Co-administration of co-crystals of psilocybin and psilocin with atypical antipsychotics

Abstract

This disclosure provides a method for treating or alleviating mental health disorders or central nervous system disorders in subjects with such need, comprising administering to the subject a composition comprising crystalline forms of cyclophosphamide and cyclophosphamide, and an atypical antipsychotic drug, wherein the crystalline form is a eutectic crystal form A of cyclophosphamide and cyclophosphamide.

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 cocrystal of psilocybin and psilocin, and its use in treating mental health disorders or central nervous system disorders in subjects with atypical antipsychotic drug needs. The psilocybin and psilocin cocrystal can be further used to induce neural plasticity 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 cause individuals to experience hallucinations or similar experiences (“hallucinogenic” compounds).

[0004] Hallucinogenic experiences have long been considered to have potential therapeutic benefits, and recent research suggests that hallucinogens may be beneficial for a wide range of clinical conditions that are unresponsive to other treatments. These examples include treatment-resistant major depressive disorder (TRD), post-traumatic stress disorder (PTSD), and addiction and abuse disorders. Such treatments typically involve a single dose of the hallucinogen, followed by the production of a typical hallucinogenic experience. For example, several recent studies on serocerabin have shown that a single dose of 25 mg is sufficient to induce a powerful hallucinogenic experience, and when combined with psychotherapeutic support for TRD, it produces beneficial clinical outcomes.

[0005] Recently, long-term use of very low doses of hallucinogens (so-called “microdose”), such as seroconvertin and lysergic acid diethylamide (LSD), has also been thought to help individuals with a variety of neuropsychiatric and central nervous system (CNS) disorders. These administrations are not accompanied by hallucinogenic experiences but have been widely reported to have various effects on overall psychological wellbeing and mental health. However, despite numerous anecdotal reports claiming broad benefits and poorly controlled studies, research on the potential clinical benefits of long-term microdose administration is far less extensive.

[0006] Examples of hallucinogens found in plants include those present in *Gynostemma pentaphyllum* (Green Nine-Headed Tree). Psychotria viridisN,N-dimethyltryptamine (DMT) from the peyote cactus and mescaline from the peyote cactus. Similarly, over 180 different fungi contain the hallucinogen selocilbin and its active metabolite selocinone. Several synthetic hallucinogens also exist, such as 3,4-methylenedioxymethylamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), and lysergic acid diacetamide (LSD). The hallucinogenic effects of selocilbin (through its active metabolite selocinone) and LSD are generally considered to be “classic” hallucinogenic experiences and include a wide range of perceptual experiences. This can include objects appearing more vivid, changes in auditory perception, changes in time perception, intense religious experiences, a sense of “oneness,” and mood changes such as euphoria or joy. Negative emotions, such as severe anxiety, fear, or paranoia, can also sometimes be experienced. One of the most common types of naturally occurring hallucinogens is xelocillin, which has been found in over 180 species of mushrooms worldwide. Mushrooms containing xelocillin also contain other neuroactive and hallucinogenic compounds, the most abundant of which is its main metabolite, xelocin. In humans, xelocillin is primarily metabolized to xelocin in the gastrointestinal system, where it is then absorbed and causes hallucinogenic effects.

[0007] Regarding the potential mechanisms of action for clinical benefits, many hallucinogenic compounds share structural similarities with serotonin (5-hydroxytryptamine, 5HT), and all of the aforementioned hallucinogens (including serotonin and xelocinone) are believed to exert their primary hallucinogenic effects through the influence of 5HT2A receptors on the surface of CNS neurons. Recent evidence also suggests the existence of intracellular 5HT2A receptors that may also play a role, although this is currently uncertain. Again, the primary mechanism explaining the clinical benefits of hallucinogens is alleged to be through their action on 5HT2A receptors.

[0008] However, these established effects of hallucinogens such as cyclophosphamide and cyclophosphamide on the 5HT2A receptor do not appear to fully explain the research and clinical findings related to their use. Therefore, other drugs affecting the 5HT2A receptor do not possess the same range of clinical characteristics or benefits as hallucinogens.

[0009] Supporting this is the recent research finding that at least the clinical effects of cyclophosphamide and LSD are partly due to increased neuroplasticity, which can occur through one or more mechanisms, not just by acting on 5HT2A receptors.

[0010] More specifically, a neuroplasticity mechanism involving allosteric regulation of tyrosine receptor kinase B (TrkB) and increased binding of brain-derived neurotrophic factor (BDNF) to this receptor has been identified. This also increases the overall effectiveness of BDNF in brain plasticity, including neurogenesis.

[0011] While hallucinogens are the presumptive treatment for mental health disorders, other medications have been proven effective for over 70 years. One class of these is antipsychotics, primarily used to treat schizophrenia and other psychoses, and increasingly as adjunctive therapy for bipolar disorder and major depressive disorder (MDD). Their clinical benefits are thought to be primarily achieved through blocking dopamine (D2) receptors (i.e., D2 receptor antagonism). However, the problem is that this same mechanism of action can cause serious side effects, including inducing symptoms similar to Parkinson's disease and other movement disorders.

[0012] For these reasons and to address these side effects, newer antipsychotic drug compounds were developed, the first of which was clozapine in 1972. Because they do not have the same side effects, they are called "atypical antipsychotics." Their clinical benefits (accompanied by a reduction in motor dysfunction) are now believed to be attributed to their effects on central 5HT2A receptors, which are thought to counteract some of the side effects induced by D2 receptor antagonism.

[0013] The atypical antipsychotic aripiprazole was approved by the U.S. Food and Drug Administration (FDA) in 2002 for the treatment of schizophrenia at a dose of 10-30 mg / day, and was subsequently approved for the treatment of bipolar disorder at a similar dose range.

[0014] Aripiprazole was subsequently approved by the FDA in 2007 as adjunctive therapy for MDD, but with a low approved dose range of 2–15 mg / day. This approval followed two Phase III clinical trials involving 743 patients with depression who had not responded well to antidepressants. In an 8-week prospective trial, placebo or aripiprazole was added to the antidepressant regimen for 6 weeks. Given the potential ability of fluoxetine or paroxetine to increase aripiprazole levels by inhibiting the hepatic cytochrome isoenzyme CYP450-2D6, the maximum dose limit for aripiprazole in combination with fluoxetine or paroxetine is 15 mg / day.

[0015] The mechanism of action of aripiprazole remains uncertain, as its action on D2 and 5HT2A receptors is insufficient to fully explain all clinical findings of the drug.

[0016] Therefore, although the hallucinogens cyclophosphamide and cyclophosphamide share a common action with the atypical antipsychotic aripiprazole (i.e., they are both thought to act on the 5HT2A receptor), this is unlikely to fully explain their clinical benefits.

[0017] Furthermore, early research suggests that these two classes of compounds may affect different aspects of neural plasticity, although this is not yet widely accepted as an explanation for clinical benefit. Some studies indicate that atypical antipsychotics may have some effect on certain aspects of neural plasticity, but this does not appear to be achieved through TrkB binding, BDNF levels or activity, or by specifically measuring changes in neurogenesis. Summary of the Invention

[0018] This disclosure provides a method for treating mental health disorders or central nervous system disorders, inducing neural plasticity, stimulating neuronal growth, increasing the number of neuronal progenitor cells, increasing BDNF levels, or reducing neuroinflammation in subjects with such needs, comprising administering to the subject crystalline forms of serotonin and serocepin: And atypical antipsychotics.

[0019] 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°.

[0020] This disclosure provides a method for treating mental health disorders or central nervous system disorders, inducing neural plasticity, stimulating neuronal growth, increasing the number of neuronal progenitor cells, increasing BDNF levels, or reducing neuroinflammation in subjects with such needs, comprising administering to the subject crystalline forms of serotonin and serocepin: And atypical antipsychotics.

[0021] The crystal form mentioned above is eutectic form A; The characteristic of eutectic crystal form A is the 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°.

[0022] This disclosure provides a method for treating mental health disorders or central nervous system disorders, inducing neural plasticity, stimulating neuronal growth, increasing the number of neuronal progenitor cells, increasing BDNF levels, or reducing neuroinflammation in subjects with such needs, comprising administering to the subject crystalline forms of serotonin and serocepin: And atypical antipsychotics.

[0023] The crystal form mentioned above is eutectic form A; The characteristic of eutectic crystal form A is the XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0024] In one embodiment, the atypical antipsychotic is aripiprazole, clozapine, ziprasidone, cariprazine, ipraridone, quetiapine, lurasidone, paliperidone, amisulpride, olanzapine, risperidone, asenapine, clozaril, epipiperazole, rumepiride, pimovarsine, or a combination thereof.

[0025] In one implementation, the atypical antipsychotic drug is aripiprazole.

[0026] In one implementation, the mental health disorder is a mood disorder, depressive disorder, mood instability disorder, mixed anxiety and depression disorder, bipolar disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder, phobia disorder, panic disorder, schizophrenia, psychosis, schizoaffective disorder, eating disorder, anorexia nervosa, bulimia nervosa, substance abuse disorder, addiction disorder, alcohol abuse or dependence, opioid abuse or dependence, cocaine abuse or dependence, mixed substance abuse or dependence, behavioral addiction, gambling disorder, trauma-related disorder, post-traumatic stress disorder, grief-related disorder, loss-related disorder, end-of-life disorder, cancer disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), personality disorder, obsessive-compulsive disorder, or a combination thereof. Attached Figure Description

[0027] Figure 1 The results showed that after treatment with xylometazoline, co-crystal form A, and co-crystal form A with aripiprazole, Ca2+ at the 5-HT2A receptor was reduced. 2+ Release (in percentage of LSD).

[0028] Figure 2 The results showed that after treatment with xylometazoline, co-crystal form A, and co-crystal form A with aripiprazole, Ca2+ at the 5-HT2B receptor was reduced. 2+ Release (in percentage of LSD).

[0029] Figure 3 The recruitment of β-inhibitory protein 2 at the 5-HT2A receptor (in percentage of LSD) was shown after treatment with xyloxetine, cocrystal form A, and cocrystal form A with aripiprazole.

[0030] Figure 4 This study showed changes in mouse behavior during the Y-maze test in animals that were orally administered cocrystal A, aripiprazole, and cocrystal A+aripiprazole daily for 15 days.

[0031] Figure 5 The changes in BDNF levels in the mouse brain were shown 1 hour after acute treatment.

[0032] Figure 6 The study showed changes in neuromic / stem cell levels in the mouse brain after oral administration of cocrystal form A alone (3 mg / kg) and in combination with aripiprazole (0.3 mg / kg) for 14 days.

[0033] Figure 7 The study showed changes in neuronal activation in mice after oral administration of cocrystal form A alone (3 mg / kg) and in combination with aripiprazole (0.3 mg / kg) for 21 days.

[0034] Figure 8 The levels of various neuroinflammatory cytokine biomarkers were shown 60 minutes after oral administration of cocrystallized A+ aripiprazole.

[0035] Figure 9 The TGF-β1 levels are shown compared to control levels after administration of cocrystal form A (0.3 mg / kg), aripiprazole (0.03 mg / kg), and cocrystal form A (0.3 mg / kg) + aripiprazole (0.03 mg / kg) on ​​days 1 and 21. Detailed Implementation

[0036] This invention is based on the groundbreaking discovery that the eutectic of selocilin and seloxin can be used to treat mental health disorders or central nervous system disorders in subjects who require it.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] As used in this article, when one implementation scheme is defined as different from another implementation scheme, the two implementation schemes are "mutually exclusive".

[0043] 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.).

[0044] 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°.

[0045] 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%.

[0046] Treatment In one embodiment, the present invention provides a method for treating mental health disorders or central nervous system disorders, inducing neural plasticity, increasing BDNF levels, or reducing neuroinflammation in subjects with such needs, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide, as well as atypical antipsychotics.

[0047] This disclosure provides a method for treating mental health disorders or central nervous system disorders, inducing neural plasticity, increasing BDNF levels, or reducing neuroinflammation in subjects with such needs, comprising administering to the subject crystalline forms of serotonin and serocepin: And atypical antipsychotics.

[0048] 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 showing 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°.

[0049] In one embodiment, the present invention provides a method for treating mental health disorders or central nervous system disorders in a subject with such need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide, as well as an atypical antipsychotic drug; wherein the crystalline form is a eutectic crystal form A. In one embodiment, eutectic crystal 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°. In another embodiment, eutectic crystal form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0050] In one 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, as well as an atypical antipsychotic drug, wherein the crystalline form is a eutectic crystal form A. In one embodiment, eutectic crystal 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°. In another embodiment, eutectic crystal form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0051] In one embodiment, the present invention provides a method for increasing BDNF levels in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide, as well as an atypical antipsychotic drug, wherein the crystalline form is a eutectic crystal form A. In one embodiment, eutectic crystal 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°. In another embodiment, eutectic crystal form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0052] In one 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, as well as an atypical antipsychotic drug, wherein the crystalline form is a eutectic crystal form A. In one embodiment, eutectic crystal 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°. In another embodiment, eutectic crystal form A is characterized by an XRPD plot containing significant peaks at 2θ angles of approximately 10.1° and approximately 19.16°.

[0053] 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.

[0054] 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).

[0055] 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 a mental health disorder or central nervous system disorder). An effective dose can be determined as described herein.

[0056] 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, 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.

[0057] As used herein, the terms “acute administration” and “acute exposure” refer to a single dose.

[0058] 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.

[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 embodiments, the atypical antipsychotic is aripiprazole, clozapine, ziprasidone, cariprazine, ipanirone, quetiapine, lurasidone, paliperidone, amisulpride, olanzapine, risperidone, asenapine, clozapine, epipiperazole, rumeperone, pimovarsine, or a combination thereof.

[0061] In some implementations, the atypical antipsychotic drug is aripiprazole.

[0062] Mental health disorders or mental illnesses refer to a wide range of disorders, including but not limited to mood disorders, depressive disorders, mood instability disorders, mixed anxiety and depression disorders, bipolar disorder, anxiety disorders, generalized anxiety disorder, social anxiety disorder, phobia disorders, panic disorder, schizophrenia, psychosis, schizoaffective disorder, eating disorders, anorexia nervosa, bulimia nervosa, substance abuse disorders, addiction disorders, alcohol abuse or dependence, opioid abuse or dependence, cocaine abuse or dependence, mixed substance abuse or dependence, behavioral addictions, gambling disorders, trauma-related disorders, post-traumatic stress disorder, grief-related disorders, loss-related disorders, end-of-life disorders, cancer-related disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), personality disorders, obsessive-compulsive disorder, and any combination thereof. A complete list of currently recognized mental health disorders is given in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5), which is incorporated herein by reference in its entirety. Central nervous system (CNS) disorders include, but are not limited to, psychological and physical trauma following burns, injuries, or any other physical cause; post-amputation; post-brain injury; post-stroke; post-heart attack; post-diabetes; chronic pain disorders; migraines; chronic headaches; chronic back pain; chronic arthritis pain; chronic pain of any cause; cognitive impairment; cognitive decline; Alzheimer's disease; dementia at any stage; dementia of any cause; age-related memory impairment; neuropsychiatric disorders; fetal alcohol spectrum disorders; autism spectrum disorders; multiple sclerosis; Parkinson's disease; Fragile X syndrome; Down syndrome; fatigue; chronic fatigue; insomnia of any cause; and all post-COVID-19 syndromes. The severity of symptoms varies, causing some individuals to experience debilitating illnesses that impair normal social functioning, while others suffer intermittent, recurrent episodes throughout their lives. Although the presentation and diagnostic criteria for mental illnesses and CNS disorders differ in some respects, there are noteworthy common endophenotypes among these disorders, and comorbidity is common.

[0063] In some implementations, the mental health disorder is a mood disorder, depressive disorder, mood instability disorder, mixed anxiety and depression disorder, bipolar disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder, phobia disorder, panic disorder, schizophrenia, psychosis, schizoaffective disorder, eating disorder, anorexia nervosa, bulimia nervosa, substance abuse disorder, addiction disorder, alcohol abuse or dependence, opioid abuse or dependence, cocaine abuse or dependence, mixed substance abuse or dependence, behavioral addiction, gambling disorder, trauma-related disorder, post-traumatic stress disorder, grief-related disorder, loss-related disorder, end-of-life disorder, cancer disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), personality disorder, obsessive-compulsive disorder, or a combination thereof.

[0064] In some implementations, the mental health disorder is a mood disorder, a mixed anxiety and depression disorder, an anxiety disorder, a generalized anxiety disorder, a social anxiety disorder, a substance abuse disorder, an addiction disorder, an alcohol abuse or dependence, an opioid abuse or dependence, a cocaine abuse or dependence, a mixed substance abuse or dependence, a behavioral addiction, a gambling disorder, a post-traumatic stress disorder, or a combination thereof.

[0065] In some implementations, the mental health disorder is an emotional disorder.

[0066] In some implementations, the mental health disorder is a mixed anxiety and depression disorder.

[0067] In some implementations, the mental health disorder is an anxiety disorder.

[0068] In some implementations, the mental health disorder is generalized anxiety disorder.

[0069] In some implementations, the mental health disorder is social anxiety disorder.

[0070] In some implementations, the mental health disorder is a substance abuse disorder.

[0071] In some implementations, the mental health disorder is an addiction disorder.

[0072] In some implementations, the mental health disorder is alcohol abuse or dependence.

[0073] In some implementations, the mental health disorder is opioid abuse or dependence.

[0074] In some implementations, the mental health disorder is cocaine abuse or dependence.

[0075] In some implementations, the mental health disorder is a mixture of substance abuse or dependence.

[0076] In some implementations, the mental health disorder is behavioral addiction.

[0077] In some implementations, the mental health disorder is gambling disorder.

[0078] In some implementations, the mental health disorder is post-traumatic stress disorder.

[0079] Depressive disorders are characterized by low mood, feeling sad or hopeless, increased irritability, sleep disturbances, decreased energy and feeling tired, poor concentration, low self-esteem or feeling worthless, lack of interest or pleasure in things, slowed movements, thinking that death would be better and self-harm, as well as active thinking and attempts at suicide, and include major depressive disorder, bipolar disorder, treatment-resistant depression and dysthymia.

[0080] Anxiety disorders are characterized by feeling tense, anxious, having difficulty breathing, avoiding people or activities, excessive worry, physical symptoms including chest pain, palpitations, sweating, nausea, stomach pain, abdominal pain, headache, neck pain, poor sleep, difficulty concentrating, sweating and dizziness, and include generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, phobia and separation anxiety disorder.

[0081] Substance abuse and addiction disorders are identified when an individual’s repeated use of alcohol or drugs results in significant impairment of health, work, school, and family. The severity of these disorders depends on the type and frequency of substance use, the social and interpersonal problems associated with the use, the impact on family, friends, work, school, and relationships, withdrawal symptoms, tolerance, failed attempts to stop, physical and mental health problems caused by the use, and cravings. These disorders can occur alone or in combination.

[0082] Post-traumatic stress disorder (PTSD) is characterized by flashbacks, nightmares, involuntary memories, emotional distress or physical reactions after recalling the trauma, avoidance of anything that might trigger such memories, avoidance of activities, social isolation, increased anger or aggression, increased irritability, involvement in risky behaviors, poor concentration, sleep problems, and enhanced startle responses, which can be further described as those with dissociative experiences.

[0083] In some implementations, the central nervous system disorder is agraphia, agnosia, Alzheimer's disease, amnesia, amyotrophic lateral sclerosis (ALS), aneurysm, loss of awareness of illness, aphasia, apraxia, body agnosia, Asperger's syndrome, ataxia, attention deficit hyperactivity disorder (ADHD), 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' paranoia, carpal tunnel syndrome, burning pain, and central pain syndrome. Central pontine myelin sheathing, central nucleus myopathy, head 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, skin-picking disorder, diabetic neuropathy, diffuse sclerosis. Dysarthria, dyscalculia, dysphagia, dysgraphia, motor disorders, dyslexia, dystonia, encephalopathy, epilepsy, erythromelalgia, essential tremor, fetal alcohol syndrome, fetal seizures, fibromyalgia, Friedreich ataxia, frontotemporal dementia, functional neurological disorders, Gaucher disease, 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, lumbar disc herniation, lupus erythematosus-neurological sequelae, Lyme disease, Meniere's disease, migraine, mild brain injury, multiple infarct dementia, multiple sclerosis, muscular dystrophy, myasthenia gravis, myoclonus, myopathy, neuralgia, neurofibromatosis, neuromuscular rigidity, 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 Disease), polyneuropathy, postherpetic neuralgia, post-traumatic stress disorder, primary lateral sclerosis, prions, progressive hemifacial atrophy, progressive supranuclear palsy, prosopagnosia, radiculopathy, reflex neurovascular dystrophy, repetitive stress injury, restless legs syndrome, Rett syndrome, Reye syndrome, sclerosis, 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, Siddenham'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.

[0084] In some implementations, the central nervous system disorder is a pain disorder, Alzheimer's disease, Parkinson's disease, cognitive impairment, or a combination thereof.

[0085] Chronic pain disorders are characterized by pain in one or more areas of the body, including headache, lower back pain, neck pain, arthritis pain, pain in the context of cancer, neuropathic pain, psychogenic pain, and include conditions such as chronic arthritis, osteoarthritis, chronic fatigue syndrome, endometriosis, fibromyalgia, inflammatory bowel disease, interstitial cystitis, temporomandibular joint dysfunction, vulvar pain, cluster headache, migraine, herpes zoster, frozen shoulder, complex regional pain syndrome, gout, postoperative pain syndrome, herniated disc, sciatica, and trigeminal neuralgia.

[0086] Cognitive impairment is characterized by impaired brain function that leads to a decline in memory and other functions, including motor, verbal, attentional and focusing, problem-solving, analytical sleep, tremors, fatigue, dizziness, headaches, hallucinations, and confabulation. It includes age-related memory disorders, Alzheimer's disease, Pick's disease, vascular dementia, post-stroke dementia, multi-infarct dementia, Parkinson's disease, frontal lobe dementia, alcohol-induced dementia, and amnesia disorders including Korsakoff syndrome.

[0087] Although drugs that function as “atypical antipsychotics” bind to dopaminergic D2 receptors, many atypical antipsychotics bind to other receptors with significantly higher potency (measured by lower nM binding). Their two most common receptors are serotonin 5-HT2A and 5-HT2B receptors. These drugs have a variety of potential benefits unrelated to their “antipsychotic” potential, especially when administered in combination at low doses. More specifically, by co-administering with cocrystal form A, atypical antipsychotics can block any potential negative effects that cocrystal form A itself might have on serotonin 5-HT2A and 5-HT2B receptors. When co-administered with low doses of atypical antipsychotics, this can enhance the effectiveness of cocrystal form A across a wide range of conditions for which the atypical antipsychotics alone do not have specific therapeutic value. Examples include a wide range of neurological and immunological conditions.

[0088] In some implementations, the method results in one or more improvements in a subject’s neuroplasticity, calcium flux, 5-HT2A receptor activity, 5-HT1A, 5-HT7, TrkB activity, BDNF activity, neurogenesis, synapsis, second messenger function measurement, or combinations thereof.

[0089] In some implementations, BDNF activity is enhanced.

[0090] 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%.

[0091] In some implementations, BDNF levels are increased by approximately 5% to approximately 75%.

[0092] In some implementations, BDNF levels are increased by approximately 5% to approximately 150%.

[0093] 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.

[0094] In some implementations, the method further includes stimulating neurogenesis or neurite growth.

[0095] In some implementations, stimulating neurogenesis or neurite growth includes increasing neuron length.

[0096] In some embodiments, the increase in 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.

[0097] In some implementations, the increased neuronal growth results in an increase in neurite length of approximately 100 μM to approximately 300 μM.

[0098] In some implementations, the increase in 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 180 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 280 μM, approximately 290 μM, approximately 300 μM, or any two of these values.

[0099] In some embodiments, the increase in 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%.

[0100] In some implementations, the increase in neuronal growth results in an increase in neurite length of approximately 20% to approximately 100%.

[0101] In some implementations, the increase in 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.

[0102] In some implementations, the method includes reducing the expression of neuroinflammatory cytokine biomarkers.

[0103] 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.

[0104] In some implementations, the neuroinflammatory cytokine biomarkers are 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.

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

[0106] In some implementations, the neuroinflammatory cytokine biomarker is G-CSF.

[0107] In some implementations, the neuroinflammatory cytokine biomarker is GM-CSF.

[0108] In some implementations, the neuroinflammatory cytokine biomarker is IFNγ.

[0109] In some implementations, the neuroinflammatory cytokine biomarker is IL-1α.

[0110] In some implementations, the neuroinflammatory cytokine biomarker is IL-1β.

[0111] In some implementations, the neuroinflammatory cytokine biomarker is IL-2.

[0112] In some implementations, the neuroinflammatory cytokine biomarker is IL-3.

[0113] In some implementations, the neuroinflammatory cytokine biomarker is IL-4.

[0114] In some implementations, the neuroinflammatory cytokine biomarker is IL-5.

[0115] In some implementations, the neuroinflammatory cytokine biomarker is IL-6.

[0116] In some implementations, the neuroinflammatory cytokine biomarker is IL-7.

[0117] In some implementations, the neuroinflammatory cytokine biomarker is IL-9.

[0118] In some implementations, the neuroinflammatory cytokine biomarker is IL-10.

[0119] In some implementations, the neuroinflammatory cytokine biomarker is IL-12p40.

[0120] In some implementations, the neuroinflammatory cytokine biomarker is IL-12p70.

[0121] In some implementations, the neuroinflammatory cytokine biomarker is IL-13.

[0122] In some implementations, the neuroinflammatory cytokine biomarker is IL-15.

[0123] In some implementations, the neuroinflammatory cytokine biomarker is Il-17.

[0124] In some implementations, the neuroinflammatory cytokine biomarker is IP-10.

[0125] In some implementations, the neuroinflammatory cytokine biomarker is KC.

[0126] In some implementations, the neuroinflammatory cytokine biomarker is LIF.

[0127] In some implementations, the neuroinflammatory cytokine biomarker is LIX.

[0128] In some implementations, the neuroinflammatory cytokine biomarker is M-CSF.

[0129] In some implementations, the neuroinflammatory cytokine biomarker is MCP-1.

[0130] In some implementations, the neuroinflammatory cytokine biomarker is MIG.

[0131] In some implementations, the neuroinflammatory cytokine biomarker is MIP-1α.

[0132] In some implementations, the neuroinflammatory cytokine biomarker is MIP-1β.

[0133] In some implementations, the neuroinflammatory cytokine biomarker is MIP-2.

[0134] In some implementations, the neuroinflammatory cytokine biomarker is RANTES.

[0135] In some implementations, the neuroinflammatory cytokine biomarker is TNFα.

[0136] In some implementations, the neuroinflammatory cytokine biomarker is VEGF.

[0137] 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%.

[0138] In some implementations, the expression of neuroinflammatory cytokine biomarkers is reduced by approximately 1% to approximately 80%.

[0139] 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.

[0140] In some implementations, neuroinflammatory cytokine biomarkers are reduced following acute exposure to the crystalline forms of xelocinone and xelociline.

[0141] In some implementations, neuroinflammatory cytokine biomarkers are reduced following chronic exposure to the crystalline forms of xelocinone and xelocinone.

[0142] In some implementations, the method reduces the risk of adverse cardiovascular events.

[0143] 5HT2B receptors are present in heart tissue, and long-term stimulation may increase the risk of valvular heart disease (VHD) in some individuals, an effect that has been known for 20 years.

[0144] Because of this effect, the clinical use of drugs containing 5HT2B receptor agonist activity is generally reduced or avoided in an attempt to mitigate this risk. This finding may limit the utility of hallucinogens for clinical treatment. Therefore, methods to reduce this risk could significantly increase the potential clinical benefits of long-term use of hallucinogens.

[0145] One possible mechanism for risk reduction is the theoretical combination of drugs that may have different effects on 5HT2B, such as agonists and antagonists. However, the actual effects cannot be known in advance because the overall effect of drugs with different binding characteristics to the same receptor cannot be predicted, and therefore the overall effect of combining drugs with different effects on the 5HT2B receptor cannot be accurately predicted. This is especially true when the drugs are not direct agonists but have indirect effects, because in this uncertain situation, it is impossible to predict how any two drugs will act together, since both the agonist and the inverse agonist attempt to bind to the same receptor simultaneously.

[0146] Adverse cardiovascular events may be caused by the administration of crystalline form A eutectic. These adverse cardiovascular events include ventricular heart disease, myocardial fibrosis, stroke, myocardial infarction, cardiovascular death, heart failure, ischemic cardiovascular events, etc.

[0147] In some implementations, reducing the risk of adverse cardiovascular events includes reducing the risk of ventricular heart disease, myocardial fibrosis, or a combination thereof.

[0148] In some implementations, reducing the risk of adverse cardiovascular events includes maintaining plasma levels of TGF-β1.

[0149] 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.

[0150] 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.

[0151] In some implementations, the atypical antipsychotic drug is administered simultaneously with the crystalline form.

[0152] In some implementations, the atypical antipsychotic drug is administered sequentially with the crystalline form.

[0153] In some implementations, the crystalline form is applied first.

[0154] In some implementation schemes, the atypical antipsychotic drug is administered first.

[0155] In some embodiments, the method further includes the application of additional agents.

[0156] In some implementations, the additional agent is a hallucinogenic compound, a mood stabilizer, an antidepressant, an antiepileptic, an anxiolytic, or a combination thereof.

[0157] In some embodiments, the additional agent is a hallucinogenic compound.

[0158] In some embodiments, the hallucinogenic compound is selected from cyclophosphine, cyclophosphine, LSD, MDMA, MDA, MEM, DMT, or combinations thereof.

[0159] In some implementations, the additional agent is a mood stabilizer.

[0160] In some implementations, the mood stabilizer is lithium.

[0161] In some implementations, the additional agent is an antidepressant.

[0162] In some implementations, the additional agent is an antiepileptic drug.

[0163] In some implementations, the additional agent is an anti-anxiety drug.

[0164] In some implementations, administration of the additional agent reduces the risk of adverse cardiovascular events.

[0165] In some implementations, reducing the risk of adverse cardiovascular events includes reducing the risk of ventricular heart disease, cardiac fibrosis, or a combination thereof.

[0166] In some implementations, the additional agent is administered simultaneously with eutectic form A and the atypical antipsychotic drug.

[0167] In some implementations, the additional agent is administered sequentially with eutectic form A and the atypical antipsychotic drug.

[0168] In some implementation schemes, eutectic form A is administered first, followed by the administration of an atypical antipsychotic drug, and then a third agent is administered.

[0169] In some implementation schemes, eutectic form A is first administered, followed by the administration of another agent, and then an atypical antipsychotic is administered.

[0170] In some implementation schemes, an atypical antipsychotic is first administered, followed by cocrystal A, and then another agent is administered.

[0171] In some implementation schemes, an atypical antipsychotic is first administered, followed by another agent, and then eutectic form A is administered.

[0172] In some implementation schemes, an additional drug is administered first, followed by the administration of a crystalline form, and then a third atypical antipsychotic is administered.

[0173] In some implementation schemes, an additional drug is administered first, followed by an atypical antipsychotic, and then a crystalline form is administered.

[0174] In one embodiment, the crystal form is eutectic form A, eutectic form B, or eutectic form C.

[0175] In one embodiment, the crystal form is eutectic form A.

[0176] 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.

[0177] 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 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.

[0178] In one embodiment, the crystal form is eutectic form B.

[0179] 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.

[0180] In one embodiment, the crystalline form is eutectic form C.

[0181] 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.

[0182] Crystalline form The following section further elaborates on the crystalline forms of serosol and serosol: 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.

[0183] In some implementations, celecoxib and celecoxib are crystallized in eutectic form A.

[0184] 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°.

[0185] In one implementation, the weight loss (1.3%) of eutectic form A between 40 and 200 °C was observed by TGMS.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] In some implementations, the eutectic form A is anhydrous.

[0192] In some implementations, eutectic crystal form A is a salt formed between serosol and serosol.

[0193] In some implementations, eutectic crystal type A is a eutectic formed between ceroxyn and ceroxyn.

[0194] In some implementations, the eutectic 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 In some implementations, cell parameters are measured at approximately 296 K.

[0195] In some implementations, the eutectic form A has a hydrogen bond geometry that is essentially as listed in Table A.

[0196] Table A DH...A DH [Å] H...A [Å] D...A [Å] DH…A [°] <![CDATA[O1-H1…N23 i ]]> 0.88(2) 1.60(2) 2.46(2) 162(2) <![CDATA[N11-H11…O3 ii ]]> 0.96(5) 2.17(4) 2.97(4) 140(6) <![CDATA[N17-H17…O2 iii ]]> 0.85(7) 1.83(7) 2.59(6) 147(8) <![CDATA[N28-H28…O1 iv ]]> 0.87(7) 2.32(6) 3.13(5) 153(10) <![CDATA[O34-H34…O3 v ]]> 0.88(10) 1.69(8) 2.49(7) 151(5) .

[0197] In some implementations, the eutectic crystal form A has atomic coordinates of non-hydrogen atoms as basically listed in Table B.

[0198] Table B x y z U(eq) O1 0.1251(14) 0.0326(16) 0.4198(4) 0.0253 O2 0.077(3) 0.0094(13) 0.3153(5) 0.0253 O3 0.190(3) 0.190(2) 0.3483(6) 0.0253 P4 0.0916(7) 0.0915(7) 0.3636(3) 0.0253 O5 -0.054(2) 0.157(3) 0.3724(5) 0.0253 C6 -0.1818(8) 0.102(5) 0.3771(8) 0.0253 C7 -0.221(2) 0.009(6) 0.4089(13) 0.0253 C8 -0.357(3) -0.030(9) 0.4084(19) 0.0253 C9 -0.466(2) 0.022(11) 0.375(2) 0.0253 C10 -0.4261(9) 0.116(10) 0.3436(15) 0.0253 N11 -0.512(3) 0.188(12) 0.3068(16) 0.0253 C12 -0.386(5) 0.277(10) 0.2836(13) 0.0253 C13 -0.265(4) 0.250(7) 0.3069(10) 0.0253 C14 -0.2791(18) 0.156(7) 0.3445(10) 0.0253 C15 -0.139(6) 0.313(5) 0.2890(13) 0.0253 C16 -0.082(4) 0.261(6) 0.2343(10) 0.0253 N17 0.054(6) 0.324(5) 0.2219(15) 0.0253 C18 0.140(5) 0.246(6) 0.1809(13) 0.0253 C19 0.146(7) 0.370(3) 0.269(2) 0.0253 C21 0.8842(18) 0.5884(19) 0.9383(6) 0.0253 C22 0.7490(17) 0.7295(10) 0.9827(10) 0.0253 N23 0.8087(12) 0.6116(8) 0.9893(5) 0.0253 C24 0.7012(15) 0.5244(13) 1.0037(8) 0.0253 C25 0.591(2) 0.533(3) 0.9591(11) 0.0253 C26 0.508(4) 0.422(3) 0.9490(17) 0.0253 C27 0.543(5) 0.306(3) 0.963(2) 0.0253 N28 0.435(7) 0.236(4) 0.942(3) 0.0253 C29 0.337(7) 0.302(6) 0.917(3) 0.0253 C30 0.212(8) 0.268(7) 0.891(3) 0.0253 C31 0.124(7) 0.356(9) 0.868(3) 0.0253 C32 0.161(6) 0.474(8) 0.872(3) 0.0253 C33 0.292(5) 0.508(6) 0.899(3) 0.0253 O34 0.330(4) 0.628(6) 0.906(3) 0.0253 C35 0.379(5) 0.422(5) 0.920(2) 0.0253 .

[0199] In some implementations, the eutectic crystal form A has atomic coordinates of hydrogen atoms as basically listed in Table C.

[0200] Table C x y z U(eq) H1 0.1396(11) 0.074(2) 0.4502(3) 0.0253 H7 -0.151(3) -0.029(5) 0.4319(14) 0.0253 H8 -0.379(5) -0.097(9) 0.431(2) 0.0253 H9 -0.563(3) -0.005(13) 0.374(2) 0.0253 H11 -0.612(2) 0.172(14) 0.3030(19) 0.0253 H12 -0.389(6) 0.337(10) 0.2556(15) 0.0253 H15A -0.075(5) 0.294(4) 0.3185(12) 0.0253 H15B -0.147(8) 0.398(5) 0.2858(18) 0.0253 H16A -0.146(5) 0.280(7) 0.2048(11) 0.0253 H16B -0.074(3) 0.176(5) 0.2375(8) 0.0253 H17 0.041(8) 0.386(5) 0.2026(19) 0.0253 H18A 0.205(4) 0.181(6) 0.1844(12) 0.0253 H18B 0.203(6) 0.295(7) 0.1601(17) 0.0253 H18C 0.075(4) 0.206(7) 0.1563(10) 0.0253 H19A 0.213(7) 0.336(3) 0.2941(19) 0.0253 H19B 0.086(8) 0.405(2) 0.296(2) 0.0253 H19C 0.211(9) 0.429(4) 0.255(2) 0.0253 H21A 0.951(2) 0.627(3) 0.9141(7) 0.0253 H21B 0.817(3) 0.575(3) 0.9093(5) 0.0253 H21C 0.944(2) 0.520(2) 0.9427(10) 0.0253 H22A 0.778(2) 0.8072(10) 0.9708(14) 0.0253 H22B 0.715(2) 0.7579(14) 1.0176(12) 0.0253 H22C 0.6710(17) 0.7266(16) 0.9571(11) 0.0253 H24A 0.6599(17) 0.542(2) 1.0390(8) 0.0253 H24B 0.742(2) 0.4463(11) 1.0054(11) 0.0253 H25A 0.635(3) 0.565(3) 0.9267(9) 0.0253 H25B 0.5179(14) 0.587(3) 0.9706(16) 0.0253 H27 0.629(5) 0.2905(18) 0.984(3) 0.0253 H28 0.436(8) 0.159(4) 0.946(4) 0.0253 H30 0.186(9) 0.185(8) 0.890(4) 0.0253 H31 0.037(8) 0.334(10) 0.851(4) 0.0253 H32 0.100(6) 0.533(9) 0.856(4) 0.0253 H34 0.294(4) 0.682(7) 0.884(3) 0.0253 .

[0201] In some implementations, serosol and serosol are crystallized in eutectic form B.

[0202] 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°.

[0203] In one implementation, the weight loss (15.8%) of eutectic form B between 40 and 200 °C was observed by TGMS.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] In some implementations, the eutectic form B is anhydrous.

[0209] In some implementations, eutectic B is a salt formed between serosol and serosol.

[0210] In some implementations, eutectic type B is a eutectic formed between ceroxin and ceroxib.

[0211] In some implementations, serosol and serosol are crystallized in eutectic form C.

[0212] 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°.

[0213] In one implementation, the weight loss (13.5%) of the eutectic form C between 40 and 160 °C was observed by TGMS.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] In some implementations, the eutectic form C is anhydrous.

[0219] In some implementations, the eutectic form C is a salt formed between serosol and serosol.

[0220] In some implementations, the eutectic crystal form C is a eutectic formed between ceroxin and ceroxib.

[0221] Pharmaceutical Composition In one embodiment, this application provides a pharmaceutical composition comprising crystalline forms of cyclophosphamide and cyclophosphamide and pharmaceutically acceptable excipients.

[0222] 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.

[0223] 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 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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).

[0228] 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.

[0229] 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.

[0230] 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

[0231] Example 1 Ca 2+ Release assay Cell culture – AequoScreen cells stably expressing human 5-HT2A or 5-HT2B (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).

[0232] Ca 2+ Assay - AequoScreen was used in CHO-K1 cells stably expressing h5HT2A or h5HT2B. TMAssay to determine the activation of Ga in a GPCR-dependent manner q / 11 After Ca 2+ Released into the cytosol. In addition to the selected receptor, the AequoZen cell line also stably expresses receptors with three Ca2+ receptors. 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.

[0233] The results are shown in Figure 1 and Figure 2 . Figure 1 The results showed that for cocrystalline form A, calcium release at the 5-HT2A receptor (in percentage of LSD) was similar to that of xylometazoline. However, surprisingly, when cocrystalline form A was combined with aripiprazole (a 5-HT2 receptor antagonist), calcium release at the 5-HT2A receptor (in percentage of LSD) was not reduced in this model. Figure 2 The results showed that, contrary to the findings at the 5-HT2A receptor, at the highest dose, calcium release (as a percentage of LSD) at the 5-HT2B receptor was lower for cocrystal form A than for cyclophosphamide. This was also observed after administration of cocrystal form A in combination with aripiprazole (a 5-HT2B receptor antagonist), where calcium release (as a percentage of LSD) was again reduced at higher doses compared to cyclophosphamide.

[0234] Example 2 Neuroplasticity: β-inhibitor 2 recruitment assay Cell Culture - CHO-K1 Cells with NanoBit TM Transfect the smBiT h5HT2A or h5HT2B plasmid with the lgBiT β-repressor protein 2 plasmid. When h5HT2A or 2B and β-repressor protein 2 come into contact with each other, the SMBIT and LGBIT peptides complement each other to produce the complete NanoBit. TM Luciferase. 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 mL M 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 or h5HT2B and the β-repressor protein 2 NanoBiT plasmid. 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.

[0235] β-inhibitory protein 2 assay – After seeding 20,000 cells / well in flat-bottomed, 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. Then, 25 μL of Nano-Glo was added. TM Live cell substrate (diluted 1 / 20 in Nano-Glo LCS dilution buffer according to the manufacturer's protocol) was used, 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). The luminescence data from the first 30 minutes were used to automatically generate the area under the time-luminescence curve (AUC) for each compound concentration. The 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.

[0236] The results are shown in Figure 3 . Figure 3 The results showed that, for cocrystalline form A, β-repressor protein 2 recruitment at the 5-HT2A receptor (as a percentage of LSD) was similar to that of cyclophosphamide, as seen in […]. Figure 1 The calcium release results are shown. (Compared to...) Figure 1 Conversely, when cocrystal form A was administered with aripiprazole, β-repressor protein 2 recruitment at the 5-HT2A receptor was significantly reduced (as a percentage of LSD) in this model, most notably at the highest dose. This suggests an unexpected interaction between the two compounds at this receptor, resulting in a combined effect on β-repressor protein 2 recruitment.

[0237] Example 3 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.

[0238] 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) mediator (230 μL), 2) cocrystal form A (0.3 mg / kg), 3) aripiprazole (0.3 mg / kg), and 4) cocrystal form A + aripiprazole (0.3 mg / kg). A PBS solution of 0.67% DMSO was used as the mediator. For immunohistochemical sampling, EdU (5-ethynyl-2'-deoxyuridine, Lumiprobe, 100 μg / g) was injected 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).

[0239] 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 dried. 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 and 9 middle.

[0240] 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) mediator, 2) cocrystal A (500 nM), 3) aripiprazole (500 nM), and 4) cocrystal A + aripiprazole (500 nM). A solution of 0.1% DMSO in growth medium was used as the mediator. 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 sectioned 9 times with a scalpel and transferred to the Geltrex-coated coverslips in the 6-well plates. The plate was 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 of 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 of PBS and then permeabilized with 3 ml of 0.1% Triton X-100 (PBT) in PBS for 10 minutes. The permeabilized samples were then subjected to immunostaining.

[0241] 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 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 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 coverslip was 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. The results are shown in Figures 10, 11, and 14A-C.

[0242] 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-iTPlus 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.

[0243] Cognitive performance, Y-maze. One day prior to testing (i.e., day-1), mice were acclimatized to a Y-maze with two familiar arms and one unfamiliar arm. On the testing day, mice were placed in the Y-maze and allowed free exploration for 5 minutes. Recorded behaviors included total movement, time spent in each arm, number of arm entries, and the number of correct alternations between the novel and familiar arms. Cognitive enhancement was reflected by an increase in time spent in the novel arm and an increase in the percentage of correct alternations.

[0244] The results are shown in Figure 4-7 . Figure 4The results showed that, compared with the control, co-crystal form A had a significant increase in short-term and working memory, aripiprazole alone had a smaller but significant increase, and the combination of co-crystal form A and aripiprazole had a significant increase in between. Figure 5 The results showed that cocrystal form A (3 mg / kg) significantly increased BDNF levels in the brain 1 hour after oral administration, as did aripiprazole (0.3 mg / kg) and the combination of cocrystal form A (3 mg / kg) and aripiprazole (0.3 mg / kg). Figure 6 The results showed that after 14 days of oral administration of cocrystal form A (3 mg / kg) alone, the levels of neuronal cells / stem cells in the mouse brain increased, and the effect was equally strong when cocrystal form A (3 mg / kg) was administered in combination with aripiprazole (0.3 mg / kg). In contrast, aripiprazole alone (0.3 mg / kg) had no significant effect. Figure 7 Changes in neuronal activation in mice were measured 21 days after oral administration. Administration of cocrystal form A alone (3 mg / kg) had no significant effect on the number of active neurons. Conversely, administration of aripiprazole alone (0.3 mg / kg) resulted in a significant increase. The combination of cocrystal form A (3 mg / kg) and aripiprazole (0.3 mg / kg) resulted in the largest increase, suggesting a possible unexpected synergistic effect.

[0245] Example 4 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 vector (saline), 3 mg / kg cocrystalline A+ aripiprazole, 3 mg / kg cilostabrine, 1 mg / kg TrKB inhibitor ANA-12, or a combination of 3 mg / kg cocrystalline A+ aripiprazole 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 vector (saline), 0.03 mg / kg cocrystalline A+ aripiprazole, and 0.3 mg / kg cocrystalline A+ aripiprazole. Plasma and brain tissue were collected 1 hour after the last (day 21) administration of the compound.

[0246] 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.

[0247] 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.

[0248] 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 a 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.

[0249] Results regarding cytokine biomarkers for neuroinflammation showed... Figure 8 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. Figure 8 The study showed percentage changes in 32 neuroinflammatory cytokine biomarkers 60 minutes after oral administration of cocrystal form A (3 mg / kg) and aripiprazole (3 mg / kg), and unexpectedly found that 29 of these were reduced to some extent. Furthermore, during this 60-minute period, the concentrations of 21 of the 32 biomarkers decreased by at least 20%. In a similar study, when animals were chronically treated with low-dose cocrystal form A (0.3 mg / kg) alone or with cocrystal form A (0.3 mg / kg) and aripiprazole (0.3 mg / kg), the combined group showed a greater effect, as the reduction in neuroinflammatory cytokine biomarkers was 25 / 30 and 28 / 30 compared to cocrystal alone, suggesting a possible synergistic effect.

[0250] Results of TGF-β1 levels showed Figure 9 middle.

[0251] The data showed that, unexpectedly, cocrystal form A and cocrystal form A + aripiprazole did 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.

[0252] 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 mental health disorder or central nervous system disorder in a subject with this need, comprising administering to the subject crystalline forms of cyclophosphamide and cyclophosphamide: And atypical antipsychotics.

2. The method according to claim 1, wherein the crystal form is eutectic form A.

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

4. The method of claim 3, wherein the XRPD plot further includes a significant peak at a 2θ angle of approximately 19.16°.

5. The method of claim 4, wherein the XRPD plot further includes significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°.

6. The method of claim 5, 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°.

7. The method of claim 2, wherein crystal form A is characterized by a DSC plot containing a sharp endothermic event at a temperature of approximately 255°C.

8. The method of claim 2, wherein crystal form A has a ratio of approximately 1:1 of cyclosporine to cyclosporine.

9. The method of claim 2, wherein crystal form A has a chemical purity of about 95% or higher.

10. The method of claim 2, wherein crystal form A contains no more than about 5 mol% of other solid forms.

11. The method of claim 2, wherein form A is a salt formed between serotonin and serosib.

12. The method according to claim 1, wherein the atypical antipsychotic is aripiprazole, clozapine, ziprasidone, cariprazine, ipraridone, quetiapine, lurasidone, paliperidone, amisulpride, olanzapine, risperidone, asenapine, clozapine, epipiperazole, rumeperone, pimovarsine, or a combination thereof.

13. The method according to claim 1, wherein the atypical antipsychotic is aripiprazole.

14. The method of claim 1, wherein the mental health disorder is a mood disorder, depressive disorder, mood instability disorder, mixed anxiety and depression disorder, bipolar disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder, phobia disorder, panic disorder, schizophrenia, psychosis, schizoaffective disorder, eating disorder, anorexia nervosa, bulimia nervosa, substance abuse disorder, addiction disorder, alcohol abuse or dependence, opioid abuse or dependence, cocaine abuse or dependence, mixed substance abuse or dependence, behavioral addiction, gambling disorder, trauma-related disorder, post-traumatic stress disorder, grief-related disorder, loss-related disorder, end-of-life disorder, cancer disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), personality disorder, obsessive-compulsive disorder, or a combination thereof.

15. The method of claim 14, wherein the mental health disorder is a mood disorder, a mixed anxiety and depression disorder, an anxiety disorder, a generalized anxiety disorder, a social anxiety disorder, a substance abuse disorder, an addiction disorder, an alcohol abuse or dependence, an opioid abuse or dependence, a cocaine abuse or dependence, a mixed substance abuse or dependence, a behavioral addiction, a gambling disorder, a post-traumatic stress disorder, or a combination thereof.

16. The method of claim 1, wherein the central nervous system disorder is a pain disorder, Alzheimer's disease, Parkinson's disease, cognitive impairment, or a combination thereof.

17. The method of claim 1, wherein the method results in one or more improvements in the subject’s neural plasticity, calcium flux, 5-HT2A receptor activity, 5-HT1A, 5-HT7, TrkB activity, BDNF activity, neurogenesis, synapsis, second messenger function measurement, or combinations thereof.

18. The method of claim 1, wherein the activity of the BDNF is enhanced.

19. The method of claim 18, wherein the BDNF level increases by about 5% to about 75%.

20. The method of claim 1, wherein the method further comprises stimulating neurogenesis or neurite growth.

21. The method of claim 20, wherein stimulating neurogenesis or neurite growth includes an increase in neuron length.

22. The method of claim 21, wherein the increase in neuron length results in an increase in neurite length of approximately 100 μM to approximately 300 μM.

23. The method of claim 21, wherein the increase in neuron length results in an increase in neurite length of about 20% to about 100%.

24. The method of claim 1, wherein the method comprises reducing the expression of neuroinflammatory cytokine biomarkers.

25. The method of claim 24, 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.

26. The method of claim 24, wherein the expression of the neuroinflammatory cytokine biomarker is reduced by about 1% to about 80%.

27. The method of claim 24, wherein the neuroinflammatory cytokine biomarkers are reduced following acute exposure to the crystalline forms of cyclophosphamide and cyclophosphamide.

28. The method of claim 24, wherein the neuroinflammatory cytokine biomarkers are reduced following chronic exposure to the crystalline forms of cyclophosphamide and cyclophosphamide.

29. The method of claim 1, wherein the method reduces the risk of adverse cardiovascular events.

30. The method of claim 29, wherein the reduction in the risk of adverse cardiovascular events includes reducing the risk of ventricular heart disease, cardiac fibrosis, or a combination thereof.

31. The method of claim 30, wherein reducing the risk of adverse cardiovascular events includes maintaining plasma levels of TGF-β1.

32. The method of claim 1, wherein the atypical antipsychotic drug is administered simultaneously with the crystalline form.

33. The method of claim 1, wherein the atypical antipsychotic drug is administered sequentially with the crystalline form.

34. The method of claim 33, wherein the crystalline form is first applied.

35. The method of claim 33, wherein the atypical antipsychotic drug is first administered.

36. The method of claim 1, further comprising administering an additional agent.

37. The method of claim 36, wherein the additional agent is a hallucinogenic compound, a mood stabilizer, an antidepressant, an antiepileptic, an anxiolytic, or a combination thereof.

38. The method of claim 37, wherein the additional agent is a hallucinogenic compound.

39. The method of claim 38, wherein the hallucinogenic compound is selected from cyclophosphine, cyclophosphine, LSD, MDMA, MDA, MEM, DMT or combinations thereof.

40. The method of claim 37, wherein the additional agent is a mood stabilizer.

41. The method of claim 40, wherein the mood stabilizer is lithium.

42. The method of claim 36, wherein the method reduces the risk of adverse cardiovascular events.

43. The method of claim 42, wherein the reduction in the risk of adverse cardiovascular events includes reducing the risk of ventricular heart disease, cardiac fibrosis, or a combination thereof.

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