Use of co-crystals of psilocybin and psilocin

Abstract

The present disclosure provides a method of treating or reducing a disease or disorder in a subject in need thereof, comprising administering to the subject a composition comprising sertraline and a crystalline form of psilocybin, wherein the crystalline form is co-crystal Form A of sertraline and psilocybin. The present disclosure further provides a method of stimulating induced neural plasticity, increasing BDNF levels, and / or reducing neuroinflammation.

Description

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Application No. 63 / 597,415, filed November 9, 2023, pursuant to 35 USC § 119(e). The disclosure of that earlier application is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to the use of psilocybin and psilocin cocrystals in the treatment of various disorders, such as neuropsychiatric disorders, neurological disorders, inflammatory disorders (including neuroinflammatory diseases or disorders), and cancer. Psilocybin and psilocin cocrystals can be further used to induce neuroplasticity, reduce neuroinflammation, and increase brain-derived neurotrophic factor (BDNF) levels, all of which are accompanied by a reduced risk of adverse cardiac events. Background Technology

[0003] Various natural plants and fungi contain hallucinogenic compounds that cause changes in brain function or activity (“neuroactive” compounds) and, at higher doses, can also lead to hallucinations or similar experiences (“hallucinogenic” compounds). One of the most common types of naturally occurring hallucinogens is seroceridine, which has been found in over 180 mushroom species worldwide. Mushrooms containing seroceridine also contain other neuroactive and hallucinogenic compounds, the most abundant of which is its main metabolite, xerocin. In humans, seroceridine is primarily metabolized into xerocin in the gastrointestinal system, which is then absorbed and causes hallucinogenic effects.

[0004] These hallucinogenic effects are dose-dependent, typically occurring at doses of at least 20 mg, and usually involve changes in visual, auditory, and cognitive experiences. These serocepin experiences may be due to the structural similarity of serocepin and xelocinone to the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), and the fact that both bind to various 5-HT receptors. Hallucinogenic experiences are thought to be primarily due to activity at 5-HT2A receptors in the brain.

[0005] Compared to cilostabene, xelocinone is chemically unstable and oxidizes rapidly upon exposure to air. For this reason, there are few clinical or survey studies on the effects of xelocinone administered alone or compared to cilostabene. Preclinical studies have shown that xelocinone has a faster absorption rate and a faster onset of action compared to cilostabene. Xelocinone binds to a different range of 5-HT receptors at different concentrations compared to cilostabene, and therefore has a different spectrum of action.

[0006] Due to the different properties of cyclocepin and cyclocepin, compounds combining cyclocepin and cyclocepin are expected to have unique and beneficial properties compared to either compound alone. Summary of the Invention

[0007] This disclosure provides methods for treating diseases or disorders in subjects with this need, methods for inducing neural plasticity, methods for stimulating neuronal growth, methods for increasing the number of neural progenitor cells, methods for increasing BDNF levels, or methods for reducing neuroinflammation, comprising administering crystalline forms of serotonin and serocepin to the subject: .

[0008] In one embodiment, the crystalline form of celecoxib and celecoxib is eutectic form A. Eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°. The XRPD plot of eutectic form A may further contain a significant peak at a 2θ angle of approximately 19.16°. The XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°. Furthermore, the XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, the crystalline form is eutectic form A. Eutectic form A is characterized by XRPD plots containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°. The eutectic form A is characterized by XRPD plots containing prominent peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0009] This disclosure also provides methods for treating diseases or disorders in subjects with this need, methods for increasing the number of neural progenitor cells, methods for increasing BDNF levels, or methods for reducing neuroinflammation, which include administering crystalline forms of serotonin and serocepin to the subject: The crystal form described therein is eutectic form A; and Crystal form A is characterized by its XRPD plot containing prominent peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0010] In one embodiment, the disease or disorder is selected from neuropsychiatric diseases or disorders, neurological diseases or disorders, inflammatory diseases or disorders, or cancer or disorders. In one embodiment, the inflammatory disease or disorder is a neuroinflammatory disease or disorder.

[0011] In one implementation, the neuropsychiatric illness or disorder is addiction, developmental condition, eating disorder, mood / emotional disorder, neurotic disorder, psychosis, and sleep disorder, or a combination thereof.

[0012] In some implementations, the neuropsychiatric illness or disorder is attention deficit hyperactivity disorder (ADHD), autism, fetal alcohol syndrome, tic disorder, bipolar disorder, depression, mania, obsessive-compulsive disorder, trichotillomania, anxiety disorder, post-traumatic stress disorder (PTSD), schizophrenia, sleep apnea, narcolepsy, insomnia, deep sleep state, or a combination thereof.

[0013] In one implementation, the neurological disease or disorder is a degenerative disease, cognitive disorder, motor disorder, chronic pain or headache disorder, neurodegenerative disease, epilepsy or epileptic seizures, or a combination thereof.

[0014] In some implementations, the neurological disease or disorder is agraphia, agnosia, Alzheimer's disease, amnesia, amyotrophic lateral sclerosis, aneurysm, pathological agnosia, aphasia, apraxia, somatognosia, Asperger's syndrome, ataxia, attention deficit hyperactivity disorder, auditory processing disorder, autism spectrum disorder, back pain, Bell's palsy, bipolar disorder, brain injury, brachial plexus injury, brain injury, brain tumor, Canavan disease, Capgras's paranoia, carpal tunnel syndrome, burning pain, central pain syndrome, central pontine myelinolysis, central nucleus myopathy, or cephalic disorders. Disorders, cerebral arteriosclerosis, cerebral atrophy, cerebral vasculitis, cervical spinal stenosis, chorea, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic pain, cluster headache, complex post-traumatic stress disorder, complex regional pain syndrome, compressive neuropathy, cranial arteritis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, periodic vomiting syndrome, cyclic mood disorder, dementia, dermatillomania, diabetic neuropathy, diffuse sclerosis, dysarthria, dyscalculia, dysphagia, dysgraphia, motor disorders, dyslexia, dyslexia, dystonia, encephalopathy, epilepsy, erythromelalgia, essential tremor, fetal alcohol syndrome, febrile seizures, fibromyalgia, Friedreich's ataxia, frontotemporal dementia, functional neurological symptoms disorder, Gaucher's disease. Diseases such as generalized anxiety disorder, gray matter heterotopia, Guillain-Barré syndrome, head injury, headache, hemifacial spasm, Huntington's disease, hypoalgesia, hypoesthesia, inflammatory myopathy, intracranial hypertension, Korsakoff syndrome, Lewy body dementia, intervertebral disc disease, and lupus erythematosus. Neurological sequelae, Lyme disease, Meniere's disease, migraine, mild brain injury, multiple infarct-related dementia, multiple sclerosis, muscular dystrophy, myasthenia gravis, myoclonus, myopathy, neuralgia, neurofibromatosis, neurotic myotonia, neuropathy, Niemann-Pick disease, optic neuritis, otosclerosis, paraplegia, paralysis, paresthesia, hemiparesis, Parkinson's disease, paraneoplastic diseases, periodic paralysis, peripheral neuropathy, phantom limb pain, Pick's disease, polyneuropathy, postherpetic neuralgia, post-traumatic stress disorder, primary lateral sclerosis, prions, progressive hemifacial atrophy, progressive supranuclear palsy, prosopagnosia, radiculopathy, reflex neurovascular dystrophy.dystrophy), repetitive stress injury, restless legs syndrome, Rett syndrome, Reye's syndrome, sclerosis, epileptic seizures, sensory processing disorders, Sjögren's syndrome, sleep apnea, spasticity, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar ataxia, stiff person syndrome, stroke, Sydenham's chorea, traumatic encephalopathy, tardive dyskinesia, tarsal tube syndrome, temporal arteritis, temporal lobe epilepsy, tinnitus, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transverse myelitis, traumatic brain injury, tremor, trichotillomania, trigeminal neuralgia, vestibular schwannoma, vertigo, Wernicke's encephalopathy, Wilson's disease or combinations thereof.

[0015] In some implementations, the neurological disease or disorder is dementia, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, chronic back pain, chronic neuropathic pain, migraine, Huntington's disease, amyotrophic lateral sclerosis, or a combination thereof.

[0016] In one embodiment, the inflammatory disease or disorder is a neuroinflammatory disease or disorder. In one embodiment, the neuroinflammatory disease or disorder is multiple sclerosis, encephalitis, systemic lupus erythematosus, myelitis, neuritis, meningitis, vasculitis, myasthenia gravis, or a combination thereof.

[0017] In one embodiment, the cancer is a nervous system cancer. In one embodiment, the nervous system cancer is a meningioma, pituitary adenoma, craniopharyngioma, schwannoma, glioma, astrocytoma, oligodendroglioma, glioblastoma, ependymal tumor, pineal tumor, pineal cell tumor, and pinealoblastoma. In some embodiments, the nervous system cancer originates from prostate cancer, pancreatic cancer, bile duct cancer, colon cancer, rectal cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, pancreatic cancer, brain cancer and head and neck cancer, melanoma, sarcoma, multiple myeloma, leukemia, or lymphoma, and then includes brain cancer, or combinations thereof.

[0018] In one implementation, increasing BDNF levels includes enhancing the subject's anti-inflammatory response. In one implementation, reducing neuroinflammation includes increasing BDNF levels. In one implementation, any method disclosed herein reduces the risk of adverse cardiovascular events. Attached Figure Description

[0019] Figure 1 The dissolution rate of eutectic form A varies with pH.

[0020] Figure 2 Peak serum serotonin levels (C) were observed after oral administration of cocrystal form A. 最大 ).

[0021] Figure 3 The total serum serotonin level was shown after oral administration of cocrystal form A.

[0022] Figure 4 The efficacy of head twitching response was shown 10 minutes after intraperitoneal administration of eutectic crystal form A.

[0023] Figure 5 The titer of head twitching response was shown 10 minutes after intraperitoneal administration of eutectic crystal form A.

[0024] Figure 6 The image shows the effects of treatment with cyprotinin, cyprosione, and cocrystal A on calcium deficiency. 2+ release.

[0025] Figure 7 The study showed β-inhibitory protein 2 recruitment after treatment with cyclophosphamide, cyclophosphamide, and cocrystal A.

[0026] Figure 8 This study demonstrated the induction of BDNF gene expression at 6 hours following administration of cocrystal A (500 nM) to brain organoids at 4 months of age.

[0027] Figure 9 The brain BDNF levels were shown 10 minutes after oral administration of cocrystal A or selociline.

[0028] Figure 10 Increased neuronal growth was observed at 6 hours after administration of cocrystal A (500 nM) to brain organoids of 4 months of age, as measured by mean neurite length.

[0029] Figure 11 The study showed increased neuronal growth at 6 hours after daily administration of cocrystal form A (500 nM) for 10 days in 6-month-old brain organoids, as measured by mean neurite length.

[0030] Figure 12 The study showed increased neuronal proliferation at 6 hours after daily administration of cocrystal form A (500 nM) for 10 days in 6-month-old brain organoids.

[0031] Figure 13 The study showed an increase in the number of progenitor neurons at 6 hours after daily administration of cocrystal form A (500 nM) for 10 days in brain organoids of 6 months of age.

[0032] Figure 14A -C shows the increase in the number of synapses (small synapses (14A), medium synapses (14B), and large synapses (14C)) at 6 hours after daily administration of cocrystal A (500 nM) for 10 days in 6-month-old brain organoids.

[0033] Figure 15 The levels of various cytokine biomarkers of neuroinflammation were shown 60 minutes after oral administration of selocillin (3 mg / kg).

[0034] Figure 16 The levels of various cytokine biomarkers of neuroinflammation were shown 60 minutes after oral administration of cocrystal form A (3 mg / kg).

[0035] Figure 17 The levels of various cytokine biomarkers of neuroinflammation were shown 60 minutes after daily oral administration of cocrystal form A (0.3 mg / kg) for 21 days.

[0036] Figure 18 The levels of various cytokine biomarkers of neuroinflammation were shown 60 minutes after daily oral administration of cocrystal form A (0.03 mg / kg) for 21 days.

[0037] Figure 19 The levels of various cytokine biomarkers of neuroinflammation were shown 60 minutes after oral administration of co-crystal form A (3 mg / kg) and ANA12 (1 mg / kg).

[0038] Figure 20 The TGF-β1 levels were shown at 1 hour, 3 hours, and 8 hours after administration of cocrystal form A (3 mg / kg) and selociline (3 mg / kg) compared to the control.

[0039] Figure 21 The figures show plasma TGF-β1 levels after administration of cocrystal form A (0.03 mg / kg and 0.3 mg / kg) compared to the control. Detailed Implementation

[0040] This invention is based on the groundbreaking discovery that the eutectic of selocilin and selone can be used to treat diseases or disorders, induce neural plasticity, stimulate neuronal growth, increase the number of neural progenitor cells, increase BDNF levels, or reduce neuroinflammation in subjects with such needs.

[0041] Before describing the compositions and methods, it should be understood that the invention is not limited to the specific processes, formulations, compositions, or methods described, as these can vary. It should also be understood that the terminology used in the specification is for the purpose of describing a particular version or embodiment only and is not intended to limit the scope of the embodiments herein, which are limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the embodiments herein, preferred methods, apparatus, and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety. Nothing herein should be construed as an admission that the embodiments herein are not entitled to any prior invention prior to such disclosure.

[0042] It must also be noted that, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” used herein and in the appended claims include plural references.

[0043] The transitional term “includes”, which is synonymous with “including,” “contains,” or “characterized in,” is inclusive or open-ended and does not exclude additional unlisted elements or methodological steps.

[0044] As used herein, the terms “consists of” or “consisting of” mean that a composition, formulation, or method includes only the elements, steps, or components specifically listed in the particular claimed embodiment or claim.

[0045] As used herein, the terms "consisting essentially of" or "consists essentially of" mean that a composition, formulation, or method includes only the elements, steps, or components specifically listed in a particular claimed embodiment or claim, and may optionally include additional elements, steps, or components that do not materially affect the essential and novel features of a particular embodiment or claim. For example, the only active ingredient in a formulation or method for treating a specified condition (e.g., nutritional depletion) is a therapeutic agent specifically listed in a particular embodiment or claim.

[0046] As used in this article, when one implementation scheme is defined as different from another implementation scheme, the two implementation schemes are "mutually exclusive".

[0047] When a numerical range is disclosed and the notation “n1…to n2” or “between n1…to n2” (where n1 and n2 are numbers) is used, unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. The range can be integers between endpoints or consecutive values, and the endpoints are included. For example, the range “1°C to 3°C” is intended to include 1°C, 3°C, and every value between them up to any number of significant digits (e.g., 1.255°C, 2.1°C, 2.9999°C, etc.).

[0048] As used herein, the term “approximately” refers to a numerical value plus or minus 10%. Therefore, approximately 50% means within the range of 45% to 55%. For example, “approximately 100°C” means a temperature within the range of 90°C to 110°C. Similarly, “approximately 10° of 2θ” means a 2θ angle within the range of 9° to 11°.

[0049] The term “substantially free” or, as used alone or in combination herein, and interchangeably with the term “substantially pure,” means a compound that is free of all other compounds within the detection limit as measured by any means, including nuclear magnetic resonance (NMR), gas chromatography / mass spectrometry (GC / MS), or liquid chromatography / mass spectrometry (LC / MS). In embodiments, “substantially free” can be less than about 1.0%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01%.

[0050] Treatment In one embodiment, the present invention provides a method for treating a disease or disorder in a subject in need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0051] In one embodiment, the present invention provides a method for treating a disease or disorder in a subject in need, comprising administering to the subject crystalline forms of xyloxetine and xyloxetine; wherein the crystalline forms of xyloxetine and xyloxetine are eutectic form A.

[0052] In one embodiment, eutectic form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°. In one embodiment, the crystalline forms of celecoxib and celecoxib are eutectic form A. Eutectic form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1°. The XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 19.16°. The XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°. Further, the XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, the crystalline form is eutectic form A. The eutectic form A is characterized by XRPD plots showing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°. The eutectic form A is also characterized by XRPD plots showing significant peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0053] In one embodiment, the present invention provides a method for treating a disease or disorder in a subject in need, comprising administering to the subject crystalline forms of xeloxin and xelociline; wherein the crystalline forms of xeloxin and xelociline are eutectic form A, wherein eutectic form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0054] In one embodiment, the present invention provides a method for treating a disease or disorder in a subject with such need, comprising administering to the subject crystalline forms of xelocinone and xelociline; wherein the crystalline forms of xelocinone and xelociline are eutectic form A, wherein eutectic form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0055] As used herein, the terms “treat,” “treated,” “treating,” or “treatment” refer to therapeutic treatment and prophylactic or preventative measures aimed at preventing or mitigating (alleviating) an undesirable physical condition, disorder, or disease, or achieving a beneficial or desired clinical outcome. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction of the severity of a condition, disorder, or disease; stabilization (i.e., non-deterioration) of the state of a condition, disorder, or disease; delay of the onset of a condition, disorder, or disease or slowing its progression; improvement of the state of a condition, disorder, or disease; and relief of a condition, disorder, or disease (whether partial or complete, induced or maintained), whether detectable or undetectable, or enhanced or improved. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival without treatment. Treatment can also be preemptive in nature, i.e., it can include disease prevention. Disease prevention can involve the complete prevention of disease, such as in the case of prevention of pathogen infection, or it can involve the prevention of disease progression. For example, disease prevention may not mean completely blocking any disease-related effects at any level, but may mean preventing the symptoms of the disease at a clinically significant or detectable level. Disease prevention may also mean preventing the disease from progressing to its later stages and extending disease-free survival compared to untreated disease-free survival.

[0056] The term “treatment” is used interchangeably with the term “method of treatment” in this document and refers to 1) therapeutic treatments or measures that cure, alleviate, reduce symptoms and / or stop the progression of a diagnosed pathological condition or disorder, and 2) prophylactic / preventative measures. Individuals requiring treatment may include those who already have a particular medical disorder and those who may eventually develop that disorder (i.e., those who require preventative measures).

[0057] The terms “therapeutic effective dose,” “effective dose,” “therapeutic effective dose,” “effective dose,” etc., refer to the amount of a title compound that will elicit a biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. Typically, this response is an improvement in patient symptoms or a desired biological outcome (e.g., improvement in symptoms of neuroinflammatory diseases). An effective dose can be determined as described herein.

[0058] The terms “administration of” and / or “administering” should be understood as referring to the provision of a therapeutically effective amount of a pharmaceutical composition to a subject requiring treatment. Routes of administration may be enteric, local, or parenteral. Therefore, routes of administration include, but are not limited to, intradermal, subcutaneous, intravenous, intraarterial, intraorbital, intracardiac, intradermal, intraperitoneal, transdermal, subarachnoid, intraspinal, oral, sublingual, buccal, rectal, nasal administration, and infusion. Suitable unit dosage forms include, but are not limited to, powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injections, implantable sustained-release formulations, lipid complexes, etc.

[0059] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cattle, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0060] In some implementations, the disease or disorder is a neuropsychiatric disease or disorder, a neurological disease or disorder, an inflammatory disease or disorder, or cancer.

[0061] In some implementations, the neuropsychiatric illness or disorder is addiction, developmental condition, eating disorder, mood / emotional disorder, neurotic disorder, psychosis, and sleep disorder, or a combination thereof.

[0062] In some implementations, the neuropsychiatric illness or disorder is attention deficit hyperactivity disorder (ADHD), autism, fetal alcohol syndrome, tic disorder, bipolar disorder, depression, mania, obsessive-compulsive disorder, trichotillomania, anxiety disorder, post-traumatic stress disorder (PTSD), schizophrenia, sleep apnea, narcolepsy, insomnia, deep sleep state, or a combination thereof.

[0063] In some embodiments, the disease or disorder is a neurological disease or disorder. In some embodiments, the neurological disease or disorder is a degenerative disease, cognitive disorder, motor disorder, chronic pain or headache disorder, neurodegenerative disease, epilepsy or seizures, or a combination thereof.

[0064] In some implementations, the neurological disease or disorder is dementia, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, chronic back pain, chronic neuropathic pain, migraine, Huntington's disease, amyotrophic lateral sclerosis, or a combination thereof.

[0065] In some embodiments, the neurological disease or disorder is epilepsy or epileptic seizures. The terms "epilepsy" and "epilepsy seizure" are used interchangeably and refer to a neurological disorder in which the activity of nerve cells in the brain is disturbed. An epileptic seizure is a clinical manifestation of abnormal, excessive, and synchronized discharges in neurons. Epileptic seizures can range in duration from brief and almost undetectable to prolonged periods of violent shaking caused by abnormal electrical activity in the brain. During an epileptic seizure, a person experiences abnormal behavior, symptoms, and sensations, sometimes including loss of consciousness.

[0066] In some implementations, an epileptic seizure is a tonic seizure, a simple partial seizure, a temporal lobe seizure, a febrile seizure, a grand mal seizure, an absence seizure, an atonic seizure, a focal loss of consciousness seizure, a frontal lobe seizure, a tonic-clonic seizure, a generalized seizure, a focal epileptic seizure, a gelastic seizure, or a combination thereof.

[0067] In some embodiments, the disease or disorder is an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is a neuroinflammatory disease or disorder. Neuroinflammatory diseases and disorders occur in response to damage or disease that triggers an immune response. Neuroinflammatory diseases or disorders are characterized by excessive neuroinflammation that can persist for a long time. Neuroinflammatory diseases or disorders are conditions involving inflammation of the nervous system, including the brain, spinal cord, and neurons. Neuroinflammatory diseases or disorders are characterized by progressive damage and loss of neurons caused by neuroinflammation.

[0068] In some embodiments, the neuroinflammatory disease or disorder is multiple sclerosis, encephalitis, systemic lupus erythematosus, myelitis, neuritis, meningitis, vasculitis, myasthenia gravis, or a combination thereof. In some embodiments, the neuroinflammatory disease or disorder is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus, gout, psoriatic arthritis, myositis, scleroderma, juvenile scleroderma, rheumatoid arthritis, vasculitis, ankylosing spondylitis, periodontitis, ulcerative colitis, Crohn's disease, sinusitis, asthma, Sjögren's syndrome, uveitis, or a combination thereof.

[0069] In some implementations, the disease or disorder is cancer. The terms “cancer” and “malignant tumor” refer to a group of diseases characterized by abnormal and uncontrolled cell proliferation that begins in one site (primary site) and has the potential to invade and spread to other sites (secondary sites, metastases), distinguishing nervous system cancers (malignant tumors) from benign tumors. Almost all organs can be affected, resulting in more than 50 types of nervous system cancers that can affect humans. Cancer or malignant tumors can be caused by a number of factors, including genetic predisposition, viral infections, exposure to ionizing radiation, exposure to environmental pollutants, tobacco and / or alcohol use, obesity, poor diet, lack of physical activity, or any combination thereof. As used herein, “vesicle” or “tumor,” including its grammatical variations, refers to new and abnormal tissue growth that can be benign or malignant. In related contexts, a vegetation indicates a vegetation-related disease or disorder, including but not limited to various nervous system cancers.

[0070] In some implementations, the cancer is a nervous system cancer.

[0071] In some embodiments, the nervous system cancers are meningiomas, pituitary adenomas, craniopharyngiomas, schwannomas, gliomas, astrocytomas, oligodendrogliomas, glioblastomas, ependymal tumors, pineal tumors, pineal cell tumors, and pinealoblastomas. In some embodiments, the nervous system cancers originate from prostate cancer, pancreatic cancer, bile duct cancer, colon cancer, rectal cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, pancreatic cancer, brain cancer and head and neck cancer, melanoma, sarcoma, multiple myeloma, leukemia, or lymphoma, and then include brain cancer, or combinations thereof.

[0072] In some embodiments, the method of treating a disease or disorder further includes increasing one or more of the following: the subject's neuroplasticity, calcium flux, 5-HT2A receptor activity, 5-HT1A receptor activity, 5-HT7 receptor activity, TrkB expression or activity, BDNF expression or activity, or combinations thereof.

[0073] In some embodiments, the method of treating a disease or disorder includes reducing the expression of neuroinflammatory cytokine biomarkers, said neuroinflammatory cytokine biomarkers including eosinophil chemokine (Eotaxin), G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, M-CSF, MCP-1, MIG, MIP-1α, MIP-1β, MIP-2, RANTES, TNFα, VEGF, or one or more combinations thereof.

[0074] In some implementations, the neuroinflammatory cytokine biomarker is eosinophil chemokine.

[0075] In some implementations, the neuroinflammatory cytokine biomarker is G-CSF.

[0076] In some implementations, the neuroinflammatory cytokine biomarker is GM-CSF.

[0077] In some implementations, the neuroinflammatory cytokine biomarker is IFNγ.

[0078] In some implementations, the neuroinflammatory cytokine biomarker is IL-1α.

[0079] In some implementations, the neuroinflammatory cytokine biomarker is IL-1β.

[0080] In some implementations, the neuroinflammatory cytokine biomarker is IL-2.

[0081] In some implementations, the neuroinflammatory cytokine biomarker is IL-3.

[0082] In some implementations, the neuroinflammatory cytokine biomarker is IL-4.

[0083] In some implementations, the neuroinflammatory cytokine biomarker is IL-5.

[0084] In some implementations, the neuroinflammatory cytokine biomarker is IL-6.

[0085] In some implementations, the neuroinflammatory cytokine biomarker is IL-7.

[0086] In some implementations, the neuroinflammatory cytokine biomarker is IL-9.

[0087] In some implementations, the neuroinflammatory cytokine biomarker is IL-10.

[0088] In some implementations, the neuroinflammatory cytokine biomarker is IL-12p40.

[0089] In some implementations, the neuroinflammatory cytokine biomarker is IL-12p70.

[0090] In some implementations, the neuroinflammatory cytokine biomarker is IL-13.

[0091] In some implementations, the neuroinflammatory cytokine biomarker is IL-15.

[0092] In some implementations, the neuroinflammatory cytokine biomarker is Il-17.

[0093] In some implementations, the neuroinflammatory cytokine biomarker is IP-10.

[0094] In some implementations, the neuroinflammatory cytokine biomarker is KC.

[0095] In some implementations, the neuroinflammatory cytokine biomarker is LIF.

[0096] In some implementations, the neuroinflammatory cytokine biomarker is LIX.

[0097] In some implementations, the neuroinflammatory cytokine biomarker is M-CSF.

[0098] In some implementations, the neuroinflammatory cytokine biomarker is MCP-1.

[0099] In some implementations, the neuroinflammatory cytokine biomarker is MIG.

[0100] In some implementations, the neuroinflammatory cytokine biomarker is MIP-1α.

[0101] In some implementations, the neuroinflammatory cytokine biomarker is MIP-1β.

[0102] In some implementations, the neuroinflammatory cytokine biomarker is MIP-2.

[0103] In some implementations, the neuroinflammatory cytokine biomarker is RANTES.

[0104] In some implementations, the neuroinflammatory cytokine biomarker is TNFα.

[0105] In some implementations, the neuroinflammatory cytokine biomarker is VEGF.

[0106] In another embodiment, the present invention provides a method for inducing neural plasticity in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0107] Neuroplasticity is a process involving adaptive structural and functional changes in the brain. It is the nervous system's ability to alter its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, function, or connections. Neuroplasticity includes changes in the strength of mature synaptic connections, as well as synaptic formation and elimination in the adult and developing brain. Neuroplasticity is assessed through a variety of functional and morphological endpoints, ranging from changes in molecular / cellular indices to synaptic transmission, neurochemical alterations, and changes in dendritic structure and dendritic spine density. Examples of techniques commonly used in neuroplasticity research include electroencephalography (EEG) / evoked potentials (ERPs), structural and functional magnetic resonance imaging (MRI), and transcranial magnetic stimulation (TMS).

[0108] In another embodiment, the present invention provides a method for stimulating neuronal growth in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0109] In one embodiment, the crystalline form of the celecoxib and celecoxib is eutectic form A. Eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°. The XRPD plot of eutectic form A may further contain a significant peak at a 2θ angle of approximately 19.16°. The XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°. Furthermore, the XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, the crystalline form is eutectic form A. Eutectic form A is characterized by XRPD plots containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°. The eutectic form A is characterized by XRPD plots containing prominent peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0110] In another embodiment, the present invention provides a method for stimulating neuronal growth in a subject with such need, comprising administering to the subject a crystalline form of serotonin and serocepin, wherein the crystalline form is a eutectic form A, wherein the eutectic form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0111] In another embodiment, the present invention provides a method for stimulating neuronal growth in a subject with such need, comprising administering to the subject a crystalline form of serotonin and serocepin, wherein the crystalline form is a eutectic form A, wherein the eutectic form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0112] In some embodiments, stimulating neuronal growth results in an increase in neurite length of approximately 100 μM to approximately 300 μM, approximately 110 μM to approximately 300 μM, approximately 120 μM to approximately 300 μM, approximately 130 μM to approximately 300 μM, approximately 140 μM to approximately 300 μM, approximately 150 μM to approximately 300 μM, approximately 160 μM to approximately 300 μM, approximately 170 μM to approximately 300 μM, approximately 180 μM to approximately 300 μM, approximately 190 μM to approximately 300 μM, approximately 200 μM to approximately 300 μM, approximately 210 μM to approximately 300 μM, approximately 220 μM to approximately 300 μM, approximately 230 μM to approximately 300 μM, approximately 240 μM to approximately 300 μM, approximately 250 μM to approximately 300 μM, and approximately 260 μM. μM to approximately 300 μM, approximately 270 μM to approximately 300 μM, approximately 280 μM to approximately 300 μM, approximately 290 μM to approximately 300 μM, approximately 100 μM to approximately 290 μM, approximately 100 μM to approximately 280 μM, approximately 100 μM to approximately 270 μM, approximately 100 μM to approximately 260 μM, approximately 100 μM to approximately 250 μM, approximately 100 μM to approximately 240 μM, approximately 100 μM to approximately 230 μM, approximately 100 μM to approximately 220 μM, approximately 100 μM to approximately 210 μM, approximately 100 μM to approximately 200 μM, approximately 100 μM to approximately 190 μM, approximately 100 μM to approximately 180 μM, approximately 100 μM to approximately 170 μM, approximately 100 μM to approximately 160 μM μM, approximately 100 μM to approximately 150 μM, approximately 100 μM to approximately 140 μM, approximately 100 μM to approximately 130 μM, or approximately 100 μM to approximately 110 μM.

[0113] In some implementations, stimulating neuronal growth results in an increase in neurite length of approximately 100 μM to approximately 300 μM.

[0114] In some implementations, stimulating neuronal growth results in an increase in neurite length of approximately 100 μM, approximately 110 μM, approximately 120 μM, approximately 130 μM, approximately 140 μM, approximately 150 μM, approximately 160 μM, approximately 170 μM, approximately 190 μM, approximately 190 μM, approximately 200 μM, approximately 210 μM, approximately 220 μM, approximately 230 μM, approximately 240 μM, approximately 250 μM, approximately 260 μM, approximately 270 μM, approximately 290 μM, approximately 290 μM, approximately 300 μM, or any two of these values.

[0115] In some embodiments, stimulating neuronal growth results in an increase in neurite length of approximately 20% to approximately 100%, approximately 25% to approximately 100%, approximately 30% to approximately 100%, approximately 35% to approximately 100%, approximately 40% to approximately 100%, approximately 45% to approximately 100%, approximately 50% to approximately 100%, approximately 55% to approximately 100%, approximately 60% to approximately 100%, approximately 65% ​​to approximately 100%, approximately 70% to approximately 100%, approximately 75% to approximately 100%, approximately 80% to approximately 100%, and approximately 85% to approximately 100%. Approximately 90% to approximately 100%, approximately 95% to approximately 100%, approximately 20% to approximately 95%, approximately 20% to approximately 90%, approximately 20% to approximately 85%, approximately 20% to approximately 80%, approximately 20% to approximately 75%, approximately 20% to approximately 70%, approximately 20% to approximately 65%, approximately 20% to approximately 60%, approximately 20% to approximately 55%, approximately 20% to approximately 50%, approximately 20% to approximately 45%, approximately 20% to approximately 40%, approximately 20% to approximately 35%, approximately 20% to approximately 30%, or approximately 20% to approximately 25%.

[0116] In some implementations, stimulating neuronal growth results in an increase in neurite length of approximately 20% to approximately 100%.

[0117] In some implementations, stimulating neuronal growth results in an increase in neurite length of approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 100%, or any two of these values.

[0118] In another embodiment, the present invention provides a method for increasing the number of neural progenitor cells in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0119] In another embodiment, the present invention provides a method for increasing the number of neural progenitor cells in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0120] In one embodiment, the crystalline form of the celecoxib and celecoxib is eutectic form A. Eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°. The XRPD plot of eutectic form A may further contain a significant peak at a 2θ angle of approximately 19.16°. The XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°. Furthermore, the XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, the crystalline form is eutectic form A. Eutectic form A is characterized by XRPD plots containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°. The eutectic form A is characterized by XRPD plots containing prominent peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0121] In another embodiment, the present invention provides a method for increasing the number of neural progenitor cells in a subject with this need, comprising administering to the subject a crystalline form of serotonin and serocepin: wherein the crystalline form is a eutectic form A; and wherein form A is characterized by an XRPD plot containing prominent peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0122] In another embodiment, the present invention provides a method for increasing the number of neural progenitor cells in a subject with this need, comprising administering to the subject a crystalline form of serotonin and serocepin: wherein the crystalline form is a eutectic form A; and wherein form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0123] In some embodiments, the number of neural progenitor cells is increased by approximately 0.1% to approximately 10%, approximately 0.2% to approximately 10%, approximately 0.3% to approximately 10%, approximately 0.4% to approximately 10%, approximately 0.5% to approximately 10%, approximately 0.6% to approximately 10%, approximately 0.7% to approximately 10%, approximately 0.8% to approximately 10%, approximately 0.9% to approximately 10%, approximately 1.0% to approximately 10%, approximately 1.1% to approximately 10%, approximately 1.2% to approximately 10%, approximately 1.3% to approximately 10%, approximately 1.4% to approximately 10%, approximately 1.5% to approximately 10%, approximately 1.6% to approximately 10%, approximately 1.7% to approximately 10%, and approximately 1.8% to approximately 10%, approximately 1.9% to approximately 10%, approximately 2.0% to approximately 10%, approximately 2.1% to approximately 10%, approximately 2.2% to approximately 10%, approximately 2.3% to approximately 10%, approximately 2.4% to approximately 10%, approximately 2.5% to approximately 10%, approximately 2.6% to approximately 10%, approximately 2.7% to approximately 10%, approximately 2.8% to approximately 10%, approximately 2.9% to approximately 10%, approximately 3.0% to approximately 10%, approximately 3.1% to approximately 10%, approximately 3.2% to approximately 10%, approximately 3.3% to approximately 10%, approximately 3.4% to approximately 10%, approximately 3.5% to approximately 10%, approximately 3.6% to approximately 10%, approximately 3.7% to approximately 10%. Approximately 3.8% to approximately 10%, approximately 3.9% to approximately 10%, approximately 4.0% to approximately 10%, approximately 4.1% to approximately 10%, approximately 4.2% to approximately 10%, approximately 4.3% to approximately 10%, approximately 4.4% to approximately 10%, approximately 4.5% to approximately 10%, approximately 4.6% to approximately 10%, approximately 4.7% to approximately 10%, approximately 4.8% to approximately 10%, approximately 4.9% to approximately 10%, approximately 5.0% to approximately 10%, approximately 5.1% to approximately 10%, approximately 5.2% to approximately 10%, approximately 5.3% to approximately 10%, approximately 5.4% to approximately 10%, approximately 5.5% to approximately 10%, approximately 5.6% to approximately 10%, large Approximately 5.7% to approximately 10%, approximately 5.8% to approximately 10%, approximately 5.9% to approximately 10%, approximately 6.0% to approximately 10%, approximately 6.1% to approximately 10%, approximately 6.2% to approximately 10%, approximately 6.3% to approximately 10%, approximately 6.4% to approximately 10%, approximately 6.5% to approximately 10%, approximately 6.6% to approximately 10%, approximately 6.7% to approximately 10%, approximately 6.8% to approximately 10%, approximately 6.9% to approximately 10%, approximately 7.0% to approximately 10%, approximately 7.1% to approximately 10%, approximately 7.2% to approximately 10%, approximately 7.3% to approximately 10%, approximately 7.4% to approximately 10%, approximately 7.5% to approximately 10%, approximately 7.6% to approximately 10%, approximately 7.7% to approximately 10%, approximately 7.8% to approximately 10%, approximately 7.9% to approximately 10%, approximately 8.0% to approximately 10%, approximately 8.1% to approximately 10%, approximately 8.2% to approximately 10%, approximately 8.3% to approximately 10%, approximately 8.4% to approximately 10%, approximately 8.5% to approximately 10%, approximately 8.6% to approximately 10%, approximately 8.7% to approximately 10%, approximately 8.8% to approximately 10%, approximately 8.9% to approximately 10%, approximately 9.0% to approximately 10%, approximately 9.1% to approximately 10%, approximately 9.2% to approximately 10%, approximately 9.3% to approximately 10%, approximately 9.4% to approximately 10%, approximately 9.5% Up to approximately 10%, approximately 9.6% to approximately 10%, approximately 9.7% to approximately 10%, approximately 9.8% to approximately 10%, approximately 9.9% to approximately 10%, approximately 0.1% to approximately 9.9%, approximately 0.1% to approximately 9.8%, approximately 0.1% to approximately 9.7%, approximately 0.1% to approximately 9.6%, approximately 0.1% to approximately 9.5%, approximately 0.1% to approximately 9.4%, approximately 0.1% to approximately 9.3%, approximately 0.1% to approximately 9.2%, approximately 0.1% to approximately 9.1%, approximately 0.1% to approximately 9.0%, approximately 0.1% to approximately 8.9%, approximately 0.1% to approximately 8.8%, approximately 0.1% to approximately 8.7%, approximately 0.1% to approximately 8.6%, approximately 0.1% to approximately 8.5%, approximately 0.1% to approximately 8.4%, approximately 0.1% to approximately 8.3%, approximately 0.1% to approximately 8.2%, approximately 0.1% to approximately 8.1%, approximately 0.1% to approximately 8.0%, approximately 0.1% to approximately 7.9%, approximately 0.1% to approximately 7.8%, approximately 0.1% to approximately 7.7%, approximately 0.1% to approximately 7.6%, approximately 0.1% to approximately 7.5%, approximately 0.1% to approximately 7.4%, approximately 0.1% to approximately 7.3%, approximately 0.1% to approximately 7.2%, approximately 0.1% to approximately 7.1%, approximately 0.1% to approximately 7.0%, approximately 0.1% to approximately 6.9%, approximately 0.1% Up to approximately 6.8%, approximately 0.1% to approximately 6.7%, approximately 0.1% to approximately 6.6%, approximately 0.1% to approximately 6.5%, approximately 0.1% to approximately 6.4%, approximately 0.1% to approximately 6.3%, approximately 0.1% to approximately 6.2%, approximately 0.1% to approximately 6.1%, approximately 0.1% to approximately 6.0%, approximately 0.1% to approximately 5.9%, approximately 0.1% to approximately 5.8%, approximately 0.1% to approximately 5.7%, approximately 0.1% to approximately 5.6%, approximately 0.1% to approximately 5.5%, approximately 0.1% to approximately 5.4%, approximately 0.1% to approximately 5.3%, approximately 0.1% to approximately 5.2%, approximately 0.1% to approximately 5.1%, approximately 0.1% to approximately 5.0%, approximately 0.1% to approximately 4.9%, approximately 0.1% to approximately 4.8%, approximately 0.1% to approximately 4.7%, approximately 0.1% to approximately 4.6%, approximately 0.1% to approximately 4.5%, approximately 0.1% to approximately 4.4%, approximately 0.1% to approximately 4.3%, approximately 0.1% to approximately 4.2%, approximately 0.1% to approximately 4.1%, approximately 0.1% to approximately 4.0%, approximately 0.1% to approximately 3.9%, approximately 0.1% Up to approximately 3.8%, approximately 0.1% to approximately 3.7%, approximately 0.1% to approximately 3.6%, approximately 0.1% to approximately 3.5%, approximately 0.1% to approximately 3.4%, approximately 0.1% to approximately 3.3%, approximately 0.1% to approximately 3.2%, approximately 0.1% to approximately 3.1%, approximately 0.1% to approximately 3.0%, approximately 0.1% to approximately 2.9%, approximately 0.1% to approximately 2.8%, approximately 0.1% to approximately 2.7%, approximately 0.1% to approximately 2.6%, approximately 0.1% to approximately 2.5%, approximately 0.1% to approximately 2.4%, approximately 0.1% to approximately 2.3%, approximately 0.1% to approximately 2.2%, approximately 0.1% to approximately 2.1%, approximately 0.1% to approximately 2.0%, approximately 0.1% to approximately 1.9%, approximately 0.1% to approximately 1.8%, approximately 0.1% to approximately 1.7%, approximately 0.1% to approximately 1.6%, approximately 0.1% to approximately 1.5%, approximately 0.1% to approximately 1.4%. %, approximately 0.1% to approximately 1.3%, approximately 0.1% to approximately 1.2%, approximately 0.1% to approximately 1.1%, approximately 0.1% to approximately 1.0%, approximately 0.1% to approximately 0.9%, approximately 0.1% to approximately 0.8%, approximately 0.1% to approximately 0.7%, approximately 0.1% to approximately 0.6%, approximately 0.1% to approximately 0.5%, approximately 0.1% to approximately 0.4%, approximately 0.1% to approximately 0.3%, or approximately 0.1% to approximately 0.2%.

[0124] In some implementations, the number of neural progenitor cells is increased by approximately 0.1% to approximately 10%.

[0125] In some implementations, the number of neural progenitor cells is increased by approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8%, approximately 0.9%, approximately 1.0%, approximately 1.1%, approximately 1.2%, approximately 1.3%, approximately 1.4%, approximately 1.5%, approximately 1.6%, approximately 1.7%, approximately 1.8%, approximately 1.9%, approximately 2.0%, approximately 2.1%, approximately 2.2%, approximately 2.3%, and approximately 2 0.4%, approximately 2.5%, approximately 2.6%, approximately 2.7%, approximately 2.8%, approximately 2.9%, approximately 3.0%, approximately 3.1%, approximately 3.2%, approximately 3.3%, approximately 3.4%, approximately 3.5%, approximately 3.6%, approximately 3.7%, approximately 3.8%, approximately 3.9%, approximately 4.0%, approximately 4.1%, approximately 4.2%, approximately 4.3%, approximately 4.4%, approximately 4.5%, approximately 4.6%, approximately 4.7%, approximately 4.8%, approximately 4.9%, approximately 5.0% %, approximately 5.1%, approximately 5.2%, approximately 5.3%, approximately 5.4%, approximately 5.5%, approximately 5.6%, approximately 5.7%, approximately 5.8%, approximately 5.9%, approximately 6.0%, approximately 6.1%, approximately 6.2%, approximately 6.3%, approximately 6.4%, approximately 6.5%, approximately 6.6%, approximately 6.7%, approximately 6.8%, approximately 6.9%, approximately 7.0%, approximately 7.1%, approximately 7.2%, approximately 7.3%, approximately 7.4%, approximately 7.5%, approximately 7.6%. Approximately 7.7%, approximately 7.8%, approximately 7.9%, approximately 8.0%, approximately 8.1%, approximately 8.2%, approximately 8.3%, approximately 8.4%, approximately 8.5%, approximately 8.6%, approximately 8.7%, approximately 8.8%, approximately 8.9%, approximately 9.0%, approximately 9.1%, approximately 9.2%, approximately 9.3%, approximately 9.4%, approximately 9.5%, approximately 9.6%, approximately 9.7%, approximately 9.8%, approximately 9.9%, approximately 10.0%, or a range between any two of these values.

[0126] In another embodiment, the present invention provides a method for increasing brain-derived neurotrophic factor (BDNF) levels in subjects with such need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0127] In another embodiment, the present invention provides a method for increasing BDNF levels in subjects who require it, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0128] In one embodiment, the crystalline form of the celecoxib and celecoxib is eutectic form A. Eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°. The XRPD plot of eutectic form A may further contain a significant peak at a 2θ angle of approximately 19.16°. The XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°. Furthermore, the XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, the crystalline form is eutectic form A. Eutectic form A is characterized by XRPD plots containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°. The eutectic form A is characterized by XRPD plots containing prominent peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0129] In another embodiment, the present invention provides a method for increasing BDNF levels in a subject with this need, comprising administering to the subject a crystalline form of serotonin and serocepin: wherein the crystalline form is a eutectic form A; and wherein crystalline form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0130] In another embodiment, the present invention provides a method for increasing BDNF levels in a subject with this need, comprising administering to the subject a crystalline form of serotonin and serocepin: wherein the crystalline form is a eutectic form A; and wherein form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0131] BDNF is the most prevalent growth factor in the central nervous system. It plays a crucial role in neuronal survival and growth, acts as a neurotransmitter regulator, and participates in neuronal plasticity (essential for learning and memory). BDNF release enhances existing neurons in the brain. Therefore, high BDNF levels are associated with improved memory and intellectual alertness. In some implementations, increased BDNF levels induce a heightened anti-inflammatory response in subjects. Selective BDNF inhibitors (or indirect BDNF inhibitors, such as the TrKB inhibitor ANA-12) prevent BDNF-induced neurite growth and thus inhibit neuronal plasticity.

[0132] In some implementations, the BDNF level is increased.

[0133] In some implementations, the BDNF level is increased by approximately 5% to approximately 150%, approximately 6% to approximately 150%, approximately 7% to approximately 150%, approximately 8% to approximately 150%, approximately 9% to approximately 150%, approximately 10% to approximately 150%, approximately 11% to approximately 150%, approximately 12% to approximately 150%, approximately 13% to approximately 150%, approximately 14% to approximately 150%, approximately 15% to approximately 150%, approximately 16% to approximately 150%, approximately 17% to approximately 150%, approximately 18% to approximately 150%, approximately 19% to approximately 150%, approximately 20% to approximately 150%, approximately 21% to approximately 150%, approximately 22% to approximately 150%, approximately 2 3% to approximately 150%, approximately 24% to approximately 150%, approximately 25% to approximately 150%, approximately 26% to approximately 150%, approximately 27% to approximately 150%, approximately 28% to approximately 150%, approximately 29% to approximately 150%, approximately 30% to approximately 150%, approximately 31% to approximately 150%, approximately 32% to approximately 150%, approximately 33% to approximately 150%, approximately 34% to approximately 150%, approximately 35% to approximately 150%, approximately 36% to approximately 150%, approximately 37% to approximately 150%, approximately 38% to approximately 150%, approximately 39% to approximately 150%, approximately 40% to approximately 150%, approximately 41% to approximately 150%, approximately 42% to approximately 150%. Approximately 150%, approximately 43% to approximately 150%, approximately 44% to approximately 150%, approximately 45% to approximately 150%, approximately 46% to approximately 150%, approximately 47% to approximately 150%, approximately 48% to approximately 150%, approximately 49% to approximately 150%, approximately 50% to approximately 150%, approximately 51% to approximately 150%, approximately 52% to approximately 150%, approximately 53% to approximately 150%, approximately 54% to approximately 150%, approximately 55% to approximately 150%, approximately 56% to approximately 150%, approximately 57% to approximately 150%, approximately 58% to approximately 150%, approximately 59% to approximately 150%, approximately 60% to approximately 150%, approximately 61% to approximately 1 50%, approximately 62% to approximately 150%, approximately 63% to approximately 150%, approximately 64% to approximately 150%, approximately 65% ​​to approximately 150%, approximately 66% to approximately 150%, approximately 67% to approximately 150%, approximately 68% to approximately 150%, approximately 69% to approximately 150%, approximately 70% to approximately 150%, approximately 71% to approximately 150%, approximately 72% to approximately 150%, approximately 73% to approximately 150%, approximately 74% to approximately 150%, approximately 75% to approximately 150%, approximately 76% to approximately 150%, approximately 77% to approximately 150%, approximately 78% to approximately 150%, approximately 79% to approximately 150%, approximately 80% to approximately 150%.Approximately 81% to approximately 150%, approximately 82% to approximately 150%, approximately 83% to approximately 150%, approximately 84% to approximately 150%, approximately 85% to approximately 150%, approximately 86% to approximately 150%, approximately 87% to approximately 150%, approximately 88% to approximately 150%, approximately 89% to approximately 150%, approximately 90% to approximately 150%, approximately 91% to approximately 150%, approximately 92% to approximately 150%, approximately 93% to approximately 150%, approximately 94% to approximately 150%, approximately 95% to approximately 150%, approximately 96% to approximately 150%, approximately 97% to approximately 150%, approximately 98% to approximately 150%, approximately 99% to approximately 150%, large Approximately 100% to approximately 150%, approximately 101% to approximately 150%, approximately 102% to approximately 150%, approximately 103% to approximately 150%, approximately 104% to approximately 150%, approximately 105% to approximately 150%, approximately 106% to approximately 150%, approximately 107% to approximately 150%, approximately 108% to approximately 150%, approximately 109% to approximately 150%, approximately 110% to approximately 150%, approximately 111% to approximately 150%, approximately 112% to approximately 150%, approximately 113% to approximately 150%, approximately 114% to approximately 150%, approximately 115% to approximately 150%, approximately 116% to approximately 150%, approximately 117% to approximately 150%. %, approximately 118% to approximately 150%, approximately 119% to approximately 150%, approximately 120% to approximately 150%, approximately 121% to approximately 150%, approximately 122% to approximately 150%, approximately 123% to approximately 150%, approximately 124% to approximately 150%, approximately 125% to approximately 150%, approximately 126% to approximately 150%, approximately 127% to approximately 150%, approximately 128% to approximately 150%, approximately 129% to approximately 150%, approximately 130% to approximately 150%, approximately 131% to approximately 150%, approximately 132% to approximately 150%, approximately 133% to approximately 150%, approximately 134% to approximately 150%, approximately 135% to approximately 150%, approximately 136% to approximately 150%, approximately 137% to approximately 150%, approximately 138% to approximately 150%, approximately 139% to approximately 150%, approximately 140% to approximately 150%, approximately 141% to approximately 150%, approximately 142% to approximately 150%, approximately 143% to approximately 150%, approximately 144% to approximately 150%, approximately 145% to approximately 150%, approximately 146% to approximately 150%, approximately 147% to approximately 150%, approximately 148% to approximately 150%, approximately 149% to approximately 150%, approximately 5% to approximately 149%, approximately 5% to approximately 148%, approximately 5% to approximately 147%, approximately 5% to approximately 146%.Approximately 5% to approximately 145%, approximately 5% to approximately 144%, approximately 5% to approximately 143%, approximately 5% to approximately 142%, approximately 5% to approximately 141%, approximately 5% to approximately 140%, approximately 5% to approximately 139%, approximately 5% to approximately 138%, approximately 5% to approximately 137%, approximately 5% to approximately 136%, approximately 5% to approximately 135%, approximately 5% to approximately 134%, approximately 5% to approximately 133%, approximately 5% to approximately 132%, approximately 5% to approximately 131%, approximately 5% to approximately 130%, approximately 5% to approximately 129%, approximately 5% to approximately 128%, approximately 5% to approximately 127%, approximately 5% to approximately 126%, approximately 5% to approximately 1 25%, approximately 5% to approximately 124%, approximately 5% to approximately 123%, approximately 5% to approximately 122%, approximately 5% to approximately 121%, approximately 5% to approximately 120%, approximately 5% to approximately 119%, approximately 5% to approximately 118%, approximately 5% to approximately 117%, approximately 5% to approximately 116%, approximately 5% to approximately 115%, approximately 5% to approximately 114%, approximately 5% to approximately 113%, approximately 5% to approximately 112%, approximately 5% to approximately 111%, approximately 5% to approximately 110%, approximately 5% to approximately 109%, approximately 5% to approximately 108%, approximately 5% to approximately 107%, approximately 5% to approximately 106%, approximately 5% to approximately 105%, approximately 5% To approximately 104%, approximately 5% to approximately 103%, approximately 5% to approximately 102%, approximately 5% to approximately 101%, approximately 5% to approximately 100%, approximately 5% to approximately 99%, approximately 5% to approximately 98%, approximately 5% to approximately 97%, approximately 5% to approximately 96%, approximately 5% to approximately 95%, approximately 5% to approximately 94%, approximately 5% to approximately 93%, approximately 5% to approximately 92%, approximately 5% to approximately 91%, approximately 5% to approximately 90%, approximately 5% to approximately 89%, approximately 5% to approximately 88%, approximately 5% to approximately 87%, approximately 5% to approximately 86%, approximately 5% to approximately 85%, approximately 5% to approximately 84%, approximately 5% to approximately 83%, approximately 5% to approximately 84%, approximately 5% to approximately 83%, approximately 5% to approximately 84%, approximately 5% to approximately 83%, approximately 5% to approximately 84%, approximately 5% to approximately 85 ...5%, Approximately 82%, approximately 5% to approximately 81%, approximately 5% to approximately 80%, approximately 5% to approximately 79%, approximately 5% to approximately 78%, approximately 5% to approximately 77%, approximately 5% to approximately 76%, approximately 5% to approximately 75%, approximately 5% to approximately 74%, approximately 5% to approximately 73%, approximately 5% to approximately 72%, approximately 5% to approximately 71%, approximately 5% to approximately 70%, approximately 5% to approximately 69%, approximately 5% to approximately 68%, approximately 5% to approximately 67%, approximately 5% to approximately 66%, approximately 5% to approximately 65%, approximately 5% to approximately 64%, approximately 5% to approximately 63%, approximately 5% to approximately 62%, approximately 5% to approximately 61%, approximately 5% to approximately 60%.Approximately 5% to approximately 59%, approximately 5% to approximately 58%, approximately 5% to approximately 57%, approximately 5% to approximately 56%, approximately 5% to approximately 55%, approximately 5% to approximately 54%, approximately 5% to approximately 53%, approximately 5% to approximately 52%, approximately 5% to approximately 51%, approximately 5% to approximately 50%, approximately 5% to approximately 49%, approximately 5% to approximately 48%, approximately 5% to approximately 47%, approximately 5% to approximately 46%, approximately 5% to approximately 45%, approximately 5% to approximately 44%, approximately 5% to approximately 43%, approximately 5% to approximately 42%, approximately 5% to approximately 41%, approximately 5% to approximately 40%, approximately 5% to approximately 39%, approximately 5% to approximately 38%, approximately 5% to approximately 37%, approximately 5% to approximately 36%, approximately 5% to approximately 35%, approximately 5% to approximately 34%, approximately 5% to approximately 33%. %, approximately 5% to approximately 32%, approximately 5% to approximately 31%, approximately 5% to approximately 30%, approximately 5% to approximately 29%, approximately 5% to approximately 28%, approximately 5% to approximately 27%, approximately 5% to approximately 26%, approximately 5% to approximately 25%, approximately 5% to approximately 24%, approximately 5% to approximately 23%, approximately 5% to approximately 22%, approximately 5% to approximately 21%, approximately 5% to approximately 20%, approximately 5% to approximately 19%, approximately 5% to approximately 18%, approximately 5% to approximately 17%, approximately 5% to approximately 16%, approximately 5% to approximately 15%, approximately 5% to approximately 14%, approximately 5% to approximately 13%, approximately 5% to approximately 12%, approximately 5% to approximately 11%, approximately 5% to approximately 10%, approximately 5% to approximately 9%, approximately 5% to approximately 8%, approximately 5% to approximately 7%, or approximately 5% to approximately 6%.

[0134] In some implementations, BDNF levels are increased by approximately 5% to approximately 75%.

[0135] In some implementations, BDNF levels are increased by approximately 5% to approximately 150%.

[0136] In some implementations, the BDNF level is increased by approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 4 2%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118% Approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, approximately 125%, approximately 126%, approximately 127%, approximately 128%, approximately 129%, approximately 130%, approximately 131%, approximately 132%, approximately 133%, approximately 134%, approximately 135%, approximately 136%, approximately 137%, approximately 138%, approximately 139%, approximately 140%, approximately 141%, approximately 142%, approximately 143%, approximately 144%, approximately 145%, approximately 146%, approximately 147%, approximately 148%, approximately 149%, approximately 150%, or a range between any two of these values.

[0137] In another embodiment, the present invention provides a method for reducing neuroinflammation in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide.

[0138] In one embodiment, the crystalline form of the celecoxib and celecoxib is eutectic form A. Eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°. The XRPD plot of eutectic form A may further contain a significant peak at a 2θ angle of approximately 19.16°. The XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°. Furthermore, the XRPD plot of eutectic form A may further contain significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, the crystalline form is eutectic form A. Eutectic form A is characterized by XRPD plots containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°. The eutectic form A is characterized by XRPD plots containing prominent peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0139] In another embodiment, the present invention provides a method for reducing neuroinflammation in a subject with this need, comprising administering to the subject a crystalline form of serotonin and serocepin: wherein the crystalline form is a eutectic form A; and wherein form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0140] In another embodiment, the present invention provides a method for reducing neuroinflammation in a subject with this need, comprising administering to the subject a crystalline form of serotonin and serocepin: wherein the crystalline form is a eutectic form A; and wherein form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1°, approximately 19.16°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

[0141] Inflammation is part of the body’s biological response to harmful stimuli. However, if left uncontrolled, it can damage healthy cells, tissues, and organs, and can cause internal scarring, tissue death, and damage to DNA in previously healthy cells, which can be measured by measuring the expression levels of neuroinflammatory biomarkers.

[0142] In some embodiments, the anti-inflammatory response includes a decrease in the expression of neuroinflammatory biomarkers. In some embodiments, neuroinflammatory biomarkers include one or more of the following: eosinophil chemokine, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, M-CSF, MCP-1, MIG, MIP-1α, MIP-1β, MIP-2, RANTES, TNFα, VEGF, or combinations thereof.

[0143] In some implementations, the neuroinflammatory cytokine biomarker is eosinophil chemokine.

[0144] In some implementations, the neuroinflammatory cytokine biomarker is G-CSF.

[0145] In some implementations, the neuroinflammatory cytokine biomarker is GM-CSF.

[0146] In some implementations, the neuroinflammatory cytokine biomarker is IFNγ.

[0147] In some implementations, the neuroinflammatory cytokine biomarker is IL-1α.

[0148] In some implementations, the neuroinflammatory cytokine biomarker is IL-1β.

[0149] In some implementations, the neuroinflammatory cytokine biomarker is IL-2.

[0150] In some implementations, the neuroinflammatory cytokine biomarker is IL-3.

[0151] In some implementations, the neuroinflammatory cytokine biomarker is IL-4.

[0152] In some implementations, the neuroinflammatory cytokine biomarker is IL-5.

[0153] In some implementations, the neuroinflammatory cytokine biomarker is IL-6.

[0154] In some implementations, the neuroinflammatory cytokine biomarker is IL-7.

[0155] In some implementations, the neuroinflammatory cytokine biomarker is IL-9.

[0156] In some implementations, the neuroinflammatory cytokine biomarker is IL-10.

[0157] In some implementations, the neuroinflammatory cytokine biomarker is IL-12p40.

[0158] In some implementations, the neuroinflammatory cytokine biomarker is IL-12p70.

[0159] In some implementations, the neuroinflammatory cytokine biomarker is IL-13.

[0160] In some implementations, the neuroinflammatory cytokine biomarker is IL-15.

[0161] In some implementations, the neuroinflammatory cytokine biomarker is Il-17.

[0162] In some implementations, the neuroinflammatory cytokine biomarker is IP-10.

[0163] In some implementations, the neuroinflammatory cytokine biomarker is KC.

[0164] In some implementations, the neuroinflammatory cytokine biomarker is LIF.

[0165] In some implementations, the neuroinflammatory cytokine biomarker is LIX.

[0166] In some implementations, the neuroinflammatory cytokine biomarker is M-CSF.

[0167] In some implementations, the neuroinflammatory cytokine biomarker is MCP-1.

[0168] In some implementations, the neuroinflammatory cytokine biomarker is MIG.

[0169] In some implementations, the neuroinflammatory cytokine biomarker is MIP-1α.

[0170] In some implementations, the neuroinflammatory cytokine biomarker is MIP-1β.

[0171] In some implementations, the neuroinflammatory cytokine biomarker is MIP-2.

[0172] In some implementations, the neuroinflammatory cytokine biomarker is RANTES.

[0173] In some implementations, the neuroinflammatory cytokine biomarker is TNFα.

[0174] In some implementations, the neuroinflammatory cytokine biomarker is VEGF.

[0175] In some embodiments, the expression of neuroinflammatory cytokine biomarkers is reduced by approximately 1% to approximately 80%, approximately 2% to approximately 80%, approximately 3% to approximately 80%, approximately 4% to approximately 80%, approximately 5% to approximately 80%, approximately 6% to approximately 80%, approximately 7% to approximately 80%, approximately 8% to approximately 80%, approximately 9% to approximately 80%, approximately 10% to approximately 80%, approximately 11% to approximately 80%, approximately 12% to approximately 80%, approximately 13% to approximately 80%, approximately 14% to approximately 80%, approximately 15% to approximately 80%, approximately 16% to approximately 80%, approximately 17% to approximately 80%, approximately 18% to approximately 80%, approximately 19% to approximately 80%, approximately 2 0% to approximately 80%, approximately 21% to approximately 80%, approximately 22% to approximately 80%, approximately 23% to approximately 80%, approximately 24% to approximately 80%, approximately 25% to approximately 80%, approximately 26% to approximately 80%, approximately 27% to approximately 80%, approximately 28% to approximately 80%, approximately 29% to approximately 80%, approximately 30% to approximately 80%, approximately 31% to approximately 80%, approximately 32% to approximately 80%, approximately 33% to approximately 80%, approximately 34% to approximately 80%, approximately 35% to approximately 80%, approximately 36% to approximately 80%, approximately 37% to approximately 80%, approximately 38% to approximately 80%, approximately 39% to approximately 80%, approximately 40% to approximately 80%, large Approximately 41% to approximately 80%, approximately 42% to approximately 80%, approximately 43% to approximately 80%, approximately 44% to approximately 80%, approximately 45% to approximately 80%, approximately 46% to approximately 80%, approximately 47% to approximately 80%, approximately 48% to approximately 80%, approximately 49% to approximately 80%, approximately 50% to approximately 80%, approximately 51% to approximately 80%, approximately 52% to approximately 80%, approximately 53% to approximately 80%, approximately 54% to approximately 80%, approximately 55% to approximately 80%, approximately 56% to approximately 80%, approximately 57% to approximately 80%, approximately 58% to approximately 80%, approximately 59% to approximately 80%, approximately 60% to approximately 80%, approximately 61% to approximately 80%. Approximately 62% to approximately 80%, approximately 63% to approximately 80%, approximately 64% to approximately 80%, approximately 65% ​​to approximately 80%, approximately 66% to approximately 80%, approximately 67% to approximately 80%, approximately 68% to approximately 80%, approximately 69% to approximately 80%, approximately 70% to approximately 80%, approximately 71% to approximately 80%, approximately 72% to approximately 80%, approximately 73% to approximately 80%, approximately 74% to approximately 80%, approximately 75% to approximately 80%, approximately 76% to approximately 80%, approximately 77% to approximately 80%, approximately 78% to approximately 80%, approximately 79% to approximately 80%, approximately 1% to approximately 79%, approximately 1% to approximately 78%, approximately 1% to approximately 77%.Approximately 1% to approximately 76%, approximately 1% to approximately 75%, approximately 1% to approximately 74%, approximately 1% to approximately 73%, approximately 1% to approximately 72%, approximately 1% to approximately 71%, approximately 1% to approximately 70%, approximately 1% to approximately 69%, approximately 1% to approximately 68%, approximately 1% to approximately 67%, approximately 1% to approximately 66%, approximately 1% to approximately 65%, approximately 1% to approximately 64%, approximately 1% to approximately 63%, approximately 1% to approximately 62%, approximately 1% to approximately 61%, approximately 1% to approximately 60%, approximately 1% to approximately 59%, approximately 1% to approximately 76%, approximately 1% to approximately 75%, approximately 1% to approximately 74%, approximately 1% to approximately 72%, approximately 1% to approximately 61%, approximately 1% to approximately 60%, approximately 1% to approximately 59%, approximately 1% to approximately 76%, approximately 1% to approximately 75%, approximately 1% to approximately 74%, approximately 1% to approximately 73%, approximately 1% to approximately 72%, approximately 1% to approximately 71%, approximately 1% to approximately 70 ... Approximately 58%, approximately 1% to approximately 57%, approximately 1% to approximately 56%, approximately 1% to approximately 55%, approximately 1% to approximately 54%, approximately 1% to approximately 53%, approximately 1% to approximately 52%, approximately 1% to approximately 51%, approximately 1% to approximately 50%, approximately 1% to approximately 49%, approximately 1% to approximately 48%, approximately 1% to approximately 47%, approximately 1% to approximately 46%, approximately 1% to approximately 45%, approximately 1% to approximately 44%, approximately 1% to approximately 43%, approximately 1% to approximately 42%, approximately 1% to approximately 41%, approximately 1% to approximately 40%, approximately 1% to approximately 39%, approximately 1% to approximately 38%, approximately 1% to approximately 37%, approximately 1% to approximately 36%, approximately 1% to approximately 35%, approximately 1% to approximately 34%, approximately 1% to approximately 33%, approximately 1% to approximately 32%, approximately 1% to approximately 31%, approximately 1% to approximately 30%, approximately 1% to approximately 29%, approximately 1% to approximately 28%, approximately 1% to approximately 27%, approximately 1% to approximately 26%, approximately 1% to approximately 25%, approximately 1% to approximately 24%, approximately 1% to approximately 23%, approximately 1% to approximately 22%, approximately 1% to approximately 2 1%, approximately 1% to approximately 20%, approximately 1% to approximately 19%, approximately 1% to approximately 18%, approximately 1% to approximately 17%, approximately 1% to approximately 16%, approximately 1% to approximately 15%, approximately 1% to approximately 14%, approximately 1% to approximately 13%, approximately 1% to approximately 12%, approximately 1% to approximately 11%, approximately 1% to approximately 10%, approximately 1% to approximately 9%, approximately 1% to approximately 8%, approximately 1% to approximately 7%, approximately 1% to approximately 6%, approximately 1% to approximately 5%, approximately 1% to approximately 4%, approximately 1% to approximately 3%, or approximately 1% to approximately 2%.

[0176] In some implementations, the expression of neuroinflammatory cytokine biomarkers is reduced by approximately 1% to approximately 80%.

[0177] In some embodiments, the expression of neuroinflammatory cytokine biomarkers is reduced by approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%. %, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, or a range between any two of these values.

[0178] In some implementations, neuroinflammatory cytokine biomarkers are reduced following acute administration or exposure to the crystalline forms of xelocinone and xelocinone.

[0179] As used herein, the terms “acute administration” and “acute exposure” refer to a single administration.

[0180] In some implementations, neuroinflammatory cytokine biomarkers decreased following chronic administration of the crystalline forms of xelocinone and xelocinone.

[0181] As used herein, the terms "chronic application" and "chronic exposure" refer to repeated daily application for at least 5 days. In some embodiments, eutectic form A is applied for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days. In some embodiments, eutectic form A is applied for 5 days. In some embodiments, eutectic form A is applied for 6 days. In some embodiments, eutectic form A is applied for 7 days. In some embodiments, eutectic form A is applied for 8 days; in some embodiments, eutectic form A is applied for 9 days. In some embodiments, eutectic form A is applied for 10 days. In some embodiments, eutectic form A is applied for 11 days. In some embodiments, eutectic form A is applied for 12 days. In some embodiments, eutectic form A is applied for 13 days. In some embodiments, eutectic form A is applied for 14 days. In some embodiments, eutectic form A is applied for 15 days. In some embodiments, eutectic form A is applied for 16 days. In some embodiments, eutectic form A is applied for 17 days. In some embodiments, eutectic form A is applied for 18 days. In some embodiments, eutectic form A is applied for 19 days. In some embodiments, eutectic form A is applied for 20 days. In some embodiments, eutectic form A is applied for 21 days. In some embodiments, eutectic form A is applied for 22 days. In some embodiments, eutectic form A is applied for 23 days. In some embodiments, eutectic form A is applied for 24 days. In some embodiments, eutectic form A is applied for 25 days. In some embodiments, eutectic crystal form A is applied for 26 days. In some embodiments, eutectic crystal form A is applied for 27 days. In some embodiments, eutectic crystal form A is applied for 28 days. In some embodiments, eutectic crystal form A is applied for 29 days. In some embodiments, eutectic crystal form A is applied for 30 days. In some embodiments, eutectic crystal form A is applied for 31 days. In some embodiments, eutectic crystal form A is applied for 32 days. In some embodiments, eutectic crystal form A is applied for 33 days. In some embodiments, eutectic crystal form A is applied for 34 days. In some embodiments, eutectic crystal form A is applied for 35 days. In some embodiments, eutectic crystal form A is applied for 36 days. In some embodiments, eutectic crystal form A is applied for 37 days. In some embodiments, eutectic crystal form A is applied for 38 days. In some embodiments, eutectic crystal form A is applied for 39 days. In some embodiments, eutectic crystal form A is applied for 40 days.

[0182] In some embodiments of the methods disclosed herein, the administration of the crystalline forms of cyclophosphamide and cyclophosphamide is acute.

[0183] In some embodiments of the methods disclosed herein, the administration of the crystalline forms of cyclophosphamide and cyclophosphamide is chronic.

[0184] In some implementations, reducing neuroinflammation includes increasing BDNF levels.

[0185] In some implementations, the BDNF level is increased by approximately 5% to approximately 150%, approximately 6% to approximately 150%, approximately 7% to approximately 150%, approximately 8% to approximately 150%, approximately 9% to approximately 150%, approximately 10% to approximately 150%, approximately 11% to approximately 150%, approximately 12% to approximately 150%, approximately 13% to approximately 150%, approximately 14% to approximately 150%, approximately 15% to approximately 150%, approximately 16% to approximately 150%, approximately 17% to approximately 150%, approximately 18% to approximately 150%, approximately 19% to approximately 150%, approximately 20% to approximately 150%, approximately 21% to approximately 150%, approximately 22% to approximately 150%, approximately 2 3% to approximately 150%, approximately 24% to approximately 150%, approximately 25% to approximately 150%, approximately 26% to approximately 150%, approximately 27% to approximately 150%, approximately 28% to approximately 150%, approximately 29% to approximately 150%, approximately 30% to approximately 150%, approximately 31% to approximately 150%, approximately 32% to approximately 150%, approximately 33% to approximately 150%, approximately 34% to approximately 150%, approximately 35% to approximately 150%, approximately 36% to approximately 150%, approximately 37% to approximately 150%, approximately 38% to approximately 150%, approximately 39% to approximately 150%, approximately 40% to approximately 150%, approximately 41% to approximately 150%, approximately 42% to approximately 150%. Approximately 150%, approximately 43% to approximately 150%, approximately 44% to approximately 150%, approximately 45% to approximately 150%, approximately 46% to approximately 150%, approximately 47% to approximately 150%, approximately 48% to approximately 150%, approximately 49% to approximately 150%, approximately 50% to approximately 150%, approximately 51% to approximately 150%, approximately 52% to approximately 150%, approximately 53% to approximately 150%, approximately 54% to approximately 150%, approximately 55% to approximately 150%, approximately 56% to approximately 150%, approximately 57% to approximately 150%, approximately 58% to approximately 150%, approximately 59% to approximately 150%, approximately 60% to approximately 150%, approximately 61% to approximately 1 50%, approximately 62% to approximately 150%, approximately 63% to approximately 150%, approximately 64% to approximately 150%, approximately 65% ​​to approximately 150%, approximately 66% to approximately 150%, approximately 67% to approximately 150%, approximately 68% to approximately 150%, approximately 69% to approximately 150%, approximately 70% to approximately 150%, approximately 71% to approximately 150%, approximately 72% to approximately 150%, approximately 73% to approximately 150%, approximately 74% to approximately 150%, approximately 75% to approximately 150%, approximately 76% to approximately 150%, approximately 77% to approximately 150%, approximately 78% to approximately 150%, approximately 79% to approximately 150%, approximately 80% to approximately 150%.Approximately 81% to approximately 150%, approximately 82% to approximately 150%, approximately 83% to approximately 150%, approximately 84% to approximately 150%, approximately 85% to approximately 150%, approximately 86% to approximately 150%, approximately 87% to approximately 150%, approximately 88% to approximately 150%, approximately 89% to approximately 150%, approximately 90% to approximately 150%, approximately 91% to approximately 150%, approximately 92% to approximately 150%, approximately 93% to approximately 150%, approximately 94% to approximately 150%, approximately 95% to approximately 150%, approximately 96% to approximately 150%, approximately 97% to approximately 150%, approximately 98% to approximately 150%, approximately 99% to approximately 150%, large Approximately 100% to approximately 150%, approximately 101% to approximately 150%, approximately 102% to approximately 150%, approximately 103% to approximately 150%, approximately 104% to approximately 150%, approximately 105% to approximately 150%, approximately 106% to approximately 150%, approximately 107% to approximately 150%, approximately 108% to approximately 150%, approximately 109% to approximately 150%, approximately 110% to approximately 150%, approximately 111% to approximately 150%, approximately 112% to approximately 150%, approximately 113% to approximately 150%, approximately 114% to approximately 150%, approximately 115% to approximately 150%, approximately 116% to approximately 150%, approximately 117% to approximately 150%. %, approximately 118% to approximately 150%, approximately 119% to approximately 150%, approximately 120% to approximately 150%, approximately 121% to approximately 150%, approximately 122% to approximately 150%, approximately 123% to approximately 150%, approximately 124% to approximately 150%, approximately 125% to approximately 150%, approximately 126% to approximately 150%, approximately 127% to approximately 150%, approximately 128% to approximately 150%, approximately 129% to approximately 150%, approximately 130% to approximately 150%, approximately 131% to approximately 150%, approximately 132% to approximately 150%, approximately 133% to approximately 150%, approximately 134% to approximately 150%, approximately 135% to approximately 150%, approximately 136% to approximately 150%, approximately 137% to approximately 150%, approximately 138% to approximately 150%, approximately 139% to approximately 150%, approximately 140% to approximately 150%, approximately 141% to approximately 150%, approximately 142% to approximately 150%, approximately 143% to approximately 150%, approximately 144% to approximately 150%, approximately 145% to approximately 150%, approximately 146% to approximately 150%, approximately 147% to approximately 150%, approximately 148% to approximately 150%, approximately 149% to approximately 150%, approximately 5% to approximately 149%, approximately 5% to approximately 148%, approximately 5% to approximately 147%, approximately 5% to approximately 146%.Approximately 5% to approximately 145%, approximately 5% to approximately 144%, approximately 5% to approximately 143%, approximately 5% to approximately 142%, approximately 5% to approximately 141%, approximately 5% to approximately 140%, approximately 5% to approximately 139%, approximately 5% to approximately 138%, approximately 5% to approximately 137%, approximately 5% to approximately 136%, approximately 5% to approximately 135%, approximately 5% to approximately 134%, approximately 5% to approximately 133%, approximately 5% to approximately 132%, approximately 5% to approximately 131%, approximately 5% to approximately 130%, approximately 5% to approximately 129%, approximately 5% to approximately 128%, approximately 5% to approximately 127%, approximately 5% to approximately 126%, approximately 5% to approximately 1 25%, approximately 5% to approximately 124%, approximately 5% to approximately 123%, approximately 5% to approximately 122%, approximately 5% to approximately 121%, approximately 5% to approximately 120%, approximately 5% to approximately 119%, approximately 5% to approximately 118%, approximately 5% to approximately 117%, approximately 5% to approximately 116%, approximately 5% to approximately 115%, approximately 5% to approximately 114%, approximately 5% to approximately 113%, approximately 5% to approximately 112%, approximately 5% to approximately 111%, approximately 5% to approximately 110%, approximately 5% to approximately 109%, approximately 5% to approximately 108%, approximately 5% to approximately 107%, approximately 5% to approximately 106%, approximately 5% to approximately 105%, approximately 5% To approximately 104%, approximately 5% to approximately 103%, approximately 5% to approximately 102%, approximately 5% to approximately 101%, approximately 5% to approximately 100%, approximately 5% to approximately 99%, approximately 5% to approximately 98%, approximately 5% to approximately 97%, approximately 5% to approximately 96%, approximately 5% to approximately 95%, approximately 5% to approximately 94%, approximately 5% to approximately 93%, approximately 5% to approximately 92%, approximately 5% to approximately 91%, approximately 5% to approximately 90%, approximately 5% to approximately 89%, approximately 5% to approximately 88%, approximately 5% to approximately 87%, approximately 5% to approximately 86%, approximately 5% to approximately 85%, approximately 5% to approximately 84%, approximately 5% to approximately 83%, approximately 5% to approximately 84%, approximately 5% to approximately 83%, approximately 5% to approximately 84%, approximately 5% to approximately 83%, approximately 5% to approximately 84%, approximately 5% to approximately 85 ...5%, Approximately 82%, approximately 5% to approximately 81%, approximately 5% to approximately 80%, approximately 5% to approximately 79%, approximately 5% to approximately 78%, approximately 5% to approximately 77%, approximately 5% to approximately 76%, approximately 5% to approximately 75%, approximately 5% to approximately 74%, approximately 5% to approximately 73%, approximately 5% to approximately 72%, approximately 5% to approximately 71%, approximately 5% to approximately 70%, approximately 5% to approximately 69%, approximately 5% to approximately 68%, approximately 5% to approximately 67%, approximately 5% to approximately 66%, approximately 5% to approximately 65%, approximately 5% to approximately 64%, approximately 5% to approximately 63%, approximately 5% to approximately 62%, approximately 5% to approximately 61%, approximately 5% to approximately 60%.Approximately 5% to approximately 59%, approximately 5% to approximately 58%, approximately 5% to approximately 57%, approximately 5% to approximately 56%, approximately 5% to approximately 55%, approximately 5% to approximately 54%, approximately 5% to approximately 53%, approximately 5% to approximately 52%, approximately 5% to approximately 51%, approximately 5% to approximately 50%, approximately 5% to approximately 49%, approximately 5% to approximately 48%, approximately 5% to approximately 47%, approximately 5% to approximately 46%, approximately 5% to approximately 45%, approximately 5% to approximately 44%, approximately 5% to approximately 43%, approximately 5% to approximately 42%, approximately 5% to approximately 41%, approximately 5% to approximately 40%, approximately 5% to approximately 39%, approximately 5% to approximately 38%, approximately 5% to approximately 37%, approximately 5% to approximately 36%, approximately 5% to approximately 35%, approximately 5% to approximately 34%, approximately 5% to approximately 33%. Approximately 5% to approximately 32%, approximately 5% to approximately 31%, approximately 5% to approximately 30%, approximately 5% to approximately 29%, approximately 5% to approximately 28%, approximately 5% to approximately 27%, approximately 5% to approximately 26%, approximately 5% to approximately 25%, approximately 5% to approximately 24%, approximately 5% to approximately 23%, approximately 5% to approximately 22%, approximately 5% to approximately 21%, approximately 5% to approximately 20%, approximately 5% to approximately 19%, approximately 5% to approximately 18%, approximately 5% to approximately 17%, approximately 5% to approximately 16%, approximately 5% to approximately 15%, approximately 5% to approximately 14%, approximately 5% to approximately 13%, approximately 5% to approximately 12%, approximately 5% to approximately 11%, approximately 5% to approximately 10%, approximately 5% to approximately 9%, approximately 5% to approximately 8%, approximately 5% to approximately 7%, or approximately 5% to approximately 6%. In some implementations, BDNF levels are increased by approximately 5% to approximately 75%. In some implementations, BDNF levels are increased by approximately 5% to approximately 150%. In some implementations, the BDNF level is increased by approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 4 2%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%, approximately 118% Approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, approximately 125%, approximately 126%, approximately 127%, approximately 128%, approximately 129%, approximately 130%, approximately 131%, approximately 132%, approximately 133%, approximately 134%, approximately 135%, approximately 136%, approximately 137%, approximately 138%, approximately 139%, approximately 140%, approximately 141%, approximately 142%, approximately 143%, approximately 144%, approximately 145%, approximately 146%, approximately 147%, approximately 148%, approximately 149%, approximately 150%, or a range between any two of these values.

[0186] In any of the methods disclosed herein, the method reduces the risk of adverse cardiovascular events.

[0187] Drugs acting as 5-HT2B receptor agonists can cause adverse cardiovascular events. Components of cocrystal A may bind to 5-HT2B receptors, potentially increasing the risk of adverse cardiovascular events. Adverse cardiovascular events may be caused by administration of cocrystal A. These events include ventricular heart disease, myocardial fibrosis, stroke, myocardial infarction, cardiovascular death, heart failure, and ischemic cardiovascular events.

[0188] In some implementations, reducing the risk of adverse cardiovascular events includes, but is not limited to, reducing the risk of ventricular heart disease, myocardial fibrosis, or a combination thereof.

[0189] In some implementations, reducing the risk of adverse cardiovascular events includes maintaining plasma levels of TGF-β1.

[0190] Transforming growth factor β (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily, which includes three different mammalian isoforms (TGF-β1, TGF-β2, and TGF-β3). TGF-β can affect acetylcholine levels, slow-wave sleep, muscle regeneration, bone mineral density, erythrocyte formation, lymphocytes (T and B cells), cytotoxic T cells (CD8), natural killer cell activity, macrophage activity, inflammatory responses, tissue growth, wound healing, angiogenesis, local inflammation and fibrosis, extracellular matrix deposition, and cognitive function.

[0191] TGF-β isoforms are upregulated and activated in myocardial diseases and play important roles in cardiac repair and remodeling, as well as in regulating the phenotype and function of cardiomyocytes, fibroblasts, immune cells, and vascular cells. Myocardial injury triggers the generation of bioactive TGF-β from latent reserves through mechanisms involving proteases, integrins, and specialized extracellular matrix (ECM) proteins. Changes in plasma TGF-β isoform levels generally indicate the risk of cardiovascular injury and adverse effects.

[0192] In one embodiment, the crystal form is eutectic form A, eutectic form B, or eutectic form C.

[0193] In one embodiment, the crystal form is eutectic form A.

[0194] In one embodiment, eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°; the XRPD plot further contains significant peaks at a 2θ angle of approximately 19.16°; significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°; and / or the XRPD plot further contains significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°. In one embodiment, the XRPD plot further contains significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, approximately 24.07°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, eutectic form A is characterized by a DSC plot containing sharp endothermic events at a temperature of approximately 255°C. In one embodiment, eutectic form A has a ratio of approximately 1:1 of cyclophosphine to cyclophosphine. In one embodiment, eutectic form A has a chemical purity of approximately 95% or higher. In some embodiments, eutectic form A contains no more than approximately 5 mol% of other solid forms. In some embodiments, eutectic form A of cyclophosphine and cyclophosphine comprises approximately 95 mol% eutectic form A, approximately 2.5 mol% cyclophosphine, and approximately 2.5 mol% cyclophosphine. In one embodiment, eutectic form A is a eutectic formed between cyclophosphine and cyclophosphine. In one embodiment, eutectic form A is a salt formed between cyclophosphine and cyclophosphine.

[0195] In one embodiment, the eutectic crystal form A is characterized by being substantially equal to the following unit cell parameters: Cell size: a = 9.3674(3) Å b = 11.2660(6) Å c = 24.2741(9) Å α = 90 degrees β = 90 degrees γ = 90 degrees Space group = P212121 Molecules / asymmetric units = 1.

[0196] In one embodiment, the unit cell parameters are measured at approximately 296 K. In one embodiment, the eutectic form A has a hydrogen bond geometry substantially as listed in Table A. In one embodiment, the eutectic form A has atomic coordinates of non-hydrogen atoms substantially as listed in Table B. In one embodiment, the eutectic form A has atomic coordinates of hydrogen atoms substantially as listed in Table C. In one embodiment, the eutectic form A is a eutectic formed between thionyl and thionylcepin. In one embodiment, the eutectic form A is a salt formed between thionyl and thionylcepin.

[0197] In one embodiment, the crystal form is eutectic form B.

[0198] In one embodiment, eutectic form B is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 18.54°; the XRPD plot further contains a significant peak at a 2θ angle of approximately 8.54°; the XRPD plot further contains significant peaks at 2θ angles of approximately 22.78°, approximately 14.27°, and approximately 21.12°, and / or the XRPD plot further contains significant peaks at 2θ angles of approximately 14.12°, approximately 10.05°, approximately 9.94°, approximately 24.94°, and approximately 25.02°. In one embodiment, eutectic form B is characterized by a DSC plot containing a wide range of endothermic events at a temperature of approximately 168.2°C. In one embodiment, eutectic form B has a cyclophosphine to cyclophosphine ratio of approximately 1.3:1. In one embodiment, eutectic form B has a cyclophosphine to cyclophosphine ratio of approximately 1:1. In one embodiment, eutectic form B has a chemical purity of approximately 95% or higher. In some embodiments, eutectic form B contains no more than about 5 mol% of other solid forms. In some embodiments, the eutectic form B of cyclophosphamide and cyclophosphamide comprises about 92 mol% of eutectic form B, about 2.5 mol% of cyclophosphamide, and about 2.5 mol% of cyclophosphamide. In one embodiment, eutectic form B is a eutectic formed between cyclophosphamide and cyclophosphamide. In one embodiment, eutectic form B is a salt formed between cyclophosphamide and cyclophosphamide.

[0199] In one embodiment, the crystalline form is eutectic form C.

[0200] In one embodiment, eutectic form C is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 9.18°; the XRPD plot further contains a significant peak at a 2θ angle of approximately 17.95°; the XRPD plot further contains significant peaks at 2θ angles of approximately 10.42°, approximately 24.22°, and approximately 18.38°; and / or the XRPD plot further contains significant peaks at 2θ angles of approximately 19.82°, approximately 17.46°, approximately 14.82°, approximately 22.38°, and approximately 14.06°. In one embodiment, eutectic form C is characterized by a DSC plot containing a wide range of endothermic events at temperatures of approximately 25-140°C, with a peak at 98.7°C. In one embodiment, eutectic form C has a ratio of approximately 1:1 thelosine to thelosin. In one embodiment, eutectic form C has a chemical purity of approximately 95% or higher. In some embodiments, eutectic form C contains no more than about 5 mol% of other solid forms. In some embodiments, the eutectic form C of cyclophosphamide and cyclophosphamide comprises about 95 mol% eutectic form C, about 2.5 mol% cyclophosphamide, and about 2.5 mol% cyclophosphamide. In one embodiment, eutectic form C is a eutectic formed between cyclophosphamide and cyclophosphamide. In one embodiment, eutectic form C is a salt formed between cyclophosphamide and cyclophosphamide.

[0201] Crystalline form The following section further elaborates on the crystalline forms of serosol and serosol: .

[0202] The eutectic crystal forms A, B and C of serosol and serosol are disclosed in WO2024 / 003610 A1, the entirety of which is incorporated herein by reference.

[0203] In some implementations, celecoxib and celecoxib are crystallized in eutectic form A.

[0204] In some embodiments, the eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°. In some embodiments, the XRPD plot of eutectic form A may additionally contain a significant peak at a 2θ angle of approximately 19.16°. In some embodiments, the XRPD plot of eutectic form A may additionally contain significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°. In some embodiments, the XRPD plot of eutectic form A may additionally contain significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°. In some implementations, the XRPD plot further includes a significant peak at a 2θ angle of approximately 10.74°, approximately 25.3°, approximately 24.07°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°.

[0205] In one implementation, the weight loss (1.3%) of eutectic form A between 40 and 200 °C was observed by TGMS.

[0206] In one embodiment, the eutectic crystal type A is characterized by a DSC diagram containing sharp endothermic events at a temperature of approximately 255°C.

[0207] In some embodiments, eutectic form A has a ratio of cyclophosphine to cyclophosphine of approximately 1:1, approximately 1.1:1, approximately 1.2:1, approximately 1.3:1, approximately 1.4:1, approximately 1.5:1, approximately 1.6:1, approximately 1.7:1, approximately 1.8:1, approximately 1.9:1, approximately 2:1, approximately 1:1.1, approximately 1:1.2, approximately 1:1.3, approximately 1:1.4, approximately 1:1.5, approximately 1:1.6, approximately 1:1.7, approximately 1:1.8, approximately 1:1.9, or approximately 1:2. In some embodiments, eutectic form A has a ratio of cyclophosphine to cyclophosphine of approximately 1:1.

[0208] In some embodiments, eutectic form A has a chemical purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher. In some embodiments, eutectic form A is substantially pure.

[0209] In some embodiments, the eutectic form A contains no more than about 0.01 mol%, about 0.02 mol%, about 0.03 mol%, about 0.04 mol%, about 0.05 mol%, about 0.06 mol%, about 0.07 mol%, about 0.08 mol%, about 0.09 mol%, about 0.1 mol%, about 0.15 mol%, about 0.2 mol%, about 0.25 mol%, about 0.3 mol%, about 0.35 mol%, about 0.4 mol%, about 0.45 mol%, about 0.5 mol%, about 0.55 mol%, about 0.6 mol%, about 0.65 mol%. Other solid forms, such as amorphous forms, are present in approximately 0.7 mol%, approximately 0.75 mol%, approximately 0.8 mol%, approximately 0.85 mol%, approximately 0.9 mol%, approximately 0.95 mol%, approximately 1 mol%, approximately 2 mol%, approximately 3 mol%, approximately 4 mol%, approximately 5 mol%, approximately 6 mol%, approximately 7 mol%, approximately 8 mol%, approximately 9 mol%, approximately 10 mol%, approximately 11 mol%, approximately 12 mol%, approximately 13 mol%, approximately 14 mol%, approximately 15 mol%, approximately 16 mol%, approximately 17 mol%, approximately 18 mol%, approximately 19 mol%, and approximately 20 mol%. In some embodiments, the eutectic form A is substantially free of other solid forms.

[0210] In some embodiments, the eutectic crystal form A of cyclophosphamide and cyclophosphamide comprises approximately 99 mol% eutectic crystal form A, approximately 0.5 mol% cyclophosphamide, and approximately 0.5 mol% cyclophosphamide; approximately 98 mol% eutectic crystal form A, approximately 1.0 mol% cyclophosphamide, and approximately 1.0 mol% cyclophosphamide; approximately 97 mol% eutectic crystal form A, approximately 1.5 mol% cyclophosphamide, and approximately 1.5 mol% cyclophosphamide; approximately 96 mol% eutectic crystal form A, approximately 2.0 mol% cyclophosphamide, and approximately 2.0 mol% cyclophosphamide; approximately 95 mol% eutectic crystal form A, approximately 2.5 mol% cyclophosphamide, and approximately... 2.5 mol% cyclophosphine; approximately 94 mol% eutectic form A, approximately 3.0 mol% cyclophosphine and approximately 3.0 mol% cyclophosphine; approximately 93 mol% eutectic form A, approximately 3.5 mol% cyclophosphine and approximately 3.5 mol% cyclophosphine; approximately 92 mol% eutectic form A, approximately 4.0 mol% cyclophosphine and approximately 4.0 mol% cyclophosphine; approximately 91 mol% eutectic form A, approximately 4.5 mol% cyclophosphine and approximately 4.5 mol% cyclophosphine; or approximately 90 mol% eutectic form A, approximately 5.0 mol% cyclophosphine and approximately 5.0 mol% cyclophosphine.

[0211] In some implementations, the eutectic form A is anhydrous.

[0212] In some implementations, eutectic crystal form A is a salt formed between serosol and serosol.

[0213] In some implementations, eutectic crystal type A is a eutectic formed between ceroxin and ceroxib.

[0214] In some implementations, the eutectic crystal form A is characterized by being substantially equal to the following unit cell parameters: Cell size: a = 9.3674(3) Å b = 11.2660(6) Å c = 24.2741(9) Å α = 90 degrees β = 90 degrees γ = 90 degrees Space group = P212121 Molecules / asymmetric units = 1.

[0215] In some implementations, cell parameters are measured at approximately 296 K.

[0216] In some implementations, the eutectic form A has a hydrogen bond geometry that is essentially as listed in Table A.

[0217] Table A .

[0218] In some implementations, the eutectic crystal form A has atomic coordinates of non-hydrogen atoms as basically listed in Table B.

[0219] Table B .

[0220] In some implementations, the eutectic crystal form A has atomic coordinates of hydrogen atoms as basically listed in Table C.

[0221] Table C .

[0222] In some implementations, serosol and serosol are crystallized in eutectic form B.

[0223] In some embodiments, eutectic form B is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 18.54°. In some embodiments, eutectic form B is further characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 8.54°. In some embodiments, eutectic form B is further characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 22.78°, approximately 14.27°, and approximately 21.12°. In some embodiments, eutectic form B is further characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 14.12°, approximately 10.05°, approximately 9.94°, approximately 24.94°, and approximately 25.02°.

[0224] In one implementation, the weight loss (15.8%) of eutectic form B between 40 and 200 °C was observed by TGMS.

[0225] In one embodiment, the eutectic crystal form B is characterized by a DSC diagram containing a wide range of endothermic events at a temperature of approximately 168.2°C.

[0226] In some embodiments, eutectic form B has a cyclophosphine to cyclophosphine ratio of approximately 1:1, approximately 1.1:1, approximately 1.2:1, approximately 1.3:1, approximately 1.4:1, approximately 1.5:1, approximately 1.6:1, approximately 1.7:1, approximately 1.8:1, approximately 1.9:1, approximately 2:1, approximately 1:1.1, approximately 1:1.2, approximately 1:1.3, approximately 1:1.4, approximately 1:1.5, approximately 1:1.6, approximately 1:1.7, approximately 1:1.8, approximately 1:1.9, or approximately 1:2. In some embodiments, eutectic form B has a cyclophosphine to cyclophosphine ratio of approximately 1.3:1. In some embodiments, eutectic form B has a cyclophosphine to cyclophosphine ratio of approximately 1:1.

[0227] In some embodiments, eutectic form B has a chemical purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher. In some embodiments, eutectic form B is substantially pure.

[0228] In some embodiments, the eutectic form B contains no more than about 0.01 mol%, about 0.02 mol%, about 0.03 mol%, about 0.04 mol%, about 0.05 mol%, about 0.06 mol%, about 0.07 mol%, about 0.08 mol%, about 0.09 mol%, about 0.1 mol%, about 0.15 mol%, about 0.2 mol%, about 0.25 mol%, about 0.3 mol%, about 0.35 mol%, about 0.4 mol%, about 0.45 mol%, about 0.5 mol%, about 0.55 mol%, about 0.6 mol%, about 0.65 mol%. Other solid forms, such as amorphous forms, are present in approximately 0.7 mol%, approximately 0.75 mol%, approximately 0.8 mol%, approximately 0.85 mol%, approximately 0.9 mol%, approximately 0.95 mol%, approximately 1 mol%, approximately 2 mol%, approximately 3 mol%, approximately 4 mol%, approximately 5 mol%, approximately 6 mol%, approximately 7 mol%, approximately 8 mol%, approximately 9 mol%, approximately 10 mol%, approximately 11 mol%, approximately 12 mol%, approximately 13 mol%, approximately 14 mol%, approximately 15 mol%, approximately 16 mol%, approximately 17 mol%, approximately 18 mol%, approximately 19 mol%, and approximately 20 mol%. In some embodiments, the eutectic form B is substantially free of other solid forms.

[0229] In some implementations, the eutectic form B is anhydrous.

[0230] In some implementations, eutectic B is a salt formed between serosol and serosol.

[0231] In some implementations, eutectic type B is a eutectic formed between ceroxin and ceroxib.

[0232] In some implementations, serosol and serosol are crystallized in eutectic form C.

[0233] In some embodiments, eutectic form C is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 9.18°. In some embodiments, eutectic form C is further characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 17.95°. In some embodiments, eutectic form C is further characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.42°, approximately 24.22°, and approximately 18.38°. In some embodiments, eutectic form C is further characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 19.82°, approximately 17.46°, approximately 14.82°, approximately 22.38°, and approximately 14.06°.

[0234] In one implementation, the weight loss (13.5%) of the eutectic form C between 40 and 160 °C was observed by TGMS.

[0235] In one embodiment, the eutectic crystal form C is characterized by a DSC plot containing a wide range of endothermic events at temperatures of approximately 25-140°C, with a peak at 98.7°C.

[0236] In some embodiments, the eutectic form C has a 1:1, approximately 1.1:1, approximately 1.2:1, approximately 1.3:1, approximately 1.4:1, approximately 1.5:1, approximately 1.6:1, approximately 1.7:1, approximately 1.8:1, approximately 1.9:1, approximately 2:1, approximately 1:1.1, approximately 1:1.2, approximately 1:1.3, approximately 1:1.4, approximately 1:1.5, approximately 1:1.6, approximately 1:1.7, approximately 1:1.8, approximately 1:1.9, or approximately 1:2 ratio of cyclosporine to cyclosporine. In some embodiments, the eutectic form C has an approximately 1:1 ratio of cyclosporine to cyclosporine.

[0237] In some embodiments, the eutectic form C has a chemical purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher. In some embodiments, the eutectic form C is substantially pure.

[0238] In some embodiments, the eutectic form C contains no more than about 0.01 mol%, about 0.02 mol%, about 0.03 mol%, about 0.04 mol%, about 0.05 mol%, about 0.06 mol%, about 0.07 mol%, about 0.08 mol%, about 0.09 mol%, about 0.1 mol%, about 0.15 mol%, about 0.2 mol%, about 0.25 mol%, about 0.3 mol%, about 0.35 mol%, about 0.4 mol%, about 0.45 mol%, about 0.5 mol%, about 0.55 mol%, about 0.6 mol%, about 0.65 mol%. Other solid forms, such as amorphous forms, are present in approximately 0.7 mol%, approximately 0.75 mol%, approximately 0.8 mol%, approximately 0.85 mol%, approximately 0.9 mol%, approximately 0.95 mol%, approximately 1 mol%, approximately 2 mol%, approximately 3 mol%, approximately 4 mol%, approximately 5 mol%, approximately 6 mol%, approximately 7 mol%, approximately 8 mol%, approximately 9 mol%, approximately 10 mol%, approximately 11 mol%, approximately 12 mol%, approximately 13 mol%, approximately 14 mol%, approximately 15 mol%, approximately 16 mol%, approximately 17 mol%, approximately 18 mol%, approximately 19 mol%, and approximately 20 mol%. In some embodiments, the eutectic form C is substantially free of other solid forms.

[0239] In some implementations, the eutectic form C is anhydrous.

[0240] In some implementations, the eutectic form C is a salt formed between serosol and serosol.

[0241] In some implementations, the eutectic crystal form C is a eutectic formed between ceroxin and ceroxib.

[0242] Pharmaceutical Composition In one embodiment, this application provides a pharmaceutical composition comprising crystalline forms of cyclophosphamide and cyclophosphamide and pharmaceutically acceptable excipients.

[0243] In one embodiment, the crystalline form is eutectic form A, eutectic form B, or form C. In one embodiment, eutectic form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°; the XRPD plot further contains a significant peak at a 2θ angle of approximately 19.16°; significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°; and / or the XRPD plot further contains significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°. In one embodiment, the XRPD plot further contains significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, approximately 24.07°, approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, or approximately 8.62°. In one embodiment, eutectic crystal form A is characterized by a DSC plot including a sharp endothermic event at a temperature of approximately 255°C. In one embodiment, eutectic crystal form A has a ratio of approximately 1:1 of xelociline to xelocinone. In one embodiment, eutectic crystal form A has a chemical purity of approximately 95% or higher. In some embodiments, the pharmaceutical composition of eutectic crystal form A contains no more than approximately 5 mol% of other solid forms. In some embodiments, the pharmaceutical composition of xelocinone and xelociline eutectic crystal form A comprises approximately 95 mol% of eutectic crystal form A, approximately 2.5 mol% of xelocinone, and approximately 2.5 mol% of xelociline. In one embodiment, eutectic crystal form A is a eutectic formed between xelocinone and xelociline. In one embodiment, eutectic crystal form A is a salt formed between xelocinone and xelociline.

[0244] In one embodiment, the eutectic crystal form A is characterized by being substantially equal to the following unit cell parameters: Cell size: a = 9.3674(3) Å b = 11.2660(6) Å c = 24.2741(9) Å α = 90 degrees β = 90 degrees γ = 90 degrees Space group = P212121 Molecules / asymmetric units = 1.

[0245] In one embodiment, the unit cell parameters are measured at approximately 296 K. In one embodiment, the eutectic form A has a hydrogen bond geometry substantially as listed in Table A. In one embodiment, the eutectic form A has atomic coordinates of non-hydrogen atoms substantially as listed in Table B. In one embodiment, the eutectic form A has atomic coordinates of hydrogen atoms substantially as listed in Table C. In one embodiment, the eutectic form A is a eutectic formed between thionyl and thionylcepin. In one embodiment, the eutectic form A is a salt formed between thionyl and thionylcepin.

[0246] In one embodiment, eutectic form B is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 18.54°; the XRPD plot further contains a significant peak at a 2θ angle of approximately 8.54°; the XRPD plot further contains significant peaks at 2θ angles of approximately 22.78°, approximately 14.27°, and approximately 21.12°, and / or the XRPD plot further contains significant peaks at 2θ angles of approximately 14.12°, approximately 10.05°, approximately 9.94°, approximately 24.94°, and approximately 25.02°. In one embodiment, eutectic form B is characterized by a DSC plot containing a wide range of endothermic events at a temperature of approximately 168.2°C. In one embodiment, eutectic form B has a cyclophosphine to cyclophosphine ratio of approximately 1.3:1. In one embodiment, eutectic form B has a cyclophosphine to cyclophosphine ratio of approximately 1:1. In one embodiment, eutectic form B has a chemical purity of approximately 95% or higher. In some embodiments, the pharmaceutical composition of co-crystal form B contains no more than about 5 mol% of other solid forms. In some embodiments, the pharmaceutical composition of co-crystal form B of xyloxetine and xyloxetine comprises about 95 mol% of co-crystal form B, about 2.5 mol% of xyloxetine, and about 2.5 mol% of xyloxetine. In one embodiment, co-crystal form B is a co-crystal formed between xyloxetine and xyloxetine. In one embodiment, co-crystal form B is a salt formed between xyloxetine and xyloxetine.

[0247] In one embodiment, eutectic form C is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 9.18°; the XRPD plot further contains a significant peak at a 2θ angle of approximately 17.95°; the XRPD plot further contains significant peaks at 2θ angles of approximately 10.42°, approximately 24.22°, and approximately 18.38°; and / or the XRPD plot further contains significant peaks at 2θ angles of approximately 19.82°, approximately 17.46°, approximately 14.82°, approximately 22.38°, and approximately 14.06°. In one embodiment, eutectic form C is characterized by a DSC plot containing a wide range of endothermic events at temperatures of approximately 25-140°C, with a peak at 98.7°C. In one embodiment, eutectic form C has a ratio of approximately 1:1 thelosine to thelosin. In one embodiment, eutectic form C has a chemical purity of approximately 95% or higher. In some embodiments, the pharmaceutical composition of cocrystalline form C contains no more than about 5 mol% of other solid forms. In some embodiments, the pharmaceutical composition of cocrystalline form C of xyloxetine and xyloxetine comprises about 95 mol% of cocrystalline form C, about 2.5 mol% of xyloxetine, and about 2.5 mol% of xyloxetine. In one embodiment, cocrystalline form C is a cocrystal formed between xyloxetine and xyloxetine. In one embodiment, cocrystalline form C is a salt formed between xyloxetine and xyloxetine.

[0248] As used herein, a “pharmaceutical composition” means a formulation comprising an active ingredient and optionally a pharmaceutically acceptable carrier, diluent, or excipient. The term “active ingredient” may be used interchangeably with “effective ingredient” and means any pharmaceutical agent capable of inducing the desired effect upon administration. Examples of active ingredients include, but are not limited to, chemical compounds, pharmaceuticals, therapeutic agents, small molecules, etc. In one embodiment, the active ingredient is celecylidene and celecylidene in a novel crystalline form, such as eutectic form A, eutectic form B, or eutectic form C as described herein.

[0249] As used herein, the terms “excipient” and “pharmaceuticalally acceptable excipient” are intended to be generally synonymous and are used interchangeably with the terms “carrier,” “pharmaceutically acceptable carrier,” “diluent,” and “pharmaceutically acceptable diluent.” “Pharmaceutically acceptable” means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipients and to the activity of the active ingredient in the formulation. Pharmaceutically acceptable carriers, excipients, or stabilizers are well known in the art, for example, Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the doses and concentrations used and may include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride, benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than about 10 residues) peptides. Proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). Examples of carriers include, but are not limited to, liposomes, nanoparticles, ointments, micelles, microspheres, microparticles, creams, emulsions, and gels. Examples of excipients include, but are not limited to, anti-adhesion agents such as magnesium stearate; binders such as sugars and their derivatives (sucrose, lactose, starch, cellulose, sugar alcohols, etc.); proteins such as gelatin and synthetic polymers; lubricants such as talc and silica; and preservatives such as antioxidants, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium sulfate, and parabens. Examples of diluents include, but are not limited to, water, alcohols, saline solutions, glycols, mineral oils, and dimethyl sulfoxide (DMSO).

[0250] In one embodiment, pharmaceutically acceptable excipients are phosphate buffer; citrate buffer; ascorbic acid; methionine; octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenolic alcohol; butanol; benzyl alcohol; methylparaben; propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol; low molecular weight (less than about 10 residues) peptides; serum albumin; gelatin; immunoglobulins; polyvinylpyrrolidone glycine; glutamine; asparagine; histidine; arginine; lysine; monosaccharides. Disaccharides; glucose; mannose; dextrin; eDTA; trehalose, lactose, dextran, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose, including cocrystal solvents, cocrystal-based ionic liquids, ionic liquids, sorbitol; sodium; brine; metal surfactants; nonionic surfactants; polyethylene glycol (PEG); magnesium stearate; water; alcohols; brine solutions; glycols; mineral oils, dimethyl sulfoxide (DMSO) or combinations thereof.

[0251] Active compounds can be effective over a wide dose range and are generally administered at therapeutically effective doses. However, it will be understood that the actual amount of compound administered will usually be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0252] The following embodiments are provided to further illustrate implementations of the invention, but are not intended to limit the scope of the invention. Although they are typical examples that may be used, other procedures, methods or techniques known to those skilled in the art may be used alternatively. Example

[0253] Example 1 Dissolution rate of eutectic Intrinsic dissolution rate (IDR) was determined in physiological media SGF (pH 1.2) and SIF (pH 6.8). IDR describes the dissolution rate normalized to surface area. The IDR was determined by using a 0.070 cm⁻¹ saturation plate. 2 The standardized surface area of ​​the passivated aluminum dye suppresses the eutectic form A, and the resulting dissolution rate is related to the solid form, without the influence of particle size and / or shape (morphology) exhibited by the solid.

[0254] The IDR method developed for eutectic form A uses a 2 mm path length to monitor the concentration of eutectic form A in the UV range of 294–312 nm.

[0255] IDR was determined in triplicate in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) at 37°C. IDR results are reported in Table 1, and the average of the three runs was calculated. Comparison of dissolution profiles in the two media is shown in Table 1. Figure 1 middle.

[0256] The intrinsic dissolution rate was determined by the slope of the linear portion of the curve. The IDR for eutectic form A in SGF was 1.12(11) x 10⁴ μg / (min * cm⁻¹). 2 ), and in SIF it is 2.57(24) x 103 μg / (min * cm 2 The IDR of eutectic form A was rapid in both media, reaching 0.5 mg / mL (10 mg tablet) within 15 minutes in SGF and within 1 hour in SIF, meaning the IDR of eutectic form A was approximately four times faster in SGF than in SIF.

[0257] The intrinsic dissolution of rotating discs was determined using a Pion AuPRO.7.0 machine equipped with six independent glass fiber probes (each connected to a diode region). Each probe was individually calibrated. Discs were prepared in passivated aluminum dye using a small IDR press.

[0258] Stock solutions of eutectic form A were prepared at a concentration of 20.0 mg / mL in SGF buffer (pH 1.2) and SIF buffer (pH 6.8). Calibration lines were prepared by measuring six standards in SGF and SIF. Standard 0 was an API-free buffer solution, and for each subsequent standard, an additional 50 μL of API solution was added to 15 mL of SGF or SIF (resulting in calibration lines with concentrations between 0 and 328 μg / mL). Calibration curves were used to calculate the amount of API dissolved during the measurements. Furthermore, calibration curves were used to select an appropriate path length (2 mm).

[0259] A suitable amount (~10 mg) of material was compressed in passivated aluminum dye (normalized surface area of ​​0.070 cm²) at a pressure of 80 kg for 45 seconds. The dye was placed in a Teflon S21103D_V2 holder with a magnet and then placed in a 20 mL glass vial. The experiment was initiated by gently adding the dissolution medium. The vial was incubated at 37 °C with continuous stirring at 100 rpm for up to 4 hours. The UV signal (in second derivative mode) in the 294–312 nm region was measured at regular time intervals. The dissolution rate was calculated on the linear portion of the curve.

[0260] These data indicate that eutectic form A exhibits rapid dissolution with pH variation.

[0261] Example 2 Serum levels of cocrystal animal- Adult male and female C57BL / 6 mice aged 8-10 weeks were randomly assigned to receive oral feeding ( po The mediator (phosphate-buffered saline) or 3 mg / kg cilostabin or cocrystal form A was administered to C57BL / 6 mice via oral feeding, and blood samples were collected from the saphenous vein (10 min, 1 h, 4 h) or during euthanasia (30 min, 3 h, 8 h). Blood levels were then used to quantify cilostabin levels via high performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) as detailed below. Data were analyzed in GraphPad (v. 10) via area under the curve (AUC) to estimate C. 最大 n = 3-12 male and female mice. Data were excluded if cyclophosphamide levels were below the lower limit of quantitation (5 ng / mL) or above the upper limit of the standard curve (4000 ng / mL).

[0262] High Performance Liquid Chromatography-Tandem Mass Spectrometry – Cylnidazole (1 mg / mL in acetonitrile) and Cylnidazole-D 10 The standard solution (100 μg / mL in acetonitrile) was maintained at −80℃. Internal standard (IS): Xylo-D 10 The deuterium atom is located on the amine side chain. Additional xyloxime was purchased, and acetonitrile was evaporated using a rotary evaporator to purify the compound for subsequent animal testing. To obtain drug-free plasma, cardiac puncture was performed after isoflurane anesthesia to collect atrial blood from C57BL / 6 mice. The blood was transferred to BD Vacutainer™ plastic blood collection tubes containing lithium heparin and incubated at 4°C with a concentration of 2,000 × 10⁻⁶. g Centrifuge for 10 minutes. Store the supernatant (plasma) at −80°C and use it to prepare calibration standards and quality control samples.

[0263] Preparation of calibration standards and quality control (QC): A stock solution of cyprotinin was prepared in water / acetonitrile (1:1 v / v) at a concentration of 40,000 ng / mL, and cyprotinin-D was prepared in acetonitrile at a concentration of 5,000 ng / mL. 10Stock solutions. Store all stock solutions at -20°C. Prepare working solutions for calibration standards by serially diluting the stock cyproheptadine to seven standard points ranging from 5 ng / mL to 4,000 ng / mL using water / acetonitrile (1:1 v / v). To prepare calibration standards, combine 5 µL of each working solution with 45 μL of drug-free mouse plasma and gently mix to produce seven standards at concentrations of 0.5, 1, 20, 100, 300, 380, and 400 ng / mL. Add 450 μL of protein precipitation solution (containing 50 ng / mL cyproheptadine-D) to each standard. 10 Acetonitrile). Each standard was then vortexed vigorously for 30 seconds and subsequently centrifuged at 14,000 rpm for 10 minutes at 4°C using a VWR micro 18R centrifuge. The supernatant was transferred to an HPLC vial insert (150 μL). Double blank samples were prepared by incorporating 5 μL of water / acetonitrile (1:1 v / v) into the plasma sample and extracting with 450 μL of acetonitrile. Blank (zero calibrator) samples (i.e., blank samples containing IS) were prepared by incorporating 5 μL of water / acetonitrile (1:1 v / v) into the plasma sample and extracting with 450 μL of the protein precipitation solution containing IS as described above. QC samples were prepared using serial dilutions of different working solutions (3600 ng / mL) following the same procedure described above. According to the bioanalytical method validation guidelines of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), low quality control (LQC) samples should be within three times the lower limit of quantitation (LLOQ); intermediate quality control (MQC) samples should be within the intermediate range; and high quality control (HQC) samples should be at least 75% of the upper limit of quantitation (ULOQ). Based on these guidelines, the QC concentrations for LQC, MQC, and HQC are set at 1.5 ng / mL, 200 ng / mL, and 360 ng / mL, respectively.

[0264] HILIC LC-MS / MS instrument: Various LC columns were tested and evaluated, including hydrophilic interaction liquid chromatography (HILIC), phenyl, phenyl-hexyl, and C18. Chromatographic separations were achieved on an Agilent 1290 Infinity ultra-high performance liquid chromatography (UHPLC) system. An autosampler maintained at 4°C was used to inject 1.7 μL of separation solution into an Agilent InfinityLab Poroshell 120 HILIC-Z equipped with an InfinityLab Poroshell 120 HILIC guard column (1.9 µm, 120 Å, 2.1 × 5 mm). ®On a UHPLC column (2.1 × 50 mm, 1.9 µm, 100 Å). Column temperature was maintained at 30 °C. A gradient binary mobile phase system consisting of (A) 10 mM ammonium formate buffer (pH 3.0) and (B) 0.1% formic acid / acetonitrile was set to flow at 1 mL / min. The gradient program started at 90% B and remained constant for 0.1 min, then decreased to 50% B over the next 0.8 min, and was subsequently increased to reach the initial condition (90% B) at 1.1 min. The initial composition was held constant for another 0.7 min to equilibrate. The total run time was 1.8 min. The flow of the mobile phase was directed to the mass spectrometer via an integrated diversion valve between 0.2 and 0.6 min to reduce ion source contamination. A methanol syringe wash was performed between injections. (Analyst...) ® The software, version 1.7, is used for data processing.

[0265] After separation, the column effluent was directed to the TurboSpray ionization source of the quadrupole-linear ion trap (Q-LIT) instrument, specifically the AB Sciex 6500 API QTrap. ® (AB Sciex, ON, Canada). Quantification was achieved using positive ionization in multiple reaction monitoring (MRM) mode. Table 10 shows the quantitative and qualitative ions and their respective declustering potential (DP), collision energy (CE), and cell exit potential (CXP). The source temperature was set at 550 °C, the ion spray voltage (ISV) at 5500 V, the curtain gas (CUR) at 40, the nebulizer gas (GS1) at 80, the heater gas pressure (GS2) at 40, and the inlet potential (EP) at 10 for all transitions. DP, CE, and CXP were optimized for each MRM transition to ensure ion abundance and signal stability (Table 2). The residence time for all transitions was 50 ms at unit resolution, and nitrogen was used in all cases. Initial optimization experiments to study the fragmentation modes of cyclophosphamide and IS were conducted using direct infusion. A Harvard syringe pump set to 7 μl / min was used to inject cyclophosphamide (100 ng / mL) and bis(50 ng / mL) into acetonitrile containing 0.1% formic acid.

[0266] Table 2. Used for Cyloxane and Cyloxane-D 10 MRM transformation and optimized MS conditions in (IS) .

[0267] Initially, the same conditions described above were used, but without analytical column testing and flow injection analysis (FIA-MS / MS). For this purpose, 5 μL of each sample was injected directly into the capillary leading to the ESI ion source of the mass spectrometer using an autosampler. An in-line filter ensured that no large contaminant particles remaining from the protein precipitation process entered the ion source.

[0268] High-resolution MS analysis: To identify interferences observed in LC-MS / MS analysis of cyclophosphamide in mouse plasma using a C18 column, experiments were performed using high-resolution mass spectrometry. Double blank samples (drug-free extracted plasma), cyclophosphamide solution in methanol / water (3:1) (1000 ng / mL), and extracted plasma samples doped with cyclophosphamide (100 ng / mL) were analyzed under the following conditions. LC-MS / MS analysis was performed using an Ultimate 3,000 UHPLC system. The LC system was coupled to a Thermo Fisher Q-Exactive source equipped with a heated electrospray ionization (HESI) source operating in positive ion mode at 3000 V. ® Quadrupole-orbit trap instrument. Capillary temperature and vaporizer temperature were set to 320°C and 350°C, respectively. Sheath gas and auxiliary gas were set to 60 and 20, respectively. The "Full Scan / DDMS2" scanning function was used to acquire data-dependent fragmentation data (DDMS2) of the new Cello sample. Full scan analysis ( m / z 50-400) using 70,000 (in m / z 200 FWHM) quality resolution, and detected in full scan m / z Any ion with a concentration of 205.15 ± 0.15 will automatically trigger MS / MS analysis. m / z 50-250), which uses 17,500 (in m / z It has a resolution of 200 FWHM and a collision energy of 30.

[0269] Prior to analysis, the instrument was calibrated at six points in positive ion mode using Pierce™ LTQ Velos ESI positive ion calibration solution containing caffeine (20 µg / mL), MRFA (1 µg / mL), and Ultramark 1621 (0.001%) in an aqueous solution of acetonitrile (50%), methanol (25%), and acetic acid (1%). A search for the chemical formula corresponding to the precise mass measurement was performed using the ChemCalc online service.

[0270] Method verification:Method validation follows the FDA and EMA Guidelines for Bioanalytical Method Validation, including accuracy, precision, selectivity, linearity, matrix effects, recovery, reproducibility, and stability.

[0271] Calibration curves, linearity, and QCs: A standard curve was constructed using seven data points ranging from 0.5 ng / mL to 400 ng / mL by determining the best fit between the peak area ratio (i.e., the peak area ratio of the analyte to the internal standard) and the analyte concentration. A χ² curve was then applied. 2 Linear regression analysis of the weighted standard curve. The suitability of the fitted regression model for the dataset was evaluated by assessing the deviation of the standards from their nominal concentrations and by evaluating the slope, intercept, and correlation coefficient (r) of the curve. Precision and accuracy were determined using six replicates (n=6) of LLOQ (0.5 ng / mL), LQC (1.5 ng / mL), MQC (200 ng / mL), and HQC (360 ng / mL) on the same day (intra-day) and over three consecutive days (inter-day). Accuracy was accepted if the mean calculated concentration was within ±15% of the nominal concentration of the QC sample and within ±20% of the nominal value of the LLOQ sample. Accuracy of LLOQ was accepted if the coefficient of variation (CV%) of LLOQ was less than 20% and less than 15% for each QC level. Standards with a signal-to-noise ratio of 3:1 are considered to be the limit of detection (LOD), while the lower limit of quantitation (LLOQ) of this method is determined with acceptable precision and accuracy (within ±20% of the nominal LLOQ concentration) based on a signal-to-noise ratio of at least 5 to 10 x 5:1 to 10:1 noise.

[0272] Matrix effect: Matrix effects were assessed at two QC levels (LQC and HQC) by comparing the instrument response of the analyte added to extracted mouse plasma samples (spiked samples) with that in pure solvent (acetonitrile / water 9:1). The matrix effect of the analytical method was determined using six C57BL / 6 mouse plasma samples obtained from six individual mice. The matrix effect was calculated using the following equation.

[0273] To investigate whether phospholipids (PL) might contribute to the observed matrix effect, MRM conversions of the three most abundant interfering phosphatidylcholine (PC) groups were monitored in a double-blank sample. The monitored PL conversions for LysoPC (C16:0) were... m / z 496.4→ m / z 184.2, for PC (C16:0 / C18:1) is m / z 760.7→ m / z184.2, and for PC (C18:1 / C18:1) is m / z 786.8→ m / z 184.2.

[0274] Selectivity: The selectivity test ensures that, as demonstrated by analysis of six different mouse plasma samples, there is no interference from co-eluting components of the sample matrix at the LLOQ level. The method is considered selective if the interference observed in double-blank samples is less than 20% of the analyte LLOQ and less than 5% of the IS.

[0275] Recovery rate: To measure extraction recovery, the instrument response of the analyte added to the extracted mouse plasma sample (spiked sample) was compared with the response of the analyte added to the unextracted plasma sample (unspiked sample) in six replicates of LQC, MQC, and HQC.

[0276] Residue: Double blanks were injected after the ULOQ to determine the residual effect associated with the analyte and IS. Residue was considered significant if the area in the double blank was greater than or equal to 20% for the analyte and greater than or equal to 5% for the IS for the LLOQ sample. [19,20] The residual effect was calculated using the following equations.

[0277] Dilution integrity: To ensure that diluted samples will have the same accuracy and precision as undiluted samples, a dilution integrity test is performed. Spiked plasma samples at a concentration of 4,000 ng / mL are extracted and then diluted with a blank to 80 ng / mL (×50 dilution). Results are considered acceptable if the calculated accuracy is between 85% and 115% of the nominal concentration and the precision is less than 15%.

[0278] stability:The stability of the samples was assessed under various conditions encountered during sample preparation and analysis, as well as under different storage conditions. This assessment involved HQC and LQC samples analyzed using freshly prepared calibration curves. To examine stability, four sets of QC samples (HQC, LQC; n = 6 for each level) were prepared and exposed to the following conditions prior to extraction and analysis: (A) room temperature for 3 hours (benchtop stability), (B) 4°C for 24 hours (autosampler stability), (C) storage at -80°C for 2 months (storage stability), and (D) undergoing 3 freeze-thaw cycles (freeze-thaw stability). In the case of the final stability study, the QC samples were frozen at -80°C for at least 24 hours, then thawed at room temperature, and then frozen again at -80°C for at least 24 hours before proceeding to the next freeze-thaw cycle.

[0279] To assess the stability of the processed samples after extraction (extraction stability), two sets of LQC and HQC samples (n=12 at each QC level) were prepared, extracted, and transferred to HPLC vials with inserts. Prior to analysis, the first set of LQC and HQC samples (n=6 at each QC level) was placed at room temperature for 3 hours. The second set of QC samples was stored at -80°C for 6 days, then thawed and analyzed.

[0280] To assess the stability of the analyte working stock solutions, LQC and HQC samples (n=6) were prepared using stock solutions stored at -20°C for 2 months. These samples were then analyzed against calibration curves and QC established using fresh stock solutions. Samples were considered stable if they fell within ±15% of their respective nominal concentrations.

[0281] System Applicability: To ensure consistent responses from the samples (i.e., system suitability), a solution of 20 ng / mL xylometabolite in acetonitrile / water (9:1) was injected five times at the start of each run, and the calculated coefficient of variation (CV) was determined as an indicator of response variation.

[0282] Applied to mouse samples: The validated method was applied to analyze the samples used in this study. Plasma concentrations of cyclophosphamide were measured using a sample of mice at the time indicated in the legend. Blood was transferred into BD Vacutainer™ plastic blood collection tubes containing lithium heparin: Hemogard and incubated at 4°C with a concentration of 2,000 × 10⁻⁶. g Centrifuge for 10 minutes. Store the supernatant (plasma) at −80°C before extraction and analysis. Thaw mouse plasma samples from pharmacokinetic studies at room temperature and gently vortex. Extract and analyze using 450 μL of protein precipitation solution (containing 50 ng / mL cyproheptadine-D). 10Acetonitrile was added to 50 μL of plasma sample to prepare the sample. Each sample was vortexed for 30 seconds and then centrifuged at 14,000 rpm for 10 minutes at 4 °C. The supernatant was transferred to an HPLC vial insert (150 μL).

[0283] The results show Figure 2 and 3 middle.

[0284] These data indicate that cocrystal A has higher serum levels compared to selociline.

[0285] Example 3 Head twitching reaction animal- Adult male and female C57BL / 6 mice aged 8–10 weeks were randomly assigned to receive intraperitoneal injection of the medium (1:1:18 ethanol:emulsifier:saline) or 0.01–10 mg / kg of the compound.

[0286] Head twitching response – Mice were placed in transparent tubes immediately after compound administration and monitored for 10 minutes to quantify head twitching response (HTR), which was recorded as atypical horizontal head shaking. The resulting dose-response curves (DRCs) were fitted using nonlinear regression (bell-shaped dose-response with Hill slope constraint of 1) and used to estimate potency and efficacy (GraphPad, Prism, v. 10).

[0287] The results show Figure 4 and 5 middle.

[0288] These data indicate that eutectic form A has improved efficacy and valence compared to serosibine.

[0289] Example 4 Ca 2+ release assay Cell culture – AequoScreen cells stably expressing human 5HT2A or 5HT2B (h5HT2A, h5HT2B) will be cultured. TM Chinese hamster ovary (CHO)-K1 cells were maintained at 37°C and 5% CO2 in F-12 DMEM containing 1 mM L-glutamine, 10% FBS and 1% penicillin / streptomycin (1% Pen / Strep).

[0290] Ca 2+ Assay - AequoScreen was used in CHO-K1 cells stably expressing h5HT2A or h5HT2B. TM Assay to determine the activation of Ga in a GPCR-dependent mannerq / 11 After Ca 2+ Released into the cytosol. In addition to the selected receptor, AequoScreen TM The cell line also stably expresses cells with three Ca2+ cells. 2+ The luminescent protein apoaequorin binds to the Ca2+ binding site. 2+ Subsequently, the jellyfish luminescent protein is activated into a jellyfish luminescent protein, which converts coelenteramide, CO2, and light. Therefore, light generation is related to the release of Ca2+ from the intracellular reservoir after GPCR activation. 2+ Release was proportional. Cells were seeded into 96-well plates (20,000 cells / well) with a flat bottom, white bottom, white walls, and poly-D-lysine coating, and incubated overnight at 37°C and 5% CO2 in Opti-MEM containing 1% FBS. Subsequently, the Opti-MEM medium was removed and replaced with fresh Opti-MEM containing 5 µM coelenterate h (Promega, Madison, WI) and 1% FBS (final volume 50 µL), and the cells were incubated at 25°C for 4 hours. After these 4 hours, the cells were treated with 50 µL of 2× concentrated ligand solution to achieve the indicated concentration and released at 1,000 at room temperature. x Centrifuge for 1 minute. Then immediately measure chemiluminescence on a Cytation 5 plate reader (top reading, gain 200, integration time 10,000 ms). All experiments included a mediator control (5% DMSO) and LSD was included as a reference agonist in all experiments.

[0291] Celosia showed high efficiency against 5-HT2A. Figure 6 (Table 3). Xylosecillin exhibits a lower valence for 5-HT2A than xylosecillin. The activity of the eutectic form A is very similar to that of xylosecillin, with no difference in valence and potency. These findings suggest that the eutectic of xylosecillin and xylosecillin possesses unexpected properties that differ from those of xylosecillin or xylosecillin alone.

[0292] Example 5 Neuroplasticity: β-inhibitor 2 recruitment assay Cell Culture - CHO-K1 Cells with NanoBit TM SMBIT and LGBIT peptides were transfected with the smBiT h5HT2A plasmid and the lgBiT β-repressor protein 2 plasmid. When h5HT2A and β-repressor protein 2 come into contact with each other, the SMBIT and LGBIT peptides complement each other to produce the complete NanoBit. TMLuciferase. When complete, this enzyme catalyzes the breakdown of the molecular coelenterate to produce light. The emitted light level is proportional to the interaction between the receptor and β-repressor protein 2. Cells were maintained at 37°C and 5% CO2 in F-12 DMEM containing 1 mM L-glutamine, 10% FBS, and 1% penicillin / streptomycin (1% Pen / Strep). For transfection, CHO-K1 cells were seeded in 6-well plates (500,000 cells / well) and incubated overnight in standard medium as described above. After overnight incubation, cells were transfected with 1 μg of h5HT2A and βarr2 NanoBiT plasmids. Transfection was performed using Lipofectamine 3000 (Fisher Scientific, Ottawa, ON) in Opti-MEM medium containing 1% FBS according to the manufacturer's protocol. After 24 hours, cells were seeded at a density of 20,000 cells / well in poly-D-lysine-coated 96-well plates and incubated overnight at 37°C and 5% CO2 in F-12DMEM containing 1 mM L-glutamine, 10% FBS and 1% penicillin / streptomycin (1% Pen / Strep) before use.

[0293] β-inhibitory protein 2 assay – After seeding 20,000 cells / well in flat-bottomed, white-backed, white-walled, poly-D-lysine-coated 96-well plates, transfected CHO-K1 cells were washed twice with Hank-buffered saline (HBSS), and 100 μL of HBSS was added to each well. 25 μL of Nano-Glo live cell substrate (diluted 1 / 20 in Nano-Glo LCS dilution buffer according to the manufacturer's protocol) was added, and the plate was transferred to a Cytation 5 plate reader. After a 1-hour equilibration period, 10 μL of 13.5× concentrated ligand solution was added, and the luminescence signal was continuously monitored for 2 hours (top reading, gain 200, integration time 10,000 ms). Each experiment was performed in triplicate, with the number of independent experiments for each compound listed in the table present in the Results section of this report. Luminescence data from the first 30 minutes were used to automatically generate the area under the time-luminescence curve (AUC) for each compound concentration. AUC data were then used for subsequent analyses. All experiments included a mediator control (5% DMSO), and lysergic acid diethylamide (LSD) was included as a reference agonist in all experiments.

[0294] Selophenide showed moderate potency to 5-HT2A. Figure 7 (Table 4). Xelosiben did not show significant activity against 5-HT2A. The eutectic form A had a higher potency and the same efficacy compared to xelosiben.

[0295] Example 6 BDNF expression, neuronal growth and neuronal proliferation Human cortical brain organoid culture conditions Human induced pluripotent stem cells (hiPSCs) were cultured in Matrigel-coated 6-well tissue culture plates. First, cells were incubated for 7 minutes in DMEM / F-12 medium containing dispersing enzymes, followed by two washes with DMEM / F-12. Cells were scraped off, centrifuged, and the clumps were resuspended in mTESR1 medium. The resuspended hiPSCs were replated and allowed to grow in mTESR1 for 48 hours. Embryoids (EBs) were generated by dissociating hiPSCs and incubating with Accutase for 1 minute, then transferred to conical tubes for centrifugation in DMEM / F-12 medium. The cell suspension was diluted to a concentration of 60,000 viable cells / ml, and Y-27632 and 5% (v / v) heat-inactivated FBS were added. 150 μL of the cell suspension was added to each well of a U-bottom ultra-low adhesion 96-well plate and incubated at 37°C. On day 2, neural induction medium was added to each well. On days 4, 6, and 8, add fresh neural induction medium. On day 10, transfer ~8 EBs to each well of an ultra-low adhesion 6-well plate. Add neural differentiation medium to each well and place them on a track-mounted shaker at 80 rpm in a 37°C incubator. On days 12, 14, and 16, aspirate the medium and add fresh neural differentiation medium. On day 18, add neural differentiation medium to each well. Then change the neural differentiation medium every 4 days until the assay begins.

[0296] Details of mouse rearing and drug injection. Fourteen-week-old female CD1 mice with an average weight of 23 g were treated intraperitoneally with the following drugs once daily for 14 consecutive days: 1) a carrier (230 μL) and 2) cocrystal form A (0.3 mg / kg). A PBS solution of 0.67% DMSO was used as the carrier. For immunohistochemical sampling, EdU (5-ethynyl-2'-deoxyuridine, Lumiprobe, 100 μg / g) was injected together with the drugs during the first 7 days. On the second day after the 14-day treatment period, the mice's brains were dissected for subsequent analyses, including immunohistochemistry and electrophysiology (E-phys).

[0297] Quantitative polymerase chain reaction (qPCR)To measure BDNF expression, RNA was extracted from organoids using Trizol. Initially, one organoid was placed in a 1.5 mL tube, 250 μL of Trizol was added, and the tissue was homogenized using a plastic stirrer. 62.5 μL of chloroform was added, the tube was inverted and incubated at room temperature for 2 minutes, then centrifuged at 12,000 xg for 15 minutes at 4°C. After centrifugation, the aqueous intermediate layer was carefully transferred to a fresh 1.5 mL tube, and 1:1 2-propanol was added. The tube was centrifuged again at 12,000 xg for 20 minutes, the supernatant was discarded, and the tube was allowed to dry. 1000 μL of 70% ethanol was added, and the tube was repeatedly inverted to mix, then centrifuged at 12,000 xg for 5 minutes at 4°C, and the supernatant was discarded. After air-drying for 15 minutes, the clump was resuspended in 20 μL of sterile water, and the concentration was determined using a Nanodrop instrument. Reverse transcription was performed using 1 μg RNA and 2 μL gDNA wipeout buffer 7X, with RNA-free water added to bring the total volume to 14 μL. The tubes were incubated at 42°C for 2 minutes and then placed on ice. Each tube was then given 1 μL reverse transcriptase (RT), 4 μL RT buffer, and 1 μL RT primer mixture to bring the total volume to 20 μL mastermix per replicate. The tubes were then incubated at 42°C for 15 minutes and then at 95°C for 3 minutes. The Qiagen SYBR Green kit was used for qPCR; each well of a 384-well plate received 5 μL SYBR Green, 2.8 μL RNase-free water, 0.6 μL each of the forward and reverse primers (Y-WHAZ & GAPDH, target BDNF), and 1 μL cDNA. Results were shown in [data missing]. Figure 8 middle.

[0298] Human cortical brain organoid culture conditions Adult male and female C57BL / 6 mice aged 8–10 weeks were treated with the compounds via oral feeding (po) at 0.3 mg / kg or 3 mg / kg and euthanized 10 minutes after oral administration to collect the whole brain.

[0299] BDNF enzyme-linked immunosorbent assay. BDNF enzyme-linked immunosorbent assay (ELISA) was used to quantify the total BDNF level in whole brain homogenates from mice, using the standard operating procedure detailed by the product manufacturer. Results showed... Figure 9 middle.

[0300] These results demonstrate a significant increase in BDNF levels in the brain within 10 minutes of oral administration, in stark contrast to an equivalent dose of selocillin.

[0301] Brain organoid neurite growth assaySix-month-old cortical organoids (CO) and median ganglion eminence organoids (MGEO) were fused to form assemblies and treated for 10 days with the following drug conditions: 1) a medium, and 2) a eutectic form A (500 nM). A solution of 0.1% DMSO in growth medium was used as the medium. The medium was replaced daily with fresh medium containing the drug. After 10 days of drug treatment, 20 mm × 20 mm square coverslips on each well of a 6-well plate were coated with 1% Geltrex in DMEM / F12 + Glutamax at room temperature for 2 hours. The coated plates were then washed with 2 ml of growth medium, and 3 ml of warm, fresh growth medium was added to each well. After plate preparation, the drug-treated organoids were sliced ​​9 times with a scalpel and transferred to the Geltrex-coated coverslips in the 6-well plates. The plates were gently vortexed to evenly distribute the organoid fragments. The organoid fragments were incubated undisturbed for 3 days to allow attachment and neurite growth. After 3 days of incubation, the attached organoid fragments were washed twice with 3 mL PBS and fixed for 1 hour at room temperature with 3 mL of 4% paraformaldehyde in PBS. The fixed neurite growth samples were washed three times with 3 mL PBS and then permeated with 3 mL of 0.1% Triton X-100 (PBT) in PBS for 10 minutes. The permeated samples were then subjected to immunostaining.

[0302] For immunostaining, samples were blocked with 5% normal donkey serum for 1 hour. After blocking, anti-Tuj1 mouse antibody (1:500) in 1 mL of blocking solution was applied overnight at room temperature. After incubation with the primary antibody, samples were washed three times with PBST (0.1% Triton X-100 in PBS). Then, donkey anti-mouse 488 secondary antibody (1:500) was applied for 2 hours at room temperature. After incubation with the secondary antibody, samples were washed three times with PBST and stained with Hoechst 33342 (1:1000 in PBST) for nuclear visualization. After a final wash with PBST, the coverslips were retrieved and mounted on a slide using Aqua-Poly / Mount. Images of neurites were obtained using a ZeissImager.M2 microscope and analyzed using Fiji (ImageJ 1.54f) software. Results are shown in [images not provided]. Figure 10 and 11 middle.

[0303] Immunohistochemistry (IHC) & image analysis.Organoid sections were washed for 10 minutes with 1xPBS on a shaking plate (set to 100), followed by washing with 0.1% PBT. Unanalyzed EdU slides were incubated with 1 ml of 5% donkey serum (diluted in 0.1% PBT) at room temperature for 1 hour. EdU slides (proliferation assay) were each washed twice with 500 μl of 3% BSA (diluted in PBS) for 2 minutes, followed by 1 mL of 0.5% Triton 100x (diluted in PBS) and incubated for 20 minutes. The Click-iT Plus kit was used for EdU staining, following the manufacturer's instructions. Slides were then washed with 500 μl of 3% BSA (diluted in PBS) and blocked with 5% donkey serum (NDS) for 1 hour. After blocking, primary antibody Ki67 (1:250 in 5% NDS) was added to EdU slides, and for non-EdU slides, Pax6 (1:250 in 5% NDS) and synaptic protein (1:250 in 5% NDS) were added, 200 μL each. The slides were covered with paraffin film and incubated overnight at 4°C in a deli cooler. On day 2, the slides were rinsed with 0.1% PBT (4x) for 10 minutes. Rabbit 488 (Rb488) (1:200) was added to label EdU-positive cells, and mouse 594 (M594) (1:200) was added to label Ki67 on the proliferation assay slides and to label Pax6 and synaptic protein on their respective slides. The slides were covered with paraffin film and incubated at room temperature for 2 hours. Slides were rinsed with 0.1% PBT (3X) and then incubated with DAPI (1:1000 in PBS) at room temperature for 10 minutes. Slides were rinsed with PBS (2X) and coverslips were added. This IHC protocol was used for both mouse and organoid models. Images were acquired using a bright-field microscope, with organoid proliferation, Pax6, and synaptic protein assays performed at 20x, and mouse Pax6 and synaptic protein assays at 63x. Images were acquired on a Zeiss imaging system. Images were processed using an M2 microscope and ImageJ (Fiji) software, and cell counting was performed based on predetermined fixed parameters set for each model system. The counts were plotted using Prism. Results are shown in […]. Figure 12 , 13 14A, 14B and 14C.

[0304] These data show that, unexpectedly, the application of selocilin and seloxin cocrystals enhances multiple measures of neural plasticity. Specifically, it increases levels of BDNF expression, neuronal growth, neuronal proliferation, and synapse number.

[0305] Example 7 Reduction of neuroinflammation and quantification of TGF-β levels animal-Adult male and female C57BL / 6 mice aged 8–10 weeks were acutely treated by oral feeding (po) with a mediator (saline), 3 mg / kg cocrystal form A, 3 mg / kg selociline, 1 mg / kg TrKB inhibitor ANA-12, or a combination of 3 mg / kg cocrystal form A and 1 mg / kg ANA-12. Plasma and brain tissue were collected 1 hour after administration. Alternatively, C57BL / 6 mice were treated by oral feeding once daily for 21 days with a mediator (saline), 0.03 mg / kg cocrystal form A, and 0.3 mg / kg cocrystal form A, and plasma and brain tissue were collected 1 hour after the last (i.e., day 21) administration of the compound.

[0306] Multiple discovery assays for cytokines - Frozen the tissue immediately and stored at -80°C before transport. The following analyses were performed on plasma and brain tissue: (1) Multiplex analysis of cytokines using plasma or tissue homogenate. Mouse cytokine 32-Plex Discovery Assay ® ; or (2) using multi-species tumor growth factor (TGF) β 3-plex Discovery Assay® from plasma or tissue homogenate.

[0307] Mouse cytokine 32-Plex Discovery Assay ® This study used Luminex xMAP technology to perform multiplex quantification of 32 mouse cytokines, chemokines, and growth factors. Multiplex analysis was performed using the Luminex™ 200 system. Eve Technologies' Mouse Cytokine 32-Plex Discovery Assay was used. ® The 32-plex simultaneously measures 32 biomarkers in the sample according to the manufacturer's protocol. The 32-plex consists of eosinophil chemokine, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, MCP-1, M-CSF, MIG, MIP-1α, MIP-1β, MIP-2, RANTES, TNFα, and VEGF. The sensitivity for these biomarkers in the 32-plex ranges from 0.3 to 30.6 pg / mL. Sensitivity values ​​for each analyte can be obtained using MilliporeSigma MILLIPLEX. ®Data were obtained using the MAP protocol. Data are expressed as a percentage or tissue concentration (pg / mL) relative to the average medium control.

[0308] TGF-β 3-Plex Discovery Assay ® This study used Luminex xMAP technology for multiplex quantification of three cytokines in mice: TGF-β1, β2, and β3. Multiplex analysis was performed using the Luminex™ 200 system. The three biomarkers were simultaneously measured in samples using Eve Technologies' TFG-β 3-Plex Discovery Assay® according to the manufacturer's protocol. The 3-plex consists of TGF-β1, TGF-β2, and TGF-β3. For the 3-plex, the assay sensitivity for these biomarkers is 2.2–6.6 pg / mL. Sensitivity values ​​for each analyte are available at MilliporeSigma MILLIPLEX. ® Obtained using the MAP protocol. Data are expressed as a percentage or tissue concentration (pg / mL) relative to the average medium control.

[0309] Results regarding cytokine biomarkers for neuroinflammation showed... Figure 15-19 In the diagram, the numbers on the x-axis represent the following: 1 = eosinophil chemokine, 2 = G-CSF, 3 = GM-CSF, 4 = IFNγ, 5 = IL-1α, 6 = IL-1β, 7 = IL-2, 8 = IL-3, 9 = IL-4, 10 = IL-5, 11 = IL-6, 12 = IL-7, 13 = IL-9, 14 = IL-10, 15 = IL-12p40, 16 = IL-12p70, 17 = IL-13, 18 = IL-15, 19 = IL-17, 20 = IP-10, 21 = KC, 22 = LIF, 23 = LIX, 24 = M-CSF, 25 = MCP-1, 26 = MIG, 27 = MIP-1α, 28 = MIP-1β, 29 = MIP-2, 30 = RANTES, 31 = TNFα, and 32 = VEGF.

[0310] These data unexpectedly show that co-crystal A reduces the expression of brain cytokine biomarkers associated with neuroinflammation. These indicate that the co-crystals of selocillin and seloxin reduce multiple cytokine levels associated with neuroinflammation.

[0311] Results of TGF-β1 levels showed Figure 20 and 21 middle.

[0312] These data show that, unexpectedly, cocrystal form A does not lead to an increase in plasma TGF-β levels, thus reducing the risk of adverse cardiac events. This differs from other drugs that bind to the 5-HT2B receptor and are therefore considered to have a strong risk of adverse cardiac events. Activation of the 5-HT2B receptor is associated with an increase in plasma TGF-β levels. This unexpected finding of no increase in TGF-β levels strongly suggests that the cocrystal of cilostabin and cilostabin can significantly reduce the risk of future cardiac side effects.

[0313] Although the present invention has been described with reference to the above embodiments, it will be understood that modifications and variations are covered within the spirit and scope of the invention. Therefore, the invention is limited only by the following claims.

Claims

1. A method for treating a disease or disorder in a subject with this need, comprising administering to the subject crystalline forms of xelocinone and xelociline: 。 2. A method for inducing neural plasticity in subjects with this need, comprising administering to the subject crystalline forms of xelocinone and xelociline: 。 3. A method for stimulating neuronal growth in a subject with this need, comprising administering to the subject crystalline forms of serotonin and serocepin: 。 4. A method for increasing the number of neural progenitor cells in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide: 。 5. A method for increasing BDNF levels in subjects with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide: 。 6. A method for reducing neuroinflammation in subjects with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide: 。 7. The method according to any one of claims 1-6, wherein the crystalline form is eutectic form A.

8. The method of claim 7, wherein crystal form A is characterized by an XRPD plot containing a significant peak at a 2θ angle of approximately 10.1°.

9. The method of claim 8, wherein the XRPD plot further includes a significant peak at a 2θ angle of approximately 19.16°.

10. The method of claim 9, wherein the XRPD plot further includes significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°.

11. The method of claim 10, wherein the XRPD plot further includes significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

12. The method of claim 7, wherein crystal form A is characterized by a DSC plot containing a sharp endothermic event at a temperature of approximately 255°C.

13. The method of claim 7, wherein crystal form A has a ratio of approximately 1:1 of cyclosporine to cyclosporine.

14. The method of claim 7, wherein crystal form A has a chemical purity of about 95% or higher.

15. The method of claim 7, wherein crystal form A contains no more than about 5 mol% of other solid forms.

16. The method of claim 1, wherein the disease or disorder is a neuropsychiatric disease or disorder, a neurological disease or disorder, an inflammatory disease or disorder, or cancer.

17. The method of claim 16, wherein the neuropsychiatric illness or disorder is addiction, developmental status, eating disorder, mood / emotional disorder, neurotic disorder, psychosis, and sleep disorder, or a combination thereof.

18. The method of claim 16, wherein the neuropsychiatric disease or disorder is attention deficit hyperactivity disorder (ADHD), autism, fetal alcohol syndrome, tic disorder, bipolar disorder, depression, mania, obsessive-compulsive disorder, trichotillomania, anxiety disorder, post-traumatic stress disorder (PTSD), schizophrenia, sleep apnea, narcolepsy, insomnia, deep sleep state, or a combination thereof.

19. The method of claim 16, wherein the neurological disease or disorder is a degenerative disease, a cognitive disorder, a motor disorder, a chronic pain or headache disorder, epilepsy or epileptic seizures, or a combination thereof.

20. The method of claim 16, wherein the neurological disease or disorder is dementia, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, chronic back pain, chronic neuropathic pain, migraine, Huntington's disease, amyotrophic lateral sclerosis, or a combination thereof.

21. The method of claim 19, wherein the neurological disease or disorder is epilepsy or epileptic seizures.

22. The method of claim 21, wherein the epilepsy or epileptic seizure is a tonic seizure, a simple partial seizure, a temporal lobe seizure, a febrile seizure, a grand mal seizure, an absence seizure, an atonic seizure, a focal loss of consciousness seizure, a frontal lobe seizure, a tonic-clonic seizure, a generalized seizure, a focal epileptic seizure, a gelastic seizure, or a combination thereof.

23. The method of claim 16, wherein the inflammatory disease or disorder is a neuroinflammatory disease or disorder.

24. The method of claim 23, wherein the neuroinflammatory disease or disorder is multiple sclerosis, encephalitis, systemic lupus erythematosus, myelitis, neuritis, meningitis, vasculitis, myasthenia gravis, or a combination thereof.

25. The method of claim 16, wherein the cancer is a nervous system cancer.

26. The method of claim 25, wherein the nervous system cancer is a meningioma, pituitary adenoma, craniopharyngioma, schwannoma, glioma, astrocytoma, oligodendroglioma, glioblastoma, ependymal tumor, pineal tumor, pineal cell tumor, and pinealoblastoma; in some embodiments, the nervous system cancer originates from prostate cancer, pancreatic cancer, bile duct cancer, colon cancer, rectal cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, pancreatic cancer, brain cancer and head and neck cancer, melanoma, sarcoma, multiple myeloma, leukemia, or lymphoma, and then includes brain cancer, or combinations thereof.

27. The method of claim 1, further comprising increasing one or more of the following: the subject's neural plasticity, calcium flux, 5-HT2A receptor activity, 5-HT1A, 5-HT7, TrkB activity, BDNF activity, or combinations thereof.

28. The method of claim 1, wherein the method comprises reducing the expression of a neuroinflammatory cytokine biomarker selected from eosinophil chemokine, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, M-CSF, MCP-1, MIG, MIP-1α, MIP-1β, MIP-2, RANTES, TNFα, VEGF, or combinations thereof.

29. The method of claim 28, wherein the expression of the neuroinflammatory biomarker is reduced by about 1% to about 80%.

30. The method of claim 28, wherein the neuroinflammatory biomarker decreases following acute exposure to the crystalline forms of cyclophosphamide and cyclophosphamide.

31. The method of claim 28, wherein the neuroinflammatory biomarker decreases following chronic exposure to the crystalline forms of serotonin and serocepin.

32. The method of claim 3, wherein stimulating neuronal growth results in an increase in neurite length of approximately 100 μM to approximately 300 μM.

33. The method of claim 3, wherein stimulating neuronal growth results in an increase in neurite length of about 20% to about 100%.

34. The method of claim 4, wherein the number of neural progenitor cells is increased by about 0.1% to about 10%.

35. The method of claim 5, wherein increasing BDNF levels includes increasing the subject's anti-inflammatory response.

36. The method of claim 5, wherein the BDNF level is increased by about 5% to about 150%.

37. The method of claim 35, wherein the anti-inflammatory response comprises a decrease in the expression of neuroinflammatory biomarkers selected from eosinophil chemokines, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, M-CSF, MCP-1, MIG, MIP-1α, MIP-1β, MIP-2, RANTES, TNFα, VEGF, or combinations thereof.

38. The method of claim 37, wherein the expression of the neuroinflammatory cytokine biomarker is reduced by about 1% to about 80%.

39. The method of claim 37, wherein the neuroinflammatory cytokine biomarkers are reduced following acute exposure to the crystalline forms of cyclophosphamide and cyclophosphamide.

40. The method of claim 37, wherein the neuroinflammatory cytokine biomarkers are reduced following chronic exposure to the crystalline forms of cyclophosphamide and cyclophosphamide.

41. The method of claim 6, wherein reducing neuroinflammation includes increasing BDNF levels.

42. The method of claim 41, wherein the BDNF level is increased by about 5% to about 150%.

43. The method of claim 6, wherein reducing neuroinflammation includes decreasing the expression of neuroinflammatory cytokine biomarkers.

44. The method according to claim 43, wherein the neuroinflammatory cytokine biomarker is eosinophil chemokine, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, M-CSF, MCP-1, MIG, MIP-1α, MIP-1β, MIP-2, RANTES, TNFα, VEGF, or a combination thereof.

45. The method of claim 43, wherein the expression of the neuroinflammatory cytokine biomarker is reduced by about 1% to about 80%.

46. ​​The method of claim 43, wherein the neuroinflammatory cytokine biomarkers are reduced following acute exposure to the crystalline forms of cyclophosphamide and cyclophosphamide.

47. The method of claim 43, wherein the neuroinflammatory cytokine biomarkers are reduced following chronic exposure to the crystalline forms of cyclophosphamide and cyclophosphamide.

48. The method according to any one of claims 1-6, wherein the method reduces the risk of adverse cardiovascular events.

49. The method of claim 48, wherein the reduction in the risk of adverse cardiovascular events includes reducing the risk of ventricular heart disease, myocardial fibrosis, or a combination thereof.

50. The method of claim 48, wherein reducing the risk of adverse cardiovascular events includes maintaining plasma levels of TGF-β1.

51. The method according to any one of claims 1-6, wherein the application of the crystalline forms of serotonin and serotonin is an acute application.

52. The method according to any one of claims 1-6, wherein the application of the crystalline forms of serotonin and serocepin is a chronic application.

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