not have sufficient reducing power to properly direct newly synthesized protein folding, retain function, and prevent aggregation, endoplasmic reticulum (ER) stress results. Under ER stress conditions, SNCA can misfold and aggregate into oligomeric sheets that are toxic to mitochondria, in addition to activating molecular pattern receptors and inflammatory pathways.

[0083] Insulin signaling plays an essential role in neuroenergetic homeostasis and neuronal survival. Inflammatory activation of mitogen-associated protein kinases (MAPKs) can inhibit insulin signaling (inducing insulin resistance) by phosphorylating various serine residues on insulin receptor substrate 1 and 2 (IRS-1 / 2), which interfere with insulin receptor tyrosine phosphorylation or the interaction of IRS-1 / 2 with the insulin receptor or other proteins in the signaling complex. Thus, inflammation caused by SNCA may contribute to insulin resistance, which disrupts mitochondrial function and promotes oxidation and ER stress, feeding forward to increase SNCA homeostasis deficiency. Interestingly, intranasal insulin administration has stimulatory activity in PD, and insulin resistance has also been linked to PD cognitive symptoms. It has been reported that 60%-80% of PD subjects have insulin resistance. Several antidiabetic drugs are under clinical evaluation for their potential benefit in PD patients (clinicaltrials.gov: NCT04251585, NCT02953665, NCT04232969).

[0084] Inflammatory chemokines promote the infiltration of lymphocytes and macrophages, which contribute to the inflammatory environment in PD. The adaptive immune response of T cells that recognize SNCA peptides contributes to the neurodegenerative process, with reactive astrocytes potentially acting as antigen-presenting cells that may aid in the spread of SNCA aggregates. Thus, infiltrating lymphocytes have the potential to contribute to PD pathophysiology by multiple mechanisms, and reducing the infiltration of inflammatory cells may have a significant impact on the disease.

[0085] ERK-mediated neuroinflammation is causally linked to levodopa-induced dyskinesia (LID) as described elsewhere herein, and genetic and pharmacological modulation of ERK activation reduces LID in rodent models. Furthermore, inflammatory signals mediated by NFkB-ERK signaling are linked to excitotoxicity, a well-established neurodegenerative mechanism linked to PD progression. This pathogenic effector mechanism in PD patients has been recapitulated in a plausible disease model, elicited by injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into marmoset monkeys (Callithrix jacchus). MPTP is a blood-brain permeable substrate for dopamine transporters and is transported by monoamine oxidase in astrocytes to the mitochondrial toxin, 1-methyl-4-phenylpyridinium (MPP +), which is selectively taken up by neurons via monoamine transporters. Administration of MPTP to animals (and humans) results in Parkinson's-like symptoms resulting from loss of dopaminergic cells (neurodegeneration) in the substantia nigra pars compacta (SNpc) and the resulting reduction in striatal dopamine concentrations and neuroinflammation. Selective damage of dopaminergic (DA) cells after MPTP intoxication is soon followed by clustering of microglia around the damaged neurons. Reaction of myeloperoxidase (MPO)-expressed microglia and H2O2 with structurally related ortho-methoxy-substituted catechols such as apocynin and vanillic acid generates reactive intermediates that bind to thiol free radicals. MPO is upregulated in activated brain microglial cells of PD patients and in MPTP-induced animal models. Similar to Parkinson's disease (specific to humans), administration of dopamine to MPTP-treated animals can significantly improve motor control but does not reduce inflammatory mechanisms and therefore does not modify or slow the disease process in animal models. Therefore, selective inhibitors of microglial ROS production or modulation of ERK activity are potentially effective pharmaceuticals for PD, aiming to alleviate or prevent DA neuron degeneration and reduce LID. Experiments with apocynin have indeed shown that this principle can be used to prevent the build-up and activation of ROS generating NADPH oxidase in the MPTP marmoset model.

[0086] The studies described herein used a solid formulation of 3β,7β-bis-(trimethylsiloxy)-5-androsten-17-one as described in US Pat. No. 8,252,947.

[0087] Example 2. Treatment of motor symptoms in the MPTP model of Parkinson's disease in marmoset monkeys. 3β,7β-bis-(trimethylsiloxy)-5-androsten-17-one (17-EAT) has a unique mechanism of action to reduce inflammatory signaling by targeting ERK and inhibiting ERK and NFkB activation in specific inflammatory signaling scaffolds that drive pathological inflammatory cascades. All experimental evidence to date suggests that 17-EAT does not inhibit the homeostatic function of ERK and NFkB. 17-EAT is blood-brain barrier permeable and reduces the expression of TNF, IL-1b, IL-6, and other inflammatory cytokines. 17-EAT is active in rodent models of systemic inflammation (type 2 diabetes, COPD, rheumatoid arthritis) and has anti-neuroinflammatory or neuroprotective activity in rodent models of Parkinson's disease, experimental autoimmune encephalomyelitis, optic neuritis, and glaucoma.

[0088] The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model used is capable of lowering striatal dopamine levels to 5% of normal controls. Using the MPTP model, a series of three independent cohorts of six marmoset monkeys (Callithrix jacchus, approximately 0.3-0.5 kg, 2-5 years old) were created with Parkinson's disease-like symptoms and then observed for three weeks to ensure the absence of parkinsonian behavior and movement abnormalities. A single dose of 17-EAT or amantadine was administered at the beginning of the fourth week to ensure the absence of behavioral side effects. All subjects were injected subcutaneously with 1-2 mg / kg MPTP on days 3, 4, and 5 of the fifth week, and days 1 and 3 of the sixth week, for a total of 6.5 mg / kg MPTP, without further treatment, and observed until the end of the seventh week, then randomized for treatment. All MPTP-treated subjects showed obvious parkinsonian behavior.

[0089] Beginning at week 8, oral administration of treatments of vehicle, amantadine, or 17-EAT formulated in acacia syrup was begun. Vehicle controls received only acacia syrup. Amantadine HCl (Sigma Aldrich, A1260-SG) was administered at a dose of 1 mg / kg daily. 17-EAT was administered at a dose of 30 mg / kg daily. During weeks 8 and 9, the activity of the test compounds on parkinsonian behavior was observed several times daily for effects on clinical signs (lack of grooming, lethargy, immobility, muscle rigidity, and tremor activity) and immobility scores were given on a scale of 0 to 4, with 0 being normal and 4 being the most severe score. Assessments were made by study personnel blinded to treatment. Subjects were observed for parkinsonian signs as in weeks 8 and 9, and for the development of LID.

[0090] All subjects received single ascending doses of levodopa (5, 7.5, 10, and 12.5 mg / kg) in combination with vehicle, amantadine, or 17-EAT on a daily basis through the middle of weeks 10 and 11, with 1-2 days of observation between levodopa doses. During weeks 11-13, LID was induced in all subjects with 12.5 mg / kg levodopa twice daily while continuing vehicle, amantadine, or 17-EAT treatment.

[0091] The severity of LID was measured by the Abnormal Involuntary Movement Score (AIMS) adapted for primate PD models. Items included assessment of limb and trunk movements, facial expressions, and lip, perioral, tongue, and jaw movements. These symptoms were scored on a scale of 0 (normal), 1 (extreme normal), 2 (mild), 3 (moderate), and 4 (severe). Parkinsonian behavior measurements continued as previously described. Treatment continued without levodopa during week 14, and subjects were euthanized 1 hour after 17-EAT treatment (one subject from each of the three groups on days 1, 2, and 3). Subjects were exsanguinated under deep anesthesia using Alfaxan (18 mg / kg im). Subjects were euthanized immediately thereafter using EUTHASOL (sodium pentobarbital, ic). The brains of each subject were removed and frozen for immunohistochemistry analysis. The SNpc was analyzed for the presence of DA-positive neurons using tyrosine hydroxylase immunoreactive (TH-IR) staining.

[0092] As shown in Table 1, the mean immobility scores for subjects treated with vehicle, amantadine, and 17-EAT were 2.71, 2.59, and 2.72, respectively, prior to treatment (week 7), and 3.0, 2.74, and 2.26, respectively, at week 1 of monotherapy (week 8). The mean immobility scores for 17-EAT monotherapy at weeks 8 and 9 were 2.26 and 2.10, respectively, significantly lower than either vehicle (3.0 and 2.8) or amantadine (2.74 and 2.72) monotherapy treatments.

[0093] [Table 1]

[0094] As shown in Figure 1, subjects receiving 12.5 mg / kg 17-EAT twice daily in combination with levodopa doses of 5, 7.5, 10, 12.5, or 25 mg / kg had improved mean immobility scores at week 9 compared to 17-EAT monotherapy. With the addition of levodopa, immobility scores improved compared to monotherapy assessed at weeks 8 and 9 (data shown for week 9 values).

[0095] A levodopa dose of 12.5 mg / kg BID administered twice daily induced LID development in all subjects. As shown in Figure 2, subjects treated with vehicle, amantadine, and 17-EAT in combination with levodopa doses of 5, 7.5, 10, 12.5, or 25 mg / kg had improved abnormal involuntary movement scores (AIMS) at week 12 compared to monotherapy. Subjects treated with vehicle, amantadine, and 17-EAT in combination with a levodopa dose of 10 mg / kg had AIMS of 6.2, 4.5, and 2.1, respectively, at week 12.

[0096] At week 14, all subjects were sacrificed and tissue samples from the substantia nigra were evaluated to measure the number of remaining tyrosine hydroxylase positive neurons. As shown in Figure 3, subjects treated with amantadine and 17-EAT had a 40% and 75% increase in the number of remaining TH+ neurons. As shown in Figure 4, subjects treated with 17-EAT maintained a higher average body weight compared to either vehicle or amantadine.

[0097] Example 3. Delaying the need to start dopamine agonist treatment and reducing motor complications Based on the inventor's clinical experience, the following results are predicted using controlled studies.

[0098] A cohort of 40 Parkinson's disease patients, aged 35-80 years, are identified by a physician as dopamine agonist-naive with recent progression of motor symptoms to a level that requires treatment to reduce them. The patients are divided into a group of patients who receive a solid formulation orally twice daily (n=20; "SSF") and a second group of patients who receive L-dopa treatment as needed to control motor symptoms (n=20; "LVD"). Patient symptoms are assessed at 3-month intervals. After 2 years, motor symptoms are adequately controlled in both groups. After 4 years, motor symptoms are adequately controlled in the SSF group, and in approximately 20% of the LVD group, motor symptoms are not fully controlled, with motor complications observed. After 6 years, control of motor symptoms in the SSF group requires the addition of low doses of L-dopa for adequate control, and patients in the LVD group have progressively greater and statistically significantly greater increases in motor symptoms, motor complications, and / or dyskinesias.

[0099] Example 4. Delaying Motor Complications Based on the inventor's clinical experience, the following results are predicted using controlled studies.

[0100] A cohort of 40 Parkinson's disease patients aged 35-80 years will be identified by a physician. A detailed examination report will be generated for each patient, showing symptoms and their severity. Common symptoms include tremors in the hands, arms, legs, jaw, and head, stiffness of the limbs and trunk, slowness of movement, and impaired balance and / or coordination. This report will establish a baseline for the patients. Patients in the experimental group (n=20, "EXPT1") will be given a solid formulation orally twice daily, with L-dopa given daily as needed to most effectively treat disease symptoms. Patients in the control group (n=20, "CONT") will be given a placebo twice daily, with L-dopa given daily as needed to most effectively treat disease symptoms. The study will run for one year, with patient outcomes measured by physicians at monthly intervals. Patients given EXPT1 and CONT report improvements in their symptoms after one to four months. The study will run for another 20 years, with patient outcomes measured by physicians during that time. The first half of the patients given EXPT1 reported no recurrence of the original symptoms or onset of new symptoms over the course of the study. The second half of the patients given EXPT1 reported no recurrence of the original symptoms or onset of motor symptoms, including motor fluctuations, and motor complications, including wearing off, freezing of gait, and acute akinesia, after 5 to 16 years. A subset of patients given CONT reported a gradual onset of motor symptoms, including motor fluctuations, and motor complications, including wearing off, freezing of gait, and acute akinesia, after 2 to 4 years. The difference in motor symptoms between the EXPT1 group and the CONT group was statistically significant.

[0101] Example 5. Delaying dyskinesia Based on the inventor's clinical experience, the following results are predicted using controlled studies.

[0102] A cohort of 40 Parkinson's disease patients aged 35-80 years will be identified by a physician. A detailed examination report will be generated for each patient, showing symptoms and their severity. Common symptoms include tremors in the hands, arms, legs, jaw, head, stiffness of the limbs and trunk, slowness of movement, and impaired balance and / or coordination, but no significant motor complications or L-dopa-induced dyskinesias. This report will establish a baseline for the patients. Experimental patients (n=20, "EXPT1") will receive a solid formulation orally twice daily and L-dopa daily as needed. Control patients (n=20, "CONT") will receive a placebo orally twice daily and L-dopa daily as needed. The study will run for 5 years, with patient outcomes measured by physicians at 3-month intervals. Patients receiving EXPT1 and CONT report improvement in their symptoms after 1-4 months. The study will run for another 20 years, with patient outcomes measured by physicians during that time. The first half of patients given EXPT1 reported no recurrence of the original symptoms or onset of new symptoms over the course of the study. The second half of patients given EXPT1 reported no recurrence of the original symptoms or onset of dyskinesias, including chorea, dystonia, ballismus, and myoclonus, after 5 to 16 years. Patients given CONT reported no recurrence of the original symptoms or onset of dyskinesias, including chorea, dystonia, ballismus, and myoclonus, after 2 to 4 years. The difference in dyskinesias between the EXPT1 vs. CONT groups was statistically significant.

[0103] Although various illustrative embodiments have been described above, any of a number of modifications may be made to the various embodiments without departing from the scope of the invention as set forth in the claims. For example, the order in which the various method steps described are performed may often be changed in alternative embodiments, and in other alternative embodiments, one or more method steps may be omitted entirely. Optional features of the various device and system embodiments may be included in some embodiments and not in others. Thus, the foregoing description has been provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as set forth in the claims.

[0104] The examples and illustrations contained herein are illustrative and not limiting, showing specific embodiments in which the subject matter may be practiced. As previously mentioned, other embodiments may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of the present disclosure. Such embodiments of the present subject matter may be referred to herein, individually or collectively, by the term "invention" for convenience only, and without the intention of spontaneously limiting the scope of the present application to any single invention or inventive concept when more than one invention is actually disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiment shown. The present disclosure is intended to encompass any and all adaptations or variations of the various embodiments. Combinations of the above-mentioned embodiments, as well as other embodiments not specifically described herein, will be apparent to those skilled in the art upon reviewing the above description.

[0105] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) mentioned herein are hereby incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in texts incorporated by reference are excluded to the extent that they conflict with definitions in this disclosure.

[0106] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0107] While the subject matter has been shown and described in detail with reference to preferred and various alternative embodiments, it will be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the disclosure.

Claims

1. 1. A medicament for use in the treatment of a neurodegenerative condition, the medicament comprising 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

2. The method of claim 1, wherein the neurodegenerative condition is Parkinson's disease.

3. 3. The method of claim 1 or 2, further comprising at least one additional pharmaceutical agent.

4. the additional medicament comprises at least one dopamine agonist; or the additional medicament comprises at least one dopamine precursor; or the additional medicament comprises L-dopa; The drug according to claim 3.

5. 5. The method of claim 4, wherein the additional medicament is administered at a delayed time after the first administration of the agent, preferably the delayed time is 2 years or more.

6. The method according to claim 1 or 2, wherein at least one motor symptom and / or at least one motor complication develops in the patient.

7. 7. The drug of claim 6, wherein the motor symptoms are selected from tremors and / or tremors in the limbs, slowing of movements (bradykinesia), muscle rigidity, rigidity, immobility (freezing), muscle spasms, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing ability, motor fluctuations, dystonia, and any combination of the foregoing, or are selected from wearing off, underdosing, onset of dose deterioration, rebound after stopping dosing, unpredictable off-phases, freezing of gait, poor on-phases, acute akinesia, dyskinesia, and any combination of the foregoing.

8. The method of claim 6, wherein the motor symptoms and / or motor complications develop more than two years after the additional medication is administered.

9. The method of claim 1 or 2, wherein the 17α-ethynylandrost-5-ene-3β,7β,17β-triol is a solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol, preferably, the solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol is a crystalline solvate of 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

10. the crystalline solvate is crystalline methanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol, or the crystalline solvate is crystalline ethanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol, or the crystalline solvate is a crystalline hydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol, or the crystalline solvate is Form III 17α-ethynylandrost-5-ene-3β,7β,17β-triol; or the crystalline solvate is Form IV 17α-ethynylandrost-5-ene-3β,7β,17β-triol; or the crystalline solvate is Form V 17α-ethynylandrost-5-ene-3β,7β,17β-triol; or 10. The method of claim 9, wherein the solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol is amorphous 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

11. A pharmaceutical composition comprising 17α-ethynylandrost-5-ene-3β,7β,17β-triol and at least one pharma- ceutically acceptable excipient for use in the treatment of a neurodegenerative condition.

12. 12. The pharmaceutical composition of claim 11, wherein the neurodegenerative condition is Parkinson's disease.

13. 13. The pharmaceutical composition of claim 11 or 12, wherein the composition comprises at least one additional pharmaceutical agent.

14. The additional medicament comprising at least one dopamine agonist, or the additional medicament comprises at least one dopamine precursor; or 14. The pharmaceutical composition of claim 13, wherein the additional pharmaceutical agent comprises L-dopa.

15. 15. The pharmaceutical composition of claim 14, wherein the additional medicament is used at a delayed time after use of the pharmaceutical composition has begun, preferably the delayed time is 2 years or more.

16. The pharmaceutical composition according to claim 11 or 12, wherein the development of at least one motor symptom and / or at least one motor complication occurs.

17. 17. The pharmaceutical composition of claim 16, wherein the motor symptoms are selected from tremors and / or tremors in the limbs, slowing of movements (bradykinesia), muscle rigidity, rigidity, immobility (freezing), muscle spasms, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing ability, motor fluctuations, dystonia, and any combination of the foregoing, or are selected from wearing off, underdosing, onset of dose deterioration, rebound after stopping dosing, unpredictable off-phases, freezing of gait, poor on-phases, acute akinesia, dyskinesia, and any combination of the foregoing.

18. 17. The pharmaceutical composition of claim 16, wherein the motor symptoms and / or motor complications develop more than two years after use of the pharmaceutical composition begins.

19. 13. The pharmaceutical composition of claim 11 or 12, wherein the 17α-ethynylandrost-5-ene-3β,7β,17β-triol is a solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol, preferably the solid state form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol is a crystalline solvate of 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

20. the crystalline solvate is crystalline methanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol, or the crystalline solvate is crystalline ethanolate 17α-ethynylandrost-5-ene-3β,7β,17β-triol, or the crystalline solvate is a crystalline hydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol, or the crystalline solvate is Form III 17α-ethynylandrost-5-ene-3β,7β,17β-triol; or the crystalline solvate is Form IV 17α-ethynylandrost-5-ene-3β,7β,17β-triol; or the crystalline solvate is Form V 17α-ethynylandrost-5-ene-3β,7β,17β-triol; or 20. The pharmaceutical composition of claim 19, wherein the solid state form is amorphous 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

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