Novel compositions and pharmaceutical compositions

Abstract

Pharmaceutical formulations of novel indole compounds and psilocybin analogs have been prepared and are provided in novel oral, transdermal, and intranasal pharmaceutical compositions for use in treating neurological, mood, or abuse diseases and disorders. The present invention relates to the administration of novel indole compounds, psilocybin, psilocybin chemical analogs, and novel indole chemical compounds; and to pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treating neurological diseases or disorders using the analogs and novel compounds.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 021,866, filed May 8, 2020, U.S. Provisional Patent Application No. 63 / 106,516, filed October 28, 2020, and U.S. Provisional Patent Application No. 63 / 134,805, filed January 7, 2021.

[0002] Field of the Disclosure The present invention relates to novel indole compounds, the administration of psilocybin, psilocybin chemical analogs, and novel indole chemical compounds; and pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treating neurological diseases or disorders using the analogs and novel compounds. [Background technology]

[0003] 2. Background of the Invention Psychoactive drugs are compounds that affect behavior, mood, thinking, or perception. Psychoactive drugs include antipsychotics, anxiolytics, stimulants, reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and mood stabilizers. Some of these compounds have historically been used for off-label psychoactive activities and are currently under active clinical efficacy investigation. In addition to potential therapeutic efficacy, these drugs must be investigated for all relevant pharmaceutical properties, including minimum and maximum dosing thresholds and the most effective delivery system.

[0004] Indole compounds represent a diverse class of compounds with broad biomedical potential across many targets including cancer, cardiovascular, gastrointestinal, and a wide range of neurological disorders. In in vivo biosynthesis, the amino acid tryptophan precursor of serotonin has been the scaffold of choice for many drugs containing the heterocyclic indole scaffold. Serotonin (5-HT) supports many important bodily functions including mood, sleep, appetite, gut motility, and sexual health. The serotonergic system consists of a class of G-coupled protein receptors, 5-HT1 through 5-HT7, as well as their subtypes (1A, 2A, 2B, etc.), that modulate a range of these biological pathways.

[0005] Most serotonergic targeted therapeutics are antidepressants, either as selective reuptake inhibitors (SSRIs), direct 5-HT modulators (atypicals), or in combination with norepinephrine inhibitors (SNRIs). Although not yet fully understood, the general mechanism of action of the approved therapeutics relies on increasing the concentration of monoamines, 5-HT and norepinephrine, in postsynaptic receptors to restore synaptic balance. However, these medications generally lack efficacy (only 20-30% more effective than placebo), have significant side effects, and have a delayed onset of weeks to months.

[0006] Sigma-1 receptors (σ receptors) are intracellular receptors expressed in specific regions of the brain. Modulation and agonism of Sigma-1 (σ1) have been shown to positively affect motor activity, mood disorders, increased brain-derived neurotrophic factor (BDNF), neuronal growth, and neurogenesis. Various classes of psychotropic drugs, including antipsychotics, antidepressants, selective serotonin reuptake inhibitors (SSRIs), and motor neuron drugs, bind to (σ1) receptors. Binding of SSRIs to σ1 receptors may mediate the serotonin-independent actions of this class of drugs. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous σ1 receptor modulator.

[0007] Psilocybin is an indole alkaloid and naturally occurring psychoactive prodrug produced by over 200 species of mushrooms. Psilocybin is a prodrug that is dephosphorylated in vivo by oral administration to produce the active compound psilocin. Both psilocybin and psilocin are indole compounds, known to be potent 5-HT agonists, and can cross the blood-brain barrier. The therapeutic value of psilocybin has been widely demonstrated by active clinical research targeting depression, anxiety, migraine, addiction, dementia, Alzheimer's disease, eating disorders, obsessive-compulsive disorder, and palliative care.

[0008] Magic mushrooms is a general term for a group of over 200 naturally occurring mushrooms that contain psilocybin and active psilocybin chemical analogs and combinations thereof. Similarly, other naturally occurring psychedelic indole compounds include N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5-MeO-DMT), lysergamide (e.g., LSD), and ibogaine. Raw fruits as well as extracts containing these natural products have been taken orally for their psychoactive effects. Precise dose-response activity has been difficult to quantitate due to the variability of individual responses, the difficulty of measuring potency of natural organisms and extracts, and the different inherent potencies and ratios of different analogs and their combinations. This is only exacerbated by serotonin receptor activity as well as sigma-1 (σ1) receptor interactions, especially for compounds such as DMT. Specifically, with regard to neurodegenerative diseases and cognitive function, agonists of the σ1 receptor (e.g., DMT) have been shown to enhance brain plasticity, which has an important role in memory and learning.

[0009] Psilocybin and its known analogues have been synthesized and bioengineered. In the mid-20th century, Sandoz Pharmaceuticals briefly marketed an oral formulation of psilocybin for adjunctive therapy in psychotherapy. The product was quickly removed from the market due to unpredictable individual responses to the dosage form. As of 2020, the U.S. Drug Enforcement Administration classifies psilocybin as a Schedule 1 drug with high potential for abuse, no accepted medical use, and no recognized safety profile for use under medical supervision.

[0010] The administration and evaluation of pharmaceutical efficacy of these compounds has proven difficult. One reason is that the plasma concentration-time curves are highly variable. In addition, psilocybin and especially DMT undergo first-pass metabolism in oral dosage forms, which reduces the availability of the pharmaceutical active ingredient before entering the systemic circulation. There is also wide individual variation in the renal excretion of the compounds. In addition, pH and monoamine oxidase (MAO) enzymatic cleavage of psilocybin to the pharmaceutical active ingredient psilocin after oral delivery may also be determinants of pharmacodynamics. As a result, the study of optimal dosages for treating various neurological disorders has not been rigorously pursued.

[0011] A 2016 Johns Hopkins study reported that relatively high doses, such as a 0.2 mg / kg dosing regimen, correlating to a plasma concentration of 4-8 ng / mL, are necessary to induce psychedelic effects. Psilocin's in vivo half-life is approximately 50 minutes, resulting in a psychedelic experience lasting 4-6 hours, during which time trained professionals monitor the subject in a clinical setting. Psychotherapy is implemented before and after the psychedelic dose to prepare the patient and integrate the experiential results into a personal response to improve depressive thoughts and behaviors, with the drug acting solely as a holistic tool. However, inpatient treatment is costly for patients and time-consuming for medical personnel, not to mention the increased risk of adverse events while the patient is under the influence of psychedelics.

[0012] Furthermore, positive psychological effects were seen with increasing doses, but as the doses increased, so did the negative side effects of anxiety, negative imagery, nausea, and headaches. Thus, professional monitoring of patients is necessary before, during, and after psychedelic sessions. Recently, microdosing has been used to administer psychedelic substances in very small, subperceptible amounts. Psychedelic substances that have been microdosed include LSD (lysergic acid diethylamide), cannabis, and psilocybin analogs. Reports of microdosing substances such as DMT and 5-MeO-DMT are scarce, as their lack of bioavailability and short half-life make their administration difficult. Microdosing has been reported to have beneficial therapeutic effects that improve mood, intellectual focus, energy levels, and creativity without disabling hallucinogenic effects.

[0013] Microdosing of psychedelic substances greatly reduces the psychoactive effects, anecdotally, and the dose is usually 1 / 10th the psychedelic dose. th ). Many clinical studies of psychedelics to alleviate depression and PTSD exclude participants with a history of cardiac disease, psychosis, and schizophrenia, as the strong psychoactive effects may exacerbate these conditions, but microdosing can alleviate these issues. Psychedelic-free treatments eliminate the need for administration of drugs in clinical settings, allowing for more traditional, flexible, and affordable drug regimens. Reports of microdosing have noted improved cognitive benefits, such as productivity, creativity, and abstract thinking; the combined evidence suggests that psychedelics reduce neuroinflammation and increase neuroplasticity and neuronal connectivity may lead to effective treatments for dementia, Alzheimer's disease, and other neurocognitive disorders.

[0014] Transdermal and intranasal application of pharmaceutical active ingredients has many advantages when used for psychoactive drugs. In particular, psilocin is a product of the conversion of psilocybin, a prodrug that is converted to psilocin in the gastrointestinal tract. By avoiding the gastrointestinal tract via transdermal application of psilocin, problems with absorption and food interactions can be avoided. Since the therapeutic effect of orally administered DMTs can only be realized by co-administration of MAOIs, transdermal systems offer a new delivery method with reduced metabolism and improved pharmacokinetic / pharmacodynamic (PK / PD) properties. Other advantages of transdermal administration include avoidance of first-pass metabolism; providing multi-day treatment with a single application, thereby improving patient compliance; and extending the activity of drugs with short half-lives due to the reservoir of drug present in the delivery system and its controlled release properties.

[0015] Systemic delivery of medicinal ingredients by administration to the nasal mucosa may be advantageous. Nasal delivery allows for the avoidance of intestinal and first-pass metabolism. In addition, nasal delivery of systemic drugs can bypass the blood-brain barrier and enter the brain via the olfactory and trigeminal pathways, which may be advantageous for medicinal administration of diseases of the central nervous system. An additional advantage of nasal administration is the rapid systemic absorption through the nasal mucosa. Combining this with compounds with short half-lives such as DMT may have significant clinical advantages over longer-acting psychedelics.

[0016] Oral delivery of drugs is often preferred over various other drug administration routes due to ease of ingestion, avoidance of pain, good patient compliance and prescription history.However, many problems are still associated with oral delivery, such as poor solubility of drugs in aqueous environment, taste, stability of drugs with formulation excipients, various dissolution rates, unknown gastrointestinal absorption problems and food effects.Oral pharmaceutical formulation is recognized as a scientific endeavor that requires specific knowledge of general fields and innovative design.

[0017] Recent studies of psilocybin and its psilocybin analogs and combinations thereof have been reported to have efficacy in models and small-scale clinical trials of abuse disorders, including post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression and anxiety, opioid addiction, alcoholism, nicotine addiction, cannabinoid addiction, headache, central nervous system inflammation, dementia, and cognitive and memory disorders. These promising experimental reports using psilocybin and its analogs demonstrate the urgent need to determine the most favorable dosage and duration of administration; improved pharmacokinetic (PK) profile, pharmacodynamic (PD) profile, or safety profile; evaluation of the benefits of long-term or maintenance treatment; development of treatment regimens that maximize biological effectiveness to treat disease; and formulations that allow the use of these compounds in other potentially advantageous benefits. Additionally, there is a need for the development of novel, safe, and effective exogenous serotonergic and / or sigma-1 modulators for treating neurological, mood, and abuse disorders or diseases. Summary of the Invention [Means for solving the problem]

[0018] overview Provided herein are novel indole compounds that have biological efficacy and increased clinical safety.

[0019] These compounds include compounds of structure (1) or a pharma- ceutically acceptable salt or solvate thereof: Structure (1) [ka] During the ceremony, X is H, CF3, or a halogen selected from the group consisting of F, Cl, Br, I, and astatine; R1 comprises an aliphatic substituent having a primary, secondary, tertiary, or quaternary amine; and R2 is hydrogen, hydroxyl, ester, ether, aldehyde, acid, amide, thiol, sulfone, sulfonamide, or combinations thereof.

[0020] A further aspect of the present invention is a compound according to structure (1) above, selected from the group consisting of: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] and any salt forms thereof.

[0021] In another embodiment of the present invention, there is provided a compound of structure (2) or a pharma- ceutically acceptable salt or solvate thereof: Structure (2) [ka] wherein R1 is selected from the group consisting of H, F, Cl, Br, I or CF3; R2 or CH3; R3 and R4 are each independently selected from the group consisting of H, CH3, C2H5, (H3C)2CH, or H2C=CH-CH2, as appropriate; R5 is selected from the group consisting of OCH3, OCOCH3, O-phosphate, O-polyethylene glycol (PEG), O-(CH2)2(COOH)2 (succinate), O-(CH2)2(COOH) (hemisuccinate) and CH2SO2NHCH3 (sulfonamide); when R1 is H, R5 is CH2SO2NHCH3.

[0022] Specific compounds of structure (2) are 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl halide, Hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine, 2-(2-bromo-4-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine. Other specific compounds of structure (2) of particular interest are 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, and 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide.

[0023] Another aspect of the present invention is a compound of structure (3) or a pharma- ceutically acceptable salt or solvate thereof: Structure (3) [ka] wherein R1 is selected from the group consisting of F, Cl, Br, I, or CF3; R2 is CH3; and R3 and R4 are each independently, as appropriate, a compound selected from the group consisting of H, CH3, C2H5, (H3C)2CH, or H2C=CH-CH2, or a pharma- ceutically acceptable salt or solvate thereof.

[0024] Specific compounds of structure (3) include 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethan-1-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethan-1-amine, (R)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, amine, (S)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-propan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-propan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethan-1-amine, N-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethan-1-amine, N-(2-(2-chloro-1H-indol-3-yl)-N,N-diethylethan-1-amine, N-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-vinyletheneamine, 2-(2-bromo-1H-indol-3-yl)-N,N-diethylethan-1-amine, N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, or N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine.

[0025] Provided herein are pharmaceutical compositions designed to release the pharmaceutical active ingredient described herein into the bloodstream through transdermal application of the pharmaceutical active ingredient to the skin and nasal cavity.These pharmaceutical compositions are transdermal or transnasal pharmaceutical formulations.The pharmaceutical active ingredient can be applied by sprayable liquid, gel, cream, lotion, ointment, transdermal patch, etc.

[0026] In one embodiment, the transdermal and intranasal pharmaceutical compositions of the pharmaceutical active ingredient may be compounds as described by structures (1), (2), (3), and compounds listed in Table (1) and any ionic or salt form thereof.

[0027] In certain embodiments, psilocybin analogs and combinations thereof include any compound that is structurally related to psilocybin and functionally mimics and / or antagonizes the action of serotonin.In another embodiment, the active pharmaceutical ingredient includes psilocybin and active analogs and combinations thereof.Active analogs of psilocybin and combinations thereof include, but are not limited to, the compounds listed in Table (2) psilocybin analogs.

[0028] [Table 2]

[0029] Provided herein are the preparation of transdermal or intranasal medicaments using the novel compounds described by structures (1), (2) and (3), the novel compounds listed in Table (1), and the psilocybin analogs of Table (2), and salts or solvates thereof, as active pharmaceutical ingredients for the treatment of neurological, mood and abuse disorders or diseases.

[0030] The transdermal and intranasal pharmaceutical compositions of the present invention provide compositions which are described for use in medicine to treat, manage or prevent disease.

[0031] In another embodiment, the pharmaceutical composition is designed for oral delivery to the human systemic circulation with rapid onset and duration.

[0032] In another embodiment, the pharmaceutical composition is designed for sustained release into the human systemic circulation via oral delivery, preferably providing a once daily dose.

[0033] The oral pharmaceutical compositions described herein can be designed for modified time release of pharmaceutical active ingredients into the human systemic circulation over an extended period of time.The compositions can be composed of solid, semi-solid, liquid, or soft delivery systems and can be administered sublingually, buccal, or by oral administration.The pharmaceutical active ingredients can be provided in tablets, capsules, soft gels, strips, sublingual strips, cachets, liquids, suspensions.

[0034] In one embodiment, the oral pharmaceutical composition contains the active pharmaceutical ingredients of the novel compounds described by structures (1), (2), (3), the novel compounds of Table (1), and the psilocybin analogs of Table (2), or salts or solvates thereof. Combinations of psilocybin analogs and / or novel indole compounds as active pharmaceutical ingredients in pharmaceutical formulations are also part of the present invention.

[0035] The invention provides the described compositions for use in the treatment, management, or prevention of a neurological disorder, a mood disorder, or an abuse disorder or disease, wherein the disorder may be depression, central nervous system inflammation, addiction, headache, or dementia, or a disorder of cognition and memory.

[0036] The present invention provides a combination of topical, nasal or oral application of the compounds and analogs described herein in combination with a pharmaceutical active ingredient approved by a regulatory agency for the treatment, management or prevention of neurological, mood and abuse disorders or diseases.The approved pharmaceutical active ingredient can be delivered to a patient in need by any delivery system approved by a regulatory agency.In one embodiment of the present invention, the approved pharmaceutical active ingredient for use in combination with the novel indole or psilocybin analog is an MAOI.In another embodiment of the present invention, the approved pharmaceutical active ingredient is a 5-HT antagonist.

[0037] Also provided herein are novel synthetic routes to provide novel indole compounds of structures (1), (2), and (3), as well as novel compounds of Table (1) and psilocybin analogs of Table (2). Novel syntheses of the described compounds are described in the specific examples and as described herein. [Brief description of the drawings]

[0038] [Figure 1] Figure 1 shows the drug release of the DMT transdermal patch according to Example 1. The results evaluated by the Franz cell diffusion model are averaged (n=3).

[0039] [Diagram 2] FIG. 2 shows the diffusion rate of the transdermal formulation by the Franz cell model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Detailed Description 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.

[0041] As used in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context clearly dictates otherwise.

[0042] The term "about" or "approximately" refers to an acceptable error of a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0043] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" refer to the eradication or amelioration of a disease or disorder, or one or more symptoms associated with a disease or disorder. In certain embodiments, the term refers to minimizing the spread or worsening of a disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject having such a disease or disorder. In some embodiments, the term refers to administration of a compound or dosage form provided herein, with or without one or more additional active agents, after the onset of symptoms of a particular disease.

[0044] As used herein, unless otherwise specified, the term "abuse disorder" refers to a disorder or disease that affects a person's brain and behavior and results in the loss of control over the use of legal or illegal drugs or medications. Prescription drugs, non-prescription drugs, and unlicensed drugs can all be abused drugs. Drugs and medications can also include substances such as amphetamines, opioids, cocaine, barbiturates, alcohol, marijuana, and nicotine.

[0045] As used herein, unless otherwise specified, the term "mood disorder" refers to a group of conditions in which disturbance of a person's mood is an underlying feature. Mood disorders can be manic (elevated mood disorder) or hypomanic (depressive) groups. This classification is described in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD).

[0046] As used herein, unless otherwise specified, the term "neurological disorder" refers to diseases of the central and peripheral nervous system, such as the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscle.These disorders include epilepsy, Alzheimer's disease and other dementias, cerebrovascular diseases including stroke, migraine, cluster headache and other headache disorders, multiple sclerosis, Parkinson's disease, neuroinfections, brain tumors, traumatic disorders of the nervous system due to head trauma, and traumatic or frightening experiences (post-traumatic stress disorder, e.g., PTSD), as well as malnutrition and neurological disorders as a result of substance abuse.The substance abused can be any number of addictive substances, particularly alcohol and drugs, and their combinations. Many bacterial infections (e.g., Mycobacterial tuberculosis, Neisseria meningitides), viral infections (e.g., Human Immunodeficiency Virus (HIV), Lyme disease, Enterovirus, West Nile Virus, Zika), fungal infections (e.g., Cryptococcus, Aspergillus), and parasitic infections (e.g., Malaria, Chagas) can affect the nervous system. Neurological symptoms can result from the infection itself or from the immune response.

[0047] As used herein, unless otherwise specified, the terms "prevent", "preventing" and "prevention" refer to the prevention of the onset, recurrence or spread of a disease or disorder or one or more symptoms thereof. In certain embodiments, the terms refer to treatment or administration with the compound dosage form provided herein, with or without one or more additional active agents, prior to the onset of symptoms, particularly to subjects at risk of a disease or disorder provided herein. These terms encompass the inhibition or alleviation of symptoms of a particular disease. In certain embodiments, subjects with a family history of the disease are candidates for a preventive regimen. Additionally, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment".

[0048] As used herein, unless otherwise specified, the terms "manage", "managing" and "management" refer to preventing or slowing the progression, spread or worsening of a disease or disorder or one or more symptoms thereof.In many cases, the beneficial effects that a subject obtains from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder.In this regard, the term "managing" encompasses treating a subject suffering from a particular disease in an attempt to prevent or minimize the recurrence of the disease.

[0049] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, lasting or transient, that may result from or be associated with administration of the composition.

[0050] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent disease or disorder or prevent its recurrence.A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that provides a prophylactic benefit in disease prevention, alone or in combination with one or more other agents.The term "prophylactically effective amount" can include an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent.

[0051] As used herein, unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with a disease or disorder. A "therapeutically effective amount" and "effective amount" of a compound refer to an amount of a therapeutic agent that alone or in combination with one or more other agents provides a therapeutic benefit in the treatment or management of a disease or disorder. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effectiveness of another therapeutic agent.

[0052] As used herein, unless otherwise specified, an "active pharmaceutical ingredient (API)" is any substance or mixture of substances that is intended to be used in the manufacture of a drug (pharmaceutical) product and that, when used in the manufacture of the drug, becomes an active ingredient in the drug product. Such substances are intended to affect the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.

[0053] As used herein, unless otherwise specified, the term "drug product" is a final dosage form, e.g., an oral, nasal or transdermal formulation, that generally contains an active pharmaceutical ingredient, but is not necessarily associated with non-active ingredients.

[0054] The terms "composition," "formulation," and "dosage form" as used herein are intended to encompass compositions containing the specified ingredient(s) (in the specified amounts, if indicated), as well as any product that results directly or indirectly from the combination of the specified ingredient(s) in the specified amounts. "Pharmaceutical" or "Pharmaceutically acceptable" means that any diluent(s), excipient(s), absorption enhancer(s) or carrier(s) in a composition, formulation, or dosage form is compatible with the other ingredient(s) and not deleterious to the recipient thereof. Unless otherwise indicated, the terms "composition," "formulation," and "dosage form" are used interchangeably herein.

[0055] As used herein, the term "transdermal" refers to being or delivering a medication in a form that is absorbed through the skin into the bloodstream.

[0056] As used herein, the term "nasal" refers to being or delivering a medication in a form for absorption through the nasal mucosa. Nasal delivery can be affected by a wide range of dosage forms, including, but not limited to, solutions, gels, suspensions, emulsions, liposomes, and particulates.

[0057] As used herein, "oral" refers to a form of medicine for absorption through the oral mucosa, sublingual membrane, buccal membrane, esophageal membrane, gastric membrane, or intestinal membrane. The term "capsule" refers to an oral composition in which the API and non-active ingredients are contained as a solid, liquid, or semi-solid within a shell composed of gelatin, polymerized cellulose, or other suitable material. The capsule is intended to be swallowed, where the composition dissolves and releases the API for systemic absorption through the esophageal, stomach, or intestinal lining.

[0058] The terms "tablet" and "cachet" include oral compositions in the shape of a sphere, round, oval, triangle, diamond, prill, or oblong, containing the API, inactive ingredients, and optionally a saliva stimulant, which are formed by direct compression of a powder formulation. Upon entry into the oral cavity, the composition dissolves and releases the API for systemic absorption via the buccal, sublingual, esophageal, stomach, or intestinal lining.

[0059] The term "strip" or "oral strip" includes oral compositions in a square, rectangular, triangular, circular, annular, or oblong shape containing the API, inactive ingredients, and optionally a saliva stimulant forming a flexible matrix. Upon entry into the oral cavity, typically placed under the tongue, the composition dissolves and releases the API for systemic absorption via the buccal, sublingual, esophageal, stomach, or intestinal lining.

[0060] As used herein, "immediate release" is defined as a formulation of an active pharmaceutical ingredient(s) taken orally, nasally, or transdermally that results in rapid absorption of the drug into the blood after administration. Immediate release can be measured in vitro using FDA industry guidelines for dissolution and / or permeability testing, or in vivo using plasma levels.

[0061] As used herein, "modified release" or "extended release" is defined as a formulation of an active pharmaceutical ingredient(s) taken orally, nasally, or transdermally that releases the active pharmaceutical ingredient over a period of hours or days to maintain a relatively constant plasma concentration of the drug. Such modification may have several purposes, such as maintaining therapeutic activity for an extended period of time, reducing toxic effects, protecting the active agent from degradation due to low pH, targeting the active agent to a predefined segment of the gastrointestinal tract for localized treatment, or targeting the release of the active agent at a specified time point. Modified release is measured by the appropriate FDA industry guidelines for modified release formulations.

[0062] The term "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0063] The terms "co-administration," "in combination with," and "in combination" include simultaneous, concurrent, or sequential administration of two or more therapeutic agents within a specific time limit. In one embodiment, the agents are present in a cell or in a subject's body at the same time or exert their biological or therapeutic effects at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, the first agent can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, or 4 weeks before) administration of the second therapeutic agent, simultaneously with administration of the second therapeutic agent, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of the second therapeutic agent.

[0064] The term "psilocybin analog" is defined herein to include any compound that is structurally related to psilocybin and functionally mimics and / or antagonizes the action of serotonin. Certain embodiments herein provide salts, cocrystals, solvates, isomers, hydrates, ions, zwitterions, complexes, prodrugs, precursors, metabolites, and / or other derivatives of psilocybin. Certain embodiments herein provide mixtures of two or more of the psilocybin analogs provided herein. As described herein, the psilocybin analogs are selected from the group consisting of the compounds listed in Table (2) and salts and solvates thereof. Certain embodiments herein provide mixtures of two or more of the psilocybin analogs provided herein.

[0065] The psilocybin analogs described herein can be synthesized using any method known to one of skill in the art. It is known that certain compounds can be provided by the application of biological processes to an article of manufacture, and the compounds are bioengineered.

[0066] The psilocybin analogs described herein may be provided by alcohol or acid-base extraction of the psychoactive compounds from natural sources containing the compounds. Extraction methods are well known to those skilled in the art.

[0067] In certain embodiments, the formulations of the present invention use psilocybin and psilocybin analogs and combinations thereof that may be obtained synthetically or bioengineered; or extracted from naturally occurring mushrooms. As described herein, some of the manufacturing processes may be novel, while others may use techniques that are well described in the art.

[0068] Provided herein are dosage forms, pharmaceutical formulations and compositions comprising a pharmaceutical active ingredient that is either (a) a novel indole of structure (1), structure (2), structure (3) or (b), or a psilocybin analog. The dosage forms, pharmaceutical formulations and compositions release the pharmaceutical active ingredient into the bloodstream upon transdermal, nasal or oral administration. In certain embodiments, the psilocybin analog is psilocin. In certain embodiments, the psilocybin analog is 4-hydroxytryptophan. In certain embodiments, the psilocybin analog is 4-hydroxytryptophol. In certain embodiments, the psilocybin analog is 4-hydroxy-indole-3-acetaldehyde. In certain embodiments, the psilocybin analog is 4-hydroxy-indole-3-acetic acid. In certain embodiments, the psilocybin analog is norpsilocin. In certain embodiments, the psilocybin analog is aeruginascin. In certain embodiments, the psilocybin analog is baeocystin. In certain embodiments, the psilocybin analog is norbeocystin. In certain embodiments, the psilocybin analog is 4-hydroxy-N-methyl-N-ethyltryptamine (4-OH-MET). In certain embodiments, the psilocybin analog is 4-hydroxydiethyltryptamine (4-OH-DET). In certain embodiments, the psilocybin analog is 4-hydroxy-N N-dipropyltryptamine (4-OH-DPT). In certain embodiments, the psilocybin analog is 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT). In certain embodiments, the psilocybin analog is N,N-dimethyltryptamine (DMT). In certain embodiments, the psilocybin analog is indole-3-acetic acid. In certain embodiments, the psilocybin analog is N,N-dimethyltryptamine-N-oxide (DMT-NO). In certain embodiments, the psilocybin analog is lysergic acid diethylamide (LSD). In certain embodiments, the psilocybin analog is O-acetylpsilocin (4-AcO-DMT). In certain embodiments, the psilocybin analog is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).In certain embodiments, the psilocybin analog is bufotenine (5-OH-DMT). In certain embodiments, the psilocybin analog is ibogaine.

[0069] In certain embodiments, exemplary compounds have the structure as shown in Structure (1): [ka] During the ceremony, X is H, CF3, or a halogen selected from the group consisting of F, Cl, Br, I, or astatine; R1 comprises an aliphatic substituent having a primary, secondary, tertiary, or quaternary amine; and R2 is hydrogen, hydroxyl, ester, ether, aldehyde, acid, amide, thiol, sulfone, sulfonamide, or combinations thereof.

[0070] In certain embodiments, the psilocybin analogs and combinations thereof provided herein include any compound that is structurally related to psilocybin and that functionally mimics and / or antagonizes the actions of serotonin.

[0071] In certain embodiments, exemplary psilocybin analogs and combinations thereof are the compounds provided in Table (2).

[0072] In certain embodiments, pharmaceutical formulations and compositions comprising an active pharmaceutical ingredient that is any of (a) an indole compound of the structural genus of Structure (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, can be used in combination with other active agents.

[0073] In certain embodiments, the pharmaceutical preparation comprises MAOI.MAOI is a family of drugs that catalyze the oxidation of monoamines, and it is known that certain psilocybin analogs and their combinations are enzymatically degraded by MAOI.MAOI includes, but is not limited to, harmala alkaloids, harmine, harmane, harmaline, hydrazine, iproniazid, isocarboxazid, nialamide, phenelzine, hydracarbazine, tranylcypromine, bifemelane, moclobemide, pirlindole, toloxatone, rasagiline, selegiline, safinamide, and other reversible inhibitors of monoamine oxidase A (RIMA).

[0074] Certain embodiments herein encompass pharmaceutical formulations and compositions comprising an active pharmaceutical ingredient that is either (a) an indole of structure (1) or (b) a psilocybin analogue and combinations thereof, and optionally a monoamine oxidase inhibitor (also known as an MAO inhibitor or MAOI), such formulations and compositions being formulated for transdermal administration.

[0075] Certain embodiments of the present invention include pharmaceutical formulations and compositions that contain a pharmaceutical active ingredient that is either (a) an indole of structure (1), structure (2) or structure (3) or (b) a psilocybin analog and combinations thereof, and optionally a monoamine oxidase inhibitor (also known as MAO inhibitor or MAOI), and such formulations and compositions are prepared for oral administration. In certain embodiments, 5-HT antagonists can be used as allosteric modulators or to improve the therapeutic benefits of psilocybin analogs. It is known that certain 5-HT antagonists can reduce the pyschoactivity induced by psilocybin analogs, which can be beneficial for treatment or to reduce side effects. Specific 5-HT antagonists include, but are not limited to, ketanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, cyproheptadine, trazadone, mirtazapine, nefazodone, niaprazine, pizotifen, metergoline or 2-bromo-LSD (BOL-148).

[0076] In certain embodiments, pharmaceutical formulations and compositions comprising the active pharmaceutical ingredient of (a) an indole of structure (1), structure (2), or structure (3), or (b) a psilocybin analog, and combinations thereof, are used to treat neurological, mood, and abuse disorders. These formulations and compositions may be prepared for transdermal administration.

[0077] In certain embodiments, pharmaceutical formulations and compositions comprising an active pharmaceutical ingredient of (a) an indole compound of the genus of structure (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, are used to treat neurological, mood, and abuse disorders. These formulations and compositions may be prepared for intranasal administration.

[0078] In certain embodiments, pharmaceutical formulations and compositions comprising the active pharmaceutical ingredients ((a) an indole compound of the genus of structures (1), (2), (3), (b) a psilocybin analog of Table (1), (c) a psilocybin analog of Table (2), or (d) a psilocybin analog of Table (2), and combinations thereof, are used to treat neurological, mood, and abuse disorders. These formulations and compositions may be prepared for oral administration. Certain embodiments provide for the use of (a) an indole compound of the genus of structures (1), (2), (3), to prepare pharmaceutical formulations and compositions for treating certain medical indications provided herein. The present invention relates to the use of the active pharmaceutical ingredient of (a) an indole of the genus of compounds of structure (1), (2), (3), (b) a psilocybin analogue of Table (1), (c) a psilocybin analogue of Table (2), or (d) a combination thereof. The pharmaceutical formulations and compositions are intended for transdermal delivery of the active pharmaceutical ingredient of (a) an indole of the genus of compounds of structure (1), (2), (3), (b) a psilocybin analogue of Table (1), (c) a psilocybin analogue of Table (2), or (d) a combination thereof in a subject in need thereof. The transdermal formulations can be made in the form of sprayable liquids, gels, creams, lotions, ointments, and transdermal patches, and are applied topically to the desired area.

[0079] Certain embodiments relate to the use of the active pharmaceutical ingredient of (a) the indole of the genus of the structure (1), (2), (3), (b) the psilocybin analogue of the structure (1), (2), (3), (b) the psilocybin analogue of the structure (1), (c) the psilocybin analogue of the structure (2), (d) the psilocybin analogue of the structure (2 ...) (c) the psilocybin analogue of the structure (2) (c) the psilocybin analogue of the structure (2) (c) the psilocybin analog

[0080] In certain embodiments, the pharmaceutical formulation may be formulated for immediate release of the API. In certain embodiments, the immediate release formulation is a transdermal or nasal composition.

[0081] In certain embodiments, the pharmaceutical formulation may be formulated for immediate release of the API. In certain embodiments, the immediate release formulation is an oral composition.

[0082] In certain embodiments, the pharmaceutical formulation may be formulated for modified release of the API. In certain embodiments, the immediate release formulation is a transdermal composition.

[0083] In certain embodiments, the pharmaceutical formulation may be formulated for modified release of the API. In certain embodiments, the immediate release formulation is an oral composition.

[0084] In certain embodiments, the transdermal compositions include transdermal patches or intranasal formulations that deliver the pharmaceutical active ingredient across the skin or mucosa into the bloodstream. In certain embodiments, embodiments herein include the use of an active pharmaceutical ingredient of (a) an indole compound of the genus of structure (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, to prepare a pharmaceutical composition for treating neurological, mood, and abuse disorders, wherein the composition is prepared for transdermal or intranasal administration.

[0085] In certain embodiments, formulations of active pharmaceutical ingredients (a) indoles of the genus of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, provide immediate release of the active pharmaceutical ingredient into plasma upon transdermal, nasal, or oral administration. In certain embodiments, formulations comprising active pharmaceutical ingredients (a) indoles of the genus of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the active pharmaceutical ingredient and optionally one or more excipients.

[0086] Certain embodiments of the transdermal, intranasal, or oral formulations of the present invention use psilocybin and psilocybin analogs and combinations thereof, which are well described in the art and may be obtained synthetically or bioengineered; or may be extracted from naturally occurring mushrooms.

[0087] Certain embodiments of the transdermal, intranasal, or oral formulations of the present invention employ psilocybin and psilocybin analogs and combinations thereof, which may be obtained synthetically or bioengineered using the novel chemical synthesis or extraction techniques described herein; or may be extracted from naturally occurring mushrooms.

[0088] In certain embodiments, the transdermal pharmaceutical administration composition is in the form of a sprayable liquid, gel, cream, lotion, ointment and transdermal patch, and the pharmaceutical active ingredient is infused with non-active ingredients that enhance the delivery properties of the composition and stabilize the pharmaceutical active ingredient. In one embodiment, the permeation enhancer can be a non-active ingredient. The permeation enhancer can include fatty acids and oils, which can be, but are not limited to, castor oil, coconut oil, medium chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, shea butter, or other esters, triglycerides, or functional derivatives thereof.

[0089] In certain embodiments, surfactants may be used in transdermal delivery systems as emulsifiers and stabilizers, and can encapsulate drugs for better stability and permeability.Surfactants include, but are not limited to, polysorbates (e.g., Tween®, polysorbate 20), sorbitan (Span®), phospholipids (lecithin), lauryl sulfate, betaine, propionate, fatty alcohols and alkanolamides, fatty acid esters, amine oxides, myristates, and azones.

[0090] In certain embodiments, co-solvents may be used in transdermal formulations to improve drug solubility and permeability while acting as humectants for better skin feel. Common co-solvents include, but are not limited to, alcohols such as ethanol, isopropanol, glycerin, propylene glycol, dipropylene glycol, polyethylene glycol, diethylene monoethyl ether, cremophor, siloxane, polyethylene, and water.

[0091] In certain embodiments, thickeners can be used in transdermal formulations to reduce separation and provide a suitable matrix for modified delivery.Common thickeners include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenans, gums, resins, polysaccharides, and high melting waxes and oils, such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosins, resins, paraffin and petrolatum.

[0092] In certain embodiments, tackifiers can be used in transdermal formulations to enhance adhesion for extended wear. Common tackifiers include, but are not limited to, gums, resins (natural or modified), carbomers, or other natural or synthetic polymers.

[0093] In certain embodiments, preservatives can be used in transdermal formulations to improve formulation stability and retard microbial growth.Common preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chloride, phenol, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts and alcohol.Finally, formulations are typically emulsified with hydrophilic components such as water or Aloe barbadensis juice.

[0094] In certain embodiments, formulations containing active pharmaceutical ingredients of (a) an indole of structure (1) or (b) a psilocybin analog and combinations thereof provide a controlled release of the active pharmaceutical ingredient transdermally upon administration. In certain embodiments, the formulations containing active pharmaceutical ingredients include a therapeutically or prophylactically effective amount of the active pharmaceutical ingredient(s) and a drug release control component capable of controlled, sustained release of the active pharmaceutical ingredient directly into the bloodstream.

[0095] In certain embodiments, the transdermal dosage form is a transdermal delivery device.Any device conventional in the art for transdermally delivering therapeutic agent to patient can be used for transdermally delivering the composition of the present invention and as a transdermal delivery device.For example, the transdermal delivery device can be a reservoir type transdermal delivery device, a polymer matrix type transdermal delivery device, or a drug-in-adhesive type transdermal delivery device or a multilaminate type transdermal delivery device.The transdermal delivery device is designed to deliver the therapeutically effective amount of the pharmaceutical active ingredient of the present invention when it contacts with the skin of a patient.

[0096] In certain embodiments, the transdermal delivery device is a drug-containing adhesive type device that includes a pharmaceutical active dispersed directly in a pressure-sensitive adhesive matrix. The adhesive matrix is ​​preferably supported on the top surface by an impermeable backing film and on the side facing the skin by an impermeable release liner. To administer the pharmaceutical active, the release liner is removed to expose the adhesive matrix and the device is contacted with the skin. The adhesive matrix adheres the device to the skin and typically functions to control the delivery rate of the pharmaceutical active. Similar to the polymer matrix design, the drug-containing adhesive design allows the pharmaceutical active to diffuse out of the adhesive matrix, contact the patient's skin, and permeate the skin. The delivery rate of the pharmaceutical active is usually determined by the diffusion rate of the pharmaceutical active(s) from the adhesive matrix. For longer extended delivery, multiple drug-containing adhesive layers can be stacked together between rate-controlling membranes. The delivery rate ensures that an effective amount of the pharmaceutical active is delivered to the patient in need of the pharmaceutical active.

[0097] In certain embodiments, the reservoir-type transdermal delivery device preferably comprises a reservoir (usually liquid or semi-solid) located between an impermeable backing film and a rate-controlling membrane covered with a pressure-sensitive adhesive skin contact layer. The reservoir may be a solution or dispersion and contains the composition of the present invention. The transdermal delivery device is preferably supported by an impermeable backing film, and the adhesive surface is protected by a release liner. To administer the active pharmaceutical ingredient of the present invention, the release liner is peeled off to expose the pressure-sensitive adhesive, which is then contacted with the skin. The active pharmaceutical ingredient of the present invention can permeate through the rate-controlling membrane, permeate through the rate-controlling membrane and adhesive, contact the skin, and permeate the skin. The delivery rate of the active pharmaceutical invention is usually determined by the rate at which the active pharmaceutical ingredient permeates the rate-controlling membrane.

[0098] In certain embodiments, the transdermal delivery device is a polymer matrix design. In the polymer matrix design, the psilocybin analogs and combinations thereof are dispersed in a polymer matrix that controls the delivery rate of the pharmaceutical active. Preferably, the polymer matrix reservoir is supported on an impermeable backing layer. An adhesive layer is attached to the surface of the polymer matrix. To administer the pharmaceutical active, the release liner is removed to expose the polymer matrix and the ring of pressure-sensitive adhesive, and the device is contacted with the skin. The adhesive holds the device against the skin such that the polymer matrix is ​​in direct contact with the skin. When the polymer matrix contacts the skin, the pharmaceutical active(s) diffuse out of the polymer matrix, contact the patient's skin, and permeate the skin. The delivery rate of the pharmaceutical active is usually determined by the diffusion rate of the pharmaceutical active from the polymer matrix.

[0099] The adhesives may include cross-linking monomer units or sites and be incorporated into the adhesive polymer. For example, cross-linking monomers may be incorporated into polyacrylate polymers. The cross-linking monomers may provide sites for cross-linking the polymer matrix after, for example, psilocybin analogs and combinations thereof are dispersed in the polymer. Known adhesives include cross-linking monomers for polyacrylate polymers, such as polymethacrylic acid esters of polyols, such as butylene diacrylate, butylene dimethacrylate and trimethylolpropane trimethacrylate, polyisobutylene-type adhesives and silicones. Other monomers that provide cross-linking sites include allyl acrylate, allyl methacrylate, diallyl maleate, silyl ethers, and silanes. The monomers are then polymerized using methods known to those skilled in the art to include an adhesive matrix of polyacrylate (acrylic), polysiloxane (silicone) or polyisobutylene (or other rubber) containing cross-linking agents, functional groups or vinyl acetate to suspend, stabilize and release the pharmaceutical active ingredient.

[0100] In one embodiment of the present invention, the transdermal delivery device may optionally include one or more permeation enhancers that increase the rate at which the medicament active ingredient permeates through the patient's skin. Preferably, the permeation enhancer is capable of permeating through a rate-controlling membrane or diffusing from a polymeric or adhesive matrix to contact the patient's skin and improve the permeation of the medicament active ingredient as defined herein through the patient's skin. Permeation enhancers suitable for use in the transdermal delivery devices and compositions of the present invention include, for example, C 2-4Examples of suitable permeation enhancers include alcohols such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, polysorbates, sorbitan, fatty acids, esters of fatty acids having about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoester content of at least 51% (monoesters are those having 10 to 20 carbon atoms), and mixtures of mono-, di-, and tri-glycerides of fatty acids. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Monoglyceride permeation enhancers include, for example, glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt skin membranes and increase API permeability. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt skin membranes and increase API permeability. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene, and humulene. In certain embodiments, the transdermal patch described herein is used co-administered with a permeation enhancer. In certain embodiments, the permeation enhancer can include oils, which can be, but are not limited to, castor oil, coconut oil, medium chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, and shea butter. Other permeation enhancers for use in transdermal patches include, for example, C 2-4Examples of suitable permeation enhancers include alcohols such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, polysorbates (Tween®), sorbitan (Span®), fatty acids, esters of fatty acids having about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoester content of at least 51% (monoesters are those having 10 to 20 carbon atoms), and mixtures of mono-, di-, and tri-glycerides of fatty acids. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Monoglyceride permeation enhancers include, for example, glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt skin membranes and increase API permeability. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene, and humulene.

[0101] In certain embodiments, the delivery rate of the active pharmaceutical ingredient may be delivered with a once-daily transdermal patch application. In certain embodiments, the delivery rate of the API may be delivered over a period of 6-12 hours. In certain embodiments, the delivery rate of the API may be delivered over a period of 12-24 hours. In certain embodiments, the delivery rate of the API may be delivered over a period of 24-48 hours. In other embodiments, the transdermal patch may be applied once every 2 days; once every 3 days; once every 4 days; once every 5 days; once every 5 days; or once every 7 days. The delivery rate options of the transdermal patch facilitate patient compliance while delivering steady-state systemic safe and effective drug concentrations.

[0102] As described herein, certain embodiments provide transdermal formulations of the pharmaceutical active ingredients described herein that are useful in methods related to different dosages and / or administration periods; providing alternative pharmacokinetic, pharmacodynamic, and / or safety profiles; enabling long-term maintenance treatment; providing testing of new indications for psilocybin analogs; and other potential advantageous benefits. In certain embodiments, the formulations provided herein (e.g., sprayable solutions, gels, creams, lotions, ointments, or transdermal patches for dermal delivery of pharmaceutical active ingredients) contain a specific pharmacoactive ingredient ((a) an indole of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2), alone or in combination) in a specific pharmacologic active amount. In certain embodiments, the particular amount of an active pharmaceutical ingredient disclosed herein in a formulation may be, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, at least about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, About 36 mg, about 37 mg, about 38 mg, about 39, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or at least 100 mg.In certain embodiments, the specified amount of psilocybin analog in the formulation may be, for example, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, , at least about 26 mg, at least about 27 mg, at least about 28 mg, at least about 29 mg, at least about 30 mg, at least about 31 mg, at least about 32 mg, at least about 33 mg, at least about 34 mg, at least about 35 mg, at least about 36 mg, at least about 37 mg, at least about 38 mg, at least about 39 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, or at least 100 mg.

[0103] In more specific embodiments, the particular amount of an active pharmaceutical ingredient disclosed herein in the formulation is, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg about 23 mg, about 24 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg about 60 mg, about 65 mg, about 70 mg, about 75 mg about 80 mg, about 85 mg, about 90 mg or at least 100 mg.

[0104] In more specific embodiments, the specified amount of the active pharmaceutical ingredient in the formulation is, for example, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, or at least 100 mg.

[0105] In certain embodiments, the active pharmaceutical ingredient in the pharmaceutical formulation is, for example, about 5 mg to 100 mg, or about 5 mg to 25 mg, or about 25 mg to 50 mg, or about 50 mg to 75 mg, or about 75 mg to 100 mg.

[0106] As described herein, certain embodiments provide transdermal formulations of pharmaceutical active ingredients described herein with respect to skin application size for transdermal delivery devices. Application area is an important metric for determining drug flux, varying dosage, and providing sufficient area for efficient transdermal delivery. In certain embodiments, the API ((a) an indole compound of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2), alone or in combination) is contained within a drug delivery device (e.g., a sprayable liquid, gel, cream, lotion, ointment, or transdermal patch) and is applied within a range of 1 cm or less, or at least 2 cm. 2 , at least 3 cm 2 , at least 4 cm 2 , at least 5 cm 2 , at least 6 cm 2, at least 7 cm 2 , at least 8cm 2 , at least 9 cm 2 , at least 10 cm 2 , at least 15 cm 2 , at least 20 cm 2 , at least 25 cm 2 , at least 30 cm 2 , at least 35 cm 2 , at least 40cm 2 , at least 45cm 2 , at least 50 cm 2 , at least 60cm 2 , at least 70cm 2 , at least 80cm 2 , at least 90cm 2 , or at least 100 cm 2 , at least 150cm 2 , at least 200 cm 2 , at least 250cm 2 , at least 300 cm 2 , at least 350cm 2 , at least 400 cm 2 , at least 450cm 2 , at least 500 cm 2 , at least 600 cm 2 , at least 700 cm 2 , at least 800 cm 2 , at least 900 cm 2 , or at least 1000 cm 2 is applied to the skin of a human or mammal over an area of ​​about 100 mm.

[0107] In certain embodiments, the APIs, alone or in combination, are contained within a drug delivery device (e.g., a sprayable liquid, gel, cream, lotion, ointment, or transdermal patch) and are within a range of less than 1 cm, or at least 2 cm. 2 , at least 3 cm 2 , at least 4 cm 2 , at least 5 cm 2 , at least 6 cm 2 , at least 7 cm 2, at least 8cm 2 , at least 9 cm 2 , at least 10 cm 2 , at least 15 cm 2 , at least 20 cm 2 , at least 25 cm 2 , at least 30 cm 2 , at least 35 cm 2 , at least 40cm 2 , at least 45cm 2 , at least 50 cm 2 , at least 60cm 2 , at least 70cm 2 , at least 80cm 2 , at least 90cm 2 , or at least 100 cm 2 is applied to the skin of a human or mammal over an area of ​​about 100 mm.

[0108] In one embodiment, the APIs, alone or in combination, are 2 ~10cm 2 , about 10cm 2 ~40cm 2 , about 40cm 2 ~100cm 2 , or more preferably 5 cm 2 ~40cm 2 is applied to the skin of a human or mammal over an area of ​​about 100 mm.

[0109] In certain embodiments, the active pharmaceutical ingredient is delivered in an oral pharmaceutical formulation composition comprising a capsule or tablet that delivers the API through the esophageal, gastric, and / or intestinal membranes into the bloodstream.

[0110] In certain embodiments, an oral composition is swallowed and the active pharmaceutical ingredient is further delivered through the esophageal, stomach, and / or intestinal membranes into the bloodstream.

[0111] In certain embodiments, oral compositions include tablets, cachets, or strips that deliver the active pharmaceutical ingredient through the sublingual, buccal, or other oral mucosa and into the bloodstream.

[0112] In certain embodiments, oral compositions include oral patches or films that deliver the active pharmaceutical ingredient into the bloodstream through the sublingual, buccal, or other oral mucosa.

[0113] In certain embodiments, an oral composition is swallowed and the active pharmaceutical ingredient is further delivered through the esophageal, stomach, and / or intestinal membranes into the bloodstream.

[0114] In certain embodiments, oral compositions include powders, solutions, or suspensions that deliver the active pharmaceutical ingredient through the sublingual, buccal, or other oral mucosa and into the bloodstream.

[0115] In certain embodiments, an oral composition is swallowed and the active pharmaceutical ingredient is further delivered through the esophageal, stomach, and / or intestinal membranes into the bloodstream.

[0116] In certain embodiments, formulations of active pharmaceutical ingredients (a) indoles of the genus of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, provide immediate release of the active pharmaceutical ingredient into plasma upon oral administration. In certain embodiments, formulations comprising active pharmaceutical ingredients (a) indoles of the genus of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the active pharmaceutical ingredient and optionally one or more excipients.

[0117] In certain embodiments, formulations of active pharmaceutical ingredients (a) indoles of the genus of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, provide modified release of the active pharmaceutical ingredient into plasma upon oral administration. In certain embodiments, formulations comprising active pharmaceutical ingredients (a) indoles of the genus of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the active pharmaceutical ingredient and optionally one or more excipients.

[0118] In certain embodiments, embodiments herein include the use of an active pharmaceutical ingredient of (a) an indole compound of the genus of structure (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for the preparation of a pharmaceutical composition for treating neurological, mood and abuse disorders, wherein the composition is formulated for oral administration.

[0119] In certain embodiments, embodiments herein include the use of an active pharmaceutical ingredient of (a) an indole compound of the genus of structure (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for the preparation of a pharmaceutical composition for treating neurological, mood and abuse disorders, wherein the composition is formulated for oral administration.

[0120] In certain embodiments, the oral compositions contain non-active ingredients that enhance the drug delivery properties and stabilize the active ingredient.

[0121] In one embodiment, fillers may be included as non-active ingredients. Fillers can act as a matrix to affect dissolution time or as a binder to improve tablet stability. Fillers can include, but are not limited to, starch, citric acid, tartaric acid, bicarbonate, phosphate, polyvinylpyrrolidone, cellulose (natural and modified), croscarmelose, glycolate, acrylate, acetate, gelatin, gum, alginate, pectin, chitosan, chitin, salt, polysaccharide, mucilage, sugar, sucrose, lactose and dextrose.

[0122] In another embodiment, lubricants may be included as non-active ingredients. Lubricants act to improve powder flow or reduce friction of manufactured parts. These may include, but are not limited to, magnesium stearate, talc, stearic acid, and silicon dioxide.

[0123] In yet another embodiment, flavorings may be included as non-active ingredients. Flavorings can mask the taste of bittering agents or improve the taste of the oral composition. These include, but are not limited to, sugar, dextrose, sucrose, sucralose, stevia, essential oils, citric acid, and natural or artificial flavors. Optionally, colorings can be included in the powder to improve visual properties or to differentiate product offerings. These colorings can be natural or artificial dyes, pigments, chelates, or metals.

[0124] In certain embodiments, oral compositions contain surfactants, which are emulsifiers and stabilizers that can encapsulate drugs for better stability, taste, permeability and drug release properties.Surfactants include, but are not limited to, vegetable oils, triglycerides, esters, polysorbates (Tween®), sorbitan (Span®), phospholipids (e.g., lecithin), lauryl sulfate, betaine, propionate, fatty acids, fatty alcohols, saponins and alkanolamides, amine oxides, cyclodextrins, myristates and azones.

[0125] In certain embodiments, oral compositions contain co-solvents to improve drug solubility, dissolution and permeability.Co-solvents include, but are not limited to, alcohols such as ethanol, isopropanol, glycerin, propylene glycol, dipropylene glycol, polyethylene glycol, diethylene monoethyl ether, cremophor, siloxane, polyethylene, and water.

[0126] In certain embodiments, oral compositions contain thickening agents to reduce dissolution and provide a suitable matrix for delivery.Thickening agents include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenans, polysaccharides, and high melting waxes and oils, such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gum, rosin, resin, paraffin and petrolatum.

[0127] In certain embodiments, the oral composition contains preservatives to improve formulation stability and retard microbial growth.Preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chloride, phenol, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts and alcohols.

[0128] In certain embodiments, oral compositions contain enteric coatings to modify and extend release in the digestive tract. Enteric coatings include high melting point waxes, fatty acids, sugars, fibers, polymers, and the like.

[0129] In another embodiment, the oral composition contains non-active ingredients that alter the physical properties of the drug delivery system, such as pH, solubility, dissolution, hydrophobicity, and stability. Many such compounds are known to those skilled in the art.

[0130] In certain embodiments, the oral composition contains a membrane permeation enhancer to increase systemic delivery. Suitable permeation enhancers for use in the oral composition include, for example, C 2-4Examples of suitable permeation enhancers include alcohols such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, sorbitan (Span®), polysorbates (e.g., Tween®, polysorbate 20), fatty acids, esters of fatty acids having about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoester content of at least 51% (monoesters are those having 10-20 carbon atoms), and mixtures of mono-, di-, and tri-glycerides of fatty acids. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Monoglyceride permeation enhancers include, for example, glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt skin membranes and increase API permeability. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt skin membranes and increase API permeability. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene, and humulene.

[0131] In certain embodiments, the active pharmaceutical ingredient of (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2), and combinations thereof, is included in at least one matrix of the oral composition. In another embodiment, the active pharmaceutical ingredient of (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2), and combinations thereof, is included in at least two matrices of the oral composition. In another embodiment, the active pharmaceutical ingredient of (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (1), and combinations thereof, is included in at least three matrices of the oral composition. In another embodiment, the active pharmaceutical ingredient (a) an indole of the genus of structure (1), (2), (3), (b) a compound of table (1), (c) a psilocybin analog, or (d) a compound of table (2), and combinations thereof, is included in at least four matrices of the oral composition. In yet another embodiment, the active pharmaceutical ingredient (a) an indole of the genus of structure (1), (2), (3), (b) a compound of table (1), (c) a psilocybin analog, or (d) a compound of table (2), and combinations thereof, is included in at least five matrices of the oral composition.

[0132] In certain embodiments, the active pharmaceutical ingredient is a single active ingredient. In a preferred embodiment, (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of table (1), (c) a psilocybin analog, or (d) a compound of table (2) is administered orally in a capsule. In a preferred embodiment, (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of table 1, (c) a psilocybin analog, or (d) a compound of table (2) is administered orally in a tablet. In a preferred embodiment, (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of table (1), (c) a psilocybin analog, or (d) a compound of table (2) is administered orally in a wafer. In a preferred embodiment, (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is administered orally in a strip. In a preferred embodiment, (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is administered orally in a transdermal patch. In a preferred embodiment, (a) an indole of a compound of the genus of structures (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is administered orally in a powder. In a preferred embodiment, (a) an indole of a compound of the genus of structure (1), (2), or (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is administered orally in a suspension. In a preferred embodiment, (a) an indole of a compound of the genus of structure (1), (2), or (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is administered orally in a liquid formulation.

[0133] In another embodiment, a mixture of psilocybin analogs is delivered in the same oral composition as described herein. In a preferred embodiment, (a) an indole of a compound of the genus of structure (1), (2), (3), (b) a compound of table (1), (c) a psilocybin analog, or (d) a compound of table (2) is orally administered alone or in combination with other (a) an indole of a compound of the genus of structure (1), (2), (3), (b) a compound of table (1), (c) a psilocybin analog, or (d) a compound of table (2) in the oral composition described herein.

[0134] In certain embodiments, the oral composition comprises at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, and / or at least 500 mg of an active pharmaceutical ingredient of (a) an indole compound of the genus of structure (1), (2), (3), (b) a psilocybin analog of Table (1), (c) a psilocybin analog of Table (2), or combinations thereof.

[0135] In certain embodiments, systemic drug release of oral compositions containing an active pharmaceutical ingredient of (a) an indole compound of the genus of structure (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2), and combinations thereof, occurs with a therapeutically active onset of 1 minute or less, 3 minutes or less, 5 minutes or less, 7 minutes or less, 9 minutes or less, 11 minutes or less, 13 minutes or less, 15 minutes or less, 17 minutes or less, 19 minutes or less, 21 minutes or less, 23 minutes or less, 25 minutes or less, 27 minutes or less, 30 minutes or less, 45 minutes or less, 60 minutes or less, 90 minutes or less, 120 minutes or less, 150 minutes or less, and 180 minutes or less.

[0136] In certain embodiments, the duration of therapeutic or prophylactic effect of an oral composition containing an active pharmaceutical ingredient of (a) an indole compound of the genus of structure (1), (2), (3), (b) a compound of Table (1), (c) a psilocybin analog, or (d) a compound of Table (2), and combinations thereof, lasts for at least 5 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 18 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, and at least 1 week.

[0137] As described herein, certain embodiments provide oral compositions of the active pharmaceutical ingredients described herein that are useful in methods involving different dosages and / or durations of administration; providing alternative pharmacokinetic, pharmacodynamic, and / or safety profiles; enabling long-term maintenance treatment; providing for the testing of new indications for psilocybin analogs; and other potentially advantageous benefits.

[0138] Provided herein are methods of preventing, managing and treating post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression, anxiety, neurological, mood or addictive disorders including addiction, substance abuse including, but not limited to, opioid addiction, alcoholism, nicotine addiction, cannabinoid addiction, headaches, central nervous system inflammation, dementia, cognition and memory by administering psilocybin analogs transdermally, intranasally or orally.

[0139] In certain embodiments, the active pharmaceutical ingredient is a single active pharmaceutical ingredient. In preferred embodiments, (a) an indole compound of the structural genus of formula (1), (2), (3), (b) a compound of table (1), (c) a psilocybin analog, or (d) a compound of table (2) is delivered by the transdermal patch delivery system. In preferred embodiments, the active pharmaceutical ingredient is delivered transdermally by the transdermal patch delivery system.

[0140] In another embodiment, a mixture of psilocybin analogs are delivered in the same transdermal delivery system. In a preferred embodiment, a psilocybin analog is delivered transdermally in a transdermal patch delivery system, either alone or in combination with other psilocybin analogs.

[0141] In another embodiment, the pharmaceutical active ingredient is co-administered with one or more therapeutic agents. The co-administered agent can be an MAOI. In another embodiment, a compound from another class of neurologically active agents is co-administered to provide synergistic therapeutic effects. Other neurologically active agents include compounds that fall into the following classes of compounds: antipsychotics, antidepressants, anxiolytics, stimulants, reuptake inhibitors (SSRIs or SSNRIs), monoamine oxidase inhibitors (MAOIs), cognitive enhancers, tricyclic antidepressants, mood stabilizers, NMDA antagonists and 5-HT antagonists.

[0142] In yet another embodiment, (a) indoles of the genus of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), either alone or in admixture, are co-administered with one or more therapeutic agents to reduce substance abuse. For the treatment of opioid addiction, other co-administered compounds can include methadone, buprenorphine, naloxone, naltrexone, etc. For the treatment of alcoholism, other co-administered compounds can include ethyl alcohol, disulfiram, naltrexone, acamprosate, benzodiazepines, etc. For the treatment of nicotine addiction, other co-administered compounds can include low-dose nicotine, bupropion, varenicline, etc.

[0143] Provided herein are methods of preventing, managing and treating post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression, anxiety, neurological, mood or addictive disorders including addiction, substance abuse including, but not limited to, opioid addiction, alcoholism, nicotine addiction, cannabinoid addiction, headaches, central nervous system inflammation, dementia, cognition and memory by transdermally administering a psilocybin analog. EXAMPLES

[0144] Example 1: Purified N,N-dimethyltryptamine (DMT 1.8% w / w, wet) was dissolved in a combination of ethyl acetate (7.2% w / w, wet) and ethanol (7.2% w / w, wet) and incorporated into Duro-Tak 4098 acrylate adhesive (83.8% w / w, wet) and mixed thoroughly. The mixture was formulated onto the siliconized side of a Scotchpak 9709 release liner at a thickness of 150 μm. The formulation was dried at 75°C and laminated onto an occlusive Scotchpak 9733 polyester backing before being applied to a transdermal patch at a thickness of 10 cm. 2 The final transdermal patches were stored in heat-sealed aluminum pouches to reduce oxidation.

[0145] Linear drug release (n=3 transdermal patches) was observed over 72 hours, with over 80% of the DMT released in 72 hours (Figure 1). The mean DMT flux was 37 ug / cm 2* hr over a 72 hour period.

[0146] Example 2: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (8.0% w / w, wet) and incorporated into Duro-Tak 4098 adhesive (90.0% w / w, wet) and mixed thoroughly. The mixture was formulated onto a release liner at a thickness of 250 μm. After the formulation was dried and laminated onto an occlusive backing, the transdermal patch was prepared to a thickness of 10 cm. 2 The final transdermal patch (6.4% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was 43 μg / cm 2* hr over a 72 hour period.

[0147] Example 3: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (8.1% w / w, wet) and incorporated into silicone adhesives Bio PSA 7-4302 (44.9% w / w, wet) and Bio PSA 7-4202 (44.9% w / w, wet) and mixed thoroughly. The mixture was formulated onto a release liner at a thickness of 150 μm. After the formulation was dried and laminated onto an occlusive backing, the transdermal patch was applied to a thickness of 10 cm. 2 The final transdermal patch (3.9% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was 31 μg / cm 2* hr over a 48 hour period.

[0148] Example 4: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (4.0% w / w, wet) and incorporated into Duro-Tak 6908 polyisobutylene adhesive (94.0% w / w, wet) and mixed thoroughly. The mixture was formulated onto a release liner at a thickness of 150 μm. After the formulation was dried and laminated onto an occlusive backing, the transdermal patch was applied to a thickness of 10 cm. 2 The final transdermal patch (5.4% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was 7 μg / cm 2* hr was measured over a 30 hour period.

[0149] Example 5: Purified DMT (3.8% w / w, wet) was dissolved in ethanol (15.9% w / w, wet) and incorporated into Duro-Tak 4098 adhesive (80.3% w / w, wet) and mixed thoroughly. The mixture was formulated onto a release liner at a thickness of 200 μm. After the formulation was dried and laminated onto an occlusive backing, the transdermal patch was prepared to a thickness of 10 cm. 2 The final transdermal patch (10.9% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was 57 μg / cm 2* hr over a 48 hour period.

[0150] Example 6 Purified DMT (4.2% w / w, wet) was dissolved in ethanol (11.2% w / w, wet) and incorporated into Duro-Tak 4098 acrylate adhesive (77.5% w / w, wet), after which isopropyl myristate (7.1% w / w, wet) was added and mixed thoroughly. The mixture was formulated onto a release liner to a thickness of 200 μm. After the formulation was dried and laminated onto an occlusive backing, the transdermal patch was applied to a thickness of 10 cm. 2 The final transdermal patch (10.3% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was 145 μg / cm 2* hr over a 48 hour period.

[0151] Example 7: Purified 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT, 3.2% w / w, wet) was dissolved in ethanol (12.4% w / w, wet) and incorporated into Duro-Tak 4098 acrylate adhesive (84.4 w / w, wet) and mixed thoroughly. The mixture was formulated to a thickness of 200 μm onto the siliconized side of a release liner. After the formulation was dried and laminated onto an occlusive polyester backing, the transdermal patch was coated to a thickness of 10 cm. 2 The final transdermal patch (9.0% w / w 4-AcO-DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average 4-AcO-DMT flux was 98 μg / cm 2* hr over a 48 hour period.

[0152] Example 8: A second DIA containing the excipients listed above is poured directly onto the backing and laminated onto the rate-controlling membrane. The DIA-coated liner from Example 1 is then laminated onto the backing / DIA / membrane material to form a multi-layer delivery system. The transdermal patch is then die-cut to the appropriate size.

[0153] The DIA cast onto the liner (which is then applied directly onto the skin) does not require as high a drug loading as the second DIA, which acts as a reservoir, allowing the drug to diffuse through the rate-controlling membrane after manufacture until equilibrium is achieved between the first DIA. When applied, the second DIA allows the drug to permeate through the membrane and into the skin at zero-order rates until the drug reservoir is fully depleted.

[0154] Example 9: N,N-Dimethyltryptamine (DMT) free base was dissolved in 25 mg / mL acetone. 7 mg / mL fumaric acid was added dropwise to precipitate the DMT fumarate salt. The precipitate was washed twice with fresh acetone and dried under nitrogen.

[0155] DMT fumarate salt (18.0% w / w) was dissolved in deionized water (82.0% w / w) to obtain a therapeutically effective aqueous gel vehicle for intranasal absorption at an appropriate pH = 6. The formulation of DMT fumarate gel can be administered via the nasal cavity in small volumes of 0.04-0.50 mL for therapeutic efficacy. Potency analysis using tryptamine internal standard quantification revealed a DMT free base concentration of 135.5 mg / mL with no other degradation by-products after storage for 106 days under dark conditions at room temperature.

[0156] Example 10: A Franz cell apparatus was used to determine API release and permeation through a human skin simulant (Strat-M membrane, Millipore) to compare patch efficacy for Examples 1-8. The receiving well (10% ethanol in water) was kept at 32 °C throughout the experiment, and all 10 mL was removed per sampling point. Drug flux was determined using the slope of zero-order permeation of the API over the specified time range. In Examples 1-9, potency analysis of the API was achieved using LC-MS, while tryptamine (50 μg / mL) was added as an internal standard and used to quantify the API with UV detection at 280 nm.

[0157] Example 11: Free base 4-AcO-DMT (8% w / w) was dissolved in ethanol (4% w / w) and further added with povidone (2% w / w), butylated hydroxytoluene (1% w / w) and FD&C Blue No.1. This solution was added to Ceolus KG 1000 microcrystalline cellulose (16% w / w) and mannitol (47% w / w) and mixed together and then dried to form a uniformly coated powder. Further, Prosolv HD 90 silicified microcrystalline cellulose (20% w / w), Cabosil silicon dioxide (1% w / w) and magnesium stearate (1% w / w) were added and blended until uniform. A die set and sufficient force were used to form 250 mg tablets for ingestion of 4-AcO-DMT for therapeutic use.

[0158] Example 12: 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethan-1-amine A mixture of tryptamine hydrochloride (1 g, 5.1 mmol) and N-chlorosuccinimide (NCS, 0.69 g, 5.2 mmol) in acetic acid (50 mL) and formic acid (15 mL) was stirred for about 20 minutes. The product 2-chloro-tryptamine (confirmed by 2D NMR spectroscopy) was dried and purified, and 211 mg (1.09 mmol) was further reacted with sodium cyanoborohydride (139.26 mg, 2.22 mmol) in methanol (21 mL) and formaldehyde (0.222 mL, 2.75 mmol) at 0 °C under nitrogen and stirred for 2.5 hours. The reaction was quenched with 1.0 M sodium hydroxide (27 mL) and extracted three times with methyl-tert-butyl ether (MTBE). The residue was dried over sodium sulfate and concentrated to a light brown oil / solid. LC-MS, 1 H and 13 Based on the C NMR data, the final product contained a majority of 2-chloro-N,N-dimethyltryptamine. 12 H 15 N2Cl m / z 222.0924, [M+H] + 223.0997 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.13 (s, 6 H) 2.34 - 2.38 (m, 2 H) 2.68 - 2.80 (m, 3 H) 6.91 - 6.99 (m, 1 H) 7.02 (t, J=7.54 Hz, 2 H) 7.20 (d, J=7.99 Hz, 2 H) 7.40 (d, J=7.81 Hz, 1 H) 11.53 (br s, 1 H)

[0159] Example 13: 2-(2-Bromo-1H-indol-3-yl)-N,N-dimethylethan-1-amine Using previously documented methods, N,N-dimethyltryptamine (2.88 mmol) was synthesized and dissolved in anhydrous acetonitrile (36 mL, 15 mg / mL) under inert conditions. This was combined with copper(II) bromide (1.93 g, 8.65 mmol) and stirred for 2 hours. The reaction was quenched with 40 mL of water and 100 mL of EtOAc was added followed by 40 mL of saturated ammonium carbonate. The organic layer was washed, dried over sodium sulfate, filtered and concentrated to a light brown oil (302.3 mg). The final major product 2-bromo-N,N-dimethyltryptamine was confirmed by LC-MS, 1D and 2D NMR spectroscopy. The formula of the product: C 12 H 15 N2Br m / z 266.0419, [M+H] + 267.0491 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.21 (s, 6 H) 2.38 - 2.47 (m, 2 H) 2.73 - 2.88 (m, 3 H) 6.93 - 7.03 (m, 1 H) 7.03 - 7.11 (m, 1 H) 7.28 (br d, J=7.99 Hz, 1 H) 7.46 - 7.51 (m, 1 H) 11.61 (br s, 1 H)

[0160] Example 14: 2-Bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate Using previously documented methods, 4-acetoxy-N,N-dimethyltryptamine (14.9 mg, 0.06 mmol) was synthesized and dissolved in anhydrous acetonitrile (1 mL) under inert conditions. Copper(II) bromide (40.5 mg, 0.18 mmol) was added and the reaction was stirred for 2 h. Upon workup, the major product 2-bromo-4-acetoxy-N,N-dimethyltryptamine was confirmed by LC-MS and 1D NMR spectroscopy. The formula of the product is: C 14 H 17 N2O2Brm / z 324.0473, [M+H] +325.0546 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.21 - 2.25 (m, 13 H) 2.32 - 2.39 (m, 12 H) 2.71 - 2.75 (m, 3 H) 6.74 (d, J=7.63 Hz, 1 H) 7.06 - 7.10 (m, 2 H) 7.18 (d, J=8.17 Hz, 2 H) 11.91 (s, 1 H)

[0161] Example 15: 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine Using previously documented methods, 4-methoxy-N,N-dimethyltryptamine (130 mg, 0.6 mmol) was synthesized and dissolved in anhydrous acetonitrile (3.6 mL). Copper(II) chloride (241 mg, 1.8 mmol) was added and stirred overnight under inert atmosphere. Quenched with water (14 mL), extracted three times with EtOAc and washed with saturated ammonium carbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to give an orange semi-solid (38.2 mg, 25% yield). This was purified by HPLC to yield 2-chloro-4-methoxy-N,N-dimethyltryptamine, which was confirmed by LC-MS, 1D and 2D NMR spectroscopy.

[0162] Product formula: C 13 H 17 N2OClm / z 252.1029, [M+H] + 253.1102 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.27 - 2.39 (m, 14 H) 2.50 - 2.60 (m, 6 H) 2.89 - 3.05 (m, 5 H) 3.84 - 3.99 (m, 9 H) 6.54 - 6.66 (m, 2 H) 6.92 (d, J=8.17 Hz, 1 H) 7.03 - 7.19 (m, 2 H) 11.71 (s, 1 H)

[0163] Example 16: 1-(-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide The nitro group of N-methyl-3-nitrobenzenesulfonamide is subsequently reduced to the aniline via palladium on carbon (H2 / Pd / C) and aqueous HCl in ethanol solvent. This product is treated with sodium nitrite to give the diazonium salt, which is subsequently reduced to the hydrazine using SnCl2 (all at 0°C). The hydrazone is generated upon condensation with 4,4-dimethyoxy-N,N-dimethylbutylamine in aqueous hydrochloric acid. The final product is generated via a Fischer indole reaction in which the hydrazone reacts with polyphosphoric acid in refluxing chloroform to initiate the cyclization.

[0164] This compound can be further halogenated at the C-2 position following the copper(II) halide protocol of the previous example.

[0165] Example 17: Computational Analysis Six different receptor models were tested according to the crystal structures recorded in the RCSB Protein Data Bank (PDB) for various serotonin receptors and sigma-1. These receptor structures included 5-HT 2A , 5-HT 2B , 5-HT 1B , and σ1 (PDB IDs are also given in the column headings).

[0166] For each static protein structure, PDB files of crystal structures containing the tryptamine scaffold and the most chemically similar bound ligand were used to maximize accuracy (e.g. LSD and ergotamine bound). The overall workflow was performed using various aspects of the Schroedinger software suite. 3D SMILES for each ligand were uploaded according to literature recommended protonation and / or charge of tryptophan, and various conformers were generated and minimized using Schroedinger LigPrep. A final list of compounds was screened using Glide scores generated by Schroedinger Glide, including the structures listed in Table 3. Validation of the technique was performed by including known agonists of the 5-HT and σ1 receptors and compared to experimental binding assay data. Docking scores for the known agonists and experimental data were comparable and within experimental error for activity. For example, the (+)-LSD enantiomer was more strongly associated with 5-HT than the (-)-LSD enantiomer. 2A It showed greater activity in vitro at the receptor and the values ​​rendered in our calculations show the same trend in activity.

[0167] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0168] This disclosure has been described in connection with specific embodiments and examples. However, unless otherwise indicated, the invention as claimed should not be unduly limited to such specific embodiments and examples. In certain embodiments, for example, the following are provided: (Item 1) A compound of the formula: Structure (2)

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Claims

1. A compound of the formula: Structure (2) 【Chemistry 5】 In the formula, R １ is Br, H, F, Cl, I or CF ３ R ２ is H or CH ３ and R ３ and R ４ are each independently selected from CH ３ , C ２ H ５ , (H ３ C) ２ CH, or H ２ C=CH-CH ２ R ５ is OCH ３ , OCOCH ３ , O-phosphate, O-polyethylene glycol (PEG), O-(CH ２ ) ２ (COOH) ２ (Succinate), O-(CH ２ ) ２ (COOH) (hemisuccinate) and CH ２ SO ２ N.H.C.H. ３ (sulfonamide); R １ is H, then R ５ is CH ２ SO ２ N.H.C.H. ３ and a pharma- ceutically acceptable salt, or solvate thereof.

2. 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine, 2- 2. The compound of claim 1, selected from the group consisting of (2-bromo-4-methoxy-1H-indol-3yl)-N,N-dimethylethan-1-amine, 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, and 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide.

3. R ５ But OCOCH ３ 2. The compound of claim 1,

4. R １ The compound of claim 1 or claim 3, wherein is Br.

5. R ２ The compound of claim 1, claim 3 or claim 4, wherein is H.

6. R ３ But, CH ３ The compound according to any one of claims 1 or 3 to 5,

7. R ３ and R ４ Each of the ３ The compound according to any one of claims 1 or 3 to 6,

8. The compound is 【Chemistry 7】 or a pharma- ceutically acceptable salt or solvate thereof.

9. A pharmaceutical composition comprising an active pharmaceutical ingredient, said active pharmaceutical ingredient being a compound according to any one of claims 1 to 8.

10. 10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is for oral, nasal or transdermal delivery of the active pharmaceutical ingredient.

11. 11. The pharmaceutical composition of claim 9 or claim 10, wherein the pharmaceutical composition is a transdermal composition, the transdermal composition being selected from the group consisting of a sprayable liquid, a gel, a cream, a lotion, an ointment, or a transdermal patch.

12. 11. The pharmaceutical composition of claim 9 or claim 10, wherein the pharmaceutical composition is an oral composition, the oral composition being a tablet, capsule, cachet or strip.

13. 11. The pharmaceutical composition of claim 9 or claim 10, wherein the pharmaceutical composition is a nasal composition, the nasal composition being selected from the group consisting of a gel, a sprayable liquid, an emulsion, or an ointment.

14. The compound is 【Chemistry 7】 or a pharma- ceutically acceptable salt or solvate thereof.

15. 2-Bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol.

16. 2-Chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol.

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