Pharmaceutically acceptable salts of psilocin and uses thereof

Abstract

The present invention features pharma- ceutically acceptable salts of psilocin and compositions thereof, which can be used to treat a disease or condition, such as neurological injury, inflammatory disease, chronic pain, or psychiatric disorder, in a subject in need thereof.

Description

[Background technology]

[0001] There has been considerable interest in the therapeutic application of psilocin based on evidence of its potential therapeutic benefits in a variety of clinical applications, including psychiatric conditions, pain disorders, and neurological conditions. However, due to the physical properties of psilocin in the solid state, such as its poor crystallinity limiting the ability to improve bulk purity upon crystallization, its susceptibility to autocatalytic oxidation during handling and long-term storage, and its poor water solubility, there is a demand for psilocin salts and formulations with improved stability, physical properties, and handling characteristics. Summary of the Invention

[0002] The present invention features a pharma- ceutically acceptable salt of psilocin, the pharma-ceutically acceptable salt being a 1:1 benzoate salt. In another aspect, the invention features a pharma- ceutically acceptable salt of psilocin, the pharma- ceutically acceptable salt being a 1:1 tartrate salt.

[0003] In a further aspect, the invention features a pharma- ceutically acceptable salt of psilocin, the pharma- ceutically acceptable salt being a 2:1 succinate salt. In another aspect, the invention features a pharma- ceutically acceptable salt of psilocin, the pharma-ceutically acceptable salt being a 2:1 salt of 1,5-naphthalenedisulfonic acid, a 1:1 salt of 1,5-naphthalenedisulfonic acid, or a mixture thereof.

[0004] In a related aspect, the invention features a pharmaceutical composition including a psilocin salt of the invention and a pharma- ceutically acceptable excipient, which can be any pharma- ceutically acceptable excipient described herein.

[0005] In another aspect, the present invention provides an aqueous solution of (i) a phosphate buffer solution having a pH of about 3 to about 9 (e.g., 3±1, 4±1, 5±1, 6±1, 7±1, 8±1, and 9±1), and (ii) a phosphate buffer solution having a pH of about 0.1 mg / mL to about 50 mg / mL (e.g., 0.1±0.1 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.5 mg / mL, 1±0.5 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, 15±1 mg / mL, 16±1 mg / mL, 17±1 mg / mL, 18±1 mg / mL, 19±1 mg / mL, 20±1 mg / mL, 21±1 mg / mL, 22±1 mg / mL, 23±1 mg / mL, 24±1 mg / mL, 25±1 mg / mL, 26±1 mg / mL, 27±1 mg / mL, 28±1 mg / mL, 29±1 mg / mL, 30±1 mg / mL, 31±1 mg / mL, 32±1 mg / mL, 33±1 mg / mL, 34±1 mg / mL, 35±1 mg / mL, 36±1 mg / mL, 37±1 mg / mL, 38±1 mg / mL, 39±1 mg / mL and any one of the pharma- ceutical acceptable salts of psilocin described herein, the aqueous pharmaceutical composition comprising: a) a 100 mg / mL aqueous solution of psilocin; b) a 100 mg / mL aqueous solution of psilocin; c) a 100 mg / mL aqueous solution of psilocin; d) a 100 mg / mL aqueous solution of psilocin; e) a 100 mg / mL aqueous solution of psilocin; f) a 100 mg / mL aqueous solution of psilocin; g / mL, 9 ± 1 mg / mL, 10 ± 1 mg / mL, 11 ± 1 mg / mL, 12 ± 1 mg / mL, 13 ± 1 mg / mL, 14 ± 1 mg / mL, 15 ± 1 mg / mL, 16 ± 1 mg / mL, 17 ± 1 mg / mL, 18 ± 1 mg / mL, 19 ± 1 mg / mL, 25 ± 5 mg / mL, 30 ± 5 mg / mL, 35 ± 5 mg / mL, 40 ± 5 mg / mL, 45 ± 5 mg / mL, and 50 ± 5 mg / mL. The aqueous pharmaceutical composition may be suitable for injection into a subject to treat a disease or condition described herein.

[0006] In some embodiments, the aqueous solution comprises from about 1 mg / mL to about 15 mg / mL (e.g., 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, and 15±1 mg / mL) of any one of the pharma- ceutically acceptable salts of psilocin described herein.

[0007] In another aspect, the invention features a crystalline form of the 2:1 succinate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as measured by X-ray powder diffractometry, as provided in Figure 4 (SUC pattern 4).

[0008] In a related aspect, the invention features a crystalline form of the 1,5-naphthalenedisulfonate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as provided in FIG. 7 or FIG. 14 (NAP Pattern 1), as measured by X-ray powder diffractometry.

[0009] In a further aspect, the invention features a crystalline form of the 1:1 tartrate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as provided in FIG. 9 or FIG. 12 (TAR pattern 3), as measured by X-ray powder diffractometry.

[0010] In another aspect, the invention features a crystalline form of the 1:1 tartrate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as measured by X-ray powder diffractometry, as provided in Figure 10 (TAR pattern 4).

[0011] In a related aspect, the invention features a crystalline form of a 1:1 tartrate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) selected from 6.7±0.5, 12.6±0.5, 13.4±0.5, 14.7±0.5, 15.8±0.5, 16.2±0.5, 17.2±0.5, 18.8±0.5, 19.9±0.5, 20.8±0.5, 21.8±0.5, 22.5±0.5, 23.4±0.5, 23.7±0.5, 24.7±0.5, 25.5±0.5, 26.5±0.5, 27.0±0.5, 28.5±0.5, and 29.4±0.5 (TAR pattern 1), as measured by X-ray powder diffractometry.

[0012] In a further aspect, the invention features a crystalline form of the 2:1 succinate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) selected from 9.7±0.5, 11.2±0.5, 12.3±0.5, 13.8±0.5, 15.9±0.5, 16.4±0.5, 19.4±0.5, 20.0±0.5, 21.3±0.5, 22.6±0.5, 23.3±0.5, 23.5±0.5, 23.8±0.5, 24.5±0.5, 24.7±0.5, 25.0±0.5, 28.0±0.5, 28.3±0.5, 29.0±0.5, and 29.4±0.5 (SUC pattern 3), as measured by X-ray powder diffractometry.

[0013] In a related aspect, the invention provides a method for the preparation of a medicament for use in treating or treating a disease comprising administering to a patient a therapeutically effective amount of at least one of the following: 9.4±0.5, 10.9±0.5, 12.3±0.5, 13.3±0.5, 14.5±0.5, 15.3±0.5, 16.3±0.5, 16.4±0.5, 18.2±0.5, 18.9±0.5, 19.3±0.5, 19.7±0.5, 20.0±0.5, 20.8±0.5, 21.3±0.5, 21.9±0.5, 22.6±0.5, 23.0±0.5, 24.0±0.5, 25.0±0.5, 26.0±0.5, 27.0±0.5, 28.0±0.5, 29.0±0.5, 30.0±0.5, 31.0±0.5, 32.0±0.5, 33.0±0.5, 34.0±0.5, 35.0±0.5, 36.0±0.5, 37.0±0.5, 38.0±0.5, 39.0±0.5, 40.0±0.5, 41.0±0.5, 42.0±0.5, 43.0±0.5, 44.0±0.5, 45.0±0.5, 46.0±0.5, 47.0±0.5, 48.0±0.5, 49.0±0.5, 50.0±0.5, 51.0±0.5, 52.0± The present invention is characterized in that the crystalline form of the 1:1 benzoate salt of psilocin has at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) selected from 22.9±0.5, 23.8±0.5, 24.1±0.5, 24.9±0.5, 25.6±0.5, 26.0±0.5, 26.3±0.5, 26.5±0.5, 26.9±0.5, 27.5±0.5, and 28.5±0.5 (BEN pattern 1).

[0014] In a related aspect, the invention features a pharmaceutical composition comprising the crystalline form of the invention and a pharma- ceutically acceptable excipient. The pharma- ceutically acceptable excipient can be any pharma- ceutically acceptable excipient described herein. In some embodiments, any one of the pharmaceutical compositions described herein is stored in a container that shields the pharmaceutical composition from exposure to light, such as an amber glass bottle, or an ambient light impermeable container.

[0015] In a related aspect, the invention features a method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject an amount of a psilocin salt of the invention sufficient to treat the disease or condition. The disease or condition can be neurological damage, neurodegenerative disease, inflammatory disease, chronic pain, or psychiatric disease. In certain embodiments, the disease or condition is an inflammatory disease (e.g., pulmonary inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn's disease, multiple sclerosis, and / or sepsis). In particular embodiments, the inflammatory disease is chronic obstructive pulmonary disease (COPD) or Alzheimer's disease. In certain embodiments, the disease or condition is neurological damage (e.g., stroke, traumatic brain injury, or spinal cord injury). In some embodiments, the disease or disorder is chronic pain (e.g., pain resulting from postoperative pain, tension headache, chronic low back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, head pain, or sciatica). In particular embodiments, the chronic pain condition is due to trigeminal autonomic headache (e.g., episodic and chronic cluster headache (CH), episodic and chronic paroxysmal migraine (PH), and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT)). In some embodiments, the trigeminal autonomic headache is episodic or chronic CH. In particular embodiments, the disease is a psychiatric disorder (e.g., depression, anxiety, addiction, post-traumatic stress disorder, eating disorder, or obsessive-compulsive behavior). In particular embodiments, the psychiatric disorder is depression or anxiety.

[0016] definition To facilitate understanding of the present invention, several terms are defined below and throughout this disclosure. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. In this specification, technical terms are used to describe certain aspects of the present invention, but their usage does not limit the present invention (except as outlined in the claims).

[0017] Terms such as indefinite and definite articles "a", "an", and "the" are intended to refer not only to a singular entity but also to include a general class within which a specific example may be used for illustration.

[0018] As used herein, the term "about" refers to a value within plus or minus 10% of the stated value. The term "administration" or "administering" refers to the method of giving a dosage of a compound or pharmaceutical composition to a subject.

[0019] As used herein, the terms "pharmacologically effective amount", "therapeutically effective amount", and the like, when used in connection with a therapeutic composition, refer to an amount sufficient to achieve a beneficial or desired result, such as a clinical result, when administered to a subject, including a mammal, e.g., a human. For example, in the context of treating depression as described herein, these terms refer to an amount of a composition sufficient to achieve a therapeutic response compared to the response obtained without administration of the composition. The amount of a given composition described herein that corresponds to such an amount may vary depending on a variety of factors, such as a given drug, pharmaceutical formulation, route of administration, type of disease or disorder, subject identity (e.g., age, sex, weight), or host being treated. An "effective amount", "pharmacologically effective amount", and the like, of a composition of the present disclosure also includes an amount that provides a beneficial or desired result in a subject compared to a control.

[0020] As used herein, the terms "treat", "treating" or "treatment" refer to the administration of a compound or pharmaceutical composition for therapeutic purposes. "Treating a disorder" or use for "therapeutic treatment" refers to administering a treatment to a patient already suffering from a disease in order to improve the condition of the patient by improving the disease or one or more symptoms thereof (e.g., by reducing one or more symptoms of inflammation). The term "therapeutic" also includes the effect of alleviating the adverse clinical effects of a particular inflammatory process (i.e., the consequences of inflammation rather than the symptoms of inflammation). The methods of the invention can be used as a primary preventative measure, i.e., measures for preventing a disease or reducing the risk of developing a disease. Prevention refers to the prophylactic treatment of a patient, i.e., a patient who may not have fully developed the disease or disorder, but who is susceptible to or otherwise at risk for the disease. Thus, in the claims and embodiments, the methods of the invention can be used for either therapeutic or prophylactic purposes.

[0021] Other features and advantages of the invention will be apparent from the following detailed description, examples, drawings, and claims. [Brief description of the drawings]

[0022] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [Figure 1] FIG. 1 shows the XRPD patterns of succinic acid silosin salts having SUC pattern 1, SUC pattern 2, or SUC pattern 3. [Diagram 2] FIG. 2 shows the XRPD pattern of L-tartrate silosin salt having TAR pattern 1 or TAR pattern 2. [Diagram 3] FIG. 3 shows the XRPD pattern of 1,5-naphthalenedisulfonic acid silosin salt having NAP pattern 1 or NAP pattern 2. [Figure 4]FIG. 4 shows the XRPD pattern of silosin succinate with SUC pattern 4 (bottom scan). [Diagram 5] FIG. 5 shows the XRPD pattern of silosin succinate with SUC pattern 5 after 7 days of static storage at 40° C. and 75% relative humidity (bottom scan). [Figure 6] FIG. 6 shows the XRPD of TAR pattern 1 obtained from a crystalline solid of silosin tartrate. [Figure 7] FIG. 7 shows the XRPD pattern of NAP pattern 1 obtained from 1,5-naphthalenedisulfonic acid silosin (bottom scan). [Figure 8] FIG. 8 shows the XRPD of BEN pattern 1 obtained from a crystalline solid of silosin benzoate. [Figure 9] FIG. 9 shows the XRPD pattern of TAR pattern 3 obtained from silosin tartrate (bottom scan). [Figure 10] FIG. 10 shows the XRPD pattern of TAR pattern 4 obtained from silosin tartrate after static storage at 40° C. and 75% relative humidity (bottom scan). [Figure 11] FIG. 11 shows the XRPD of SUC pattern 3 obtained from a crystalline solid of silosin succinate. [Figure 12] FIG. 12 shows the XRPD of silosin tartrate with TAR pattern 3, produced using seed material from a silosin salt with TAR pattern 2 (bottom scan). [Figure 13] FIG. 13 shows the XRPD of free base psilocin pattern 1 obtained from the crystalline solid remaining after dissolution in saline. [Figure 14] FIG. 14 shows the XRPD of NAP pattern 1 obtained from the crystalline solid remaining after dissolution in saline. [Figure 15] FIG. 15 shows the XRPD of BEN pattern 1 obtained from the crystalline solid remaining after dissolution in saline. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] To identify psilocin with improved properties, a salt screen was performed using 24 different counterions and three different solvent systems. Crystalline materials with novel XRPD patterns were isolated from the experiments and evaluated for 13 counterions and their properties. After identification of suitable salts with optimal properties, a polymorphic screen of these salts was performed.

[0024] Psilocin has the structure:

[0025] [ka]

[0026] has. Psilocybin (psilocybin) is a phosphate prodrug of psilocin, and when administered to a subject, psilocybin is metabolized to form psilocin. Psilocybin undergoes enzymatic dephosphorylation to lose the phosphate group and reveal the hydroxyl group of psilocin. Psilocybin exists as a zwitterion in which the phosphate and amine ionize each other. The presence of the zwitterion not only limits the solubility of psilocybin, but also inhibits its ability to form salts with alternative acids that can exist under physiologically tolerable conditions. Removal of the phosphate group allows the formation of salt forms of dimethylamine of psilocin with alternative acids, which cannot be produced with psilocybin. Because psilocin can exist in a non-ionized form, it is much more lipid soluble than psilocybin and therefore can cross the blood-brain barrier more effectively to elicit a response. Psilocybin has a high affinity for and can activate the 5-HT2A receptor, which plays a major role in regulating mood, sexual behavior, aggression, impulsivity, cognitive function, appetite, pain, sleep, and memory, among other behaviors. As a result, psilocin exerts an effect at the 5-HT2A receptor that mimics that of the endogenous neurotransmitter serotonin. The present disclosure provides methods for novel stable and soluble salt forms of psilocin that are useful in therapy, such as for treating patients with psychiatric disorders or neurological injuries.

[0027] treatment The present disclosure provides psilocin salt forms useful for the treatment of psychiatric disorders, nerve injuries, pain, head pain (e.g., headaches), inflammatory disorders, and anxiety.

[0028] Mental illness The psilocin salt forms of the present invention can be used to treat psychiatric disorders. The psychiatric disorder can be any psychiatric disorder described herein. In some embodiments, the psychiatric disorder is depression, anxiety, addiction, post-traumatic stress disorder (PTSD), eating disorder, or obsessive behavior. In some embodiments, the psychiatric disorder can be depression. The psychiatric disorder can be anxiety. Anxiety can be experienced by subjects receiving palliative care or enrolled in a hospice program. In certain embodiments, subjects experiencing anxiety have symptoms such as hyperarousal, fatigue, racing thoughts, irritability, excessive worry, and / or fear.

[0029] A subject diagnosed with a mental illness may be diagnosed by a doctor, clinician, or therapist based on a physical examination and by evaluation of the subject's symptoms.For example, a blood test is used to evaluate blood concentration levels of certain biomarkers, such as hormones, calcium, vitamin D, electrolytes, and iron, to diagnose depression.In addition, or alternatively, for patients who may be depressed, a doctor, clinician, or therapist may administer a depression screening test to assist in diagnosing depression.In some embodiments, the methods described herein can be used to treat psychogenic pain conditions.In some embodiments, the psychogenic pain condition can be fibromyalgia, chronic fatigue, migraine, or back pain.

[0030] Nerve damage The psilocin salt forms of the present invention can be used to treat nerve injury. The nerve injury can be any nerve injury. In some embodiments, the nerve injury is stroke, traumatic brain injury, or spinal cord injury. The nerve injury treatment methods described herein can reduce acute inflammation. In certain embodiments, hyperactivity of the hippocampus is reduced. In particular embodiments, the methods of the present invention are used to treat nerve injury, such as stroke, traumatic brain injury, and spinal cord injury, by administering psilocin salts as needed for pain, inflammation, and / or other symptoms associated with nerve injury.

[0031] Neurodegenerative diseases The psilocin salt forms of the present invention can be used to treat neurodegenerative diseases, which may be, inter alia, Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0032] inflammatory diseases The psilocin salt forms of the present invention can be used to treat inflammatory diseases. The inflammatory disease to be treated can be pulmonary inflammation (e.g., chronic obstructive pulmonary disease (COPD)), neuroinflammation (e.g., inflammation associated with Alzheimer's disease), chronic inflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn's disease, multiple sclerosis, and / or sepsis.

[0033] chronic pain The psilocin salt forms of the present invention can be used to treat conditions associated with chronic pain. Chronic pain can be due to post-operative pain, tension headache, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica. Chronic pain can also result from surgery. Chronic pain can also be pain associated with a specific disease or condition, such as nephropathy, multiple sclerosis, shingles, or complex regional pain syndrome. In this specification, a disorder or condition associated with cephalic pain is a disorder or condition that has cephalic / headache (e.g., headache) as one of its symptoms. Examples of such disorders or conditions include trigeminal autonomic headaches, such as episodic and chronic cluster headaches (CH), episodic and chronic paroxysmal migraine (PH), and short-lasting unilateral neuralgiform headache with conjunctival congestion and tearing (SUNCT). Other examples of disorders or conditions that can be treated according to the present invention include vascular headaches (e.g., migraine), tension headaches, headaches associated with the use of and withdrawal from substances (e.g., triptans such as sumatriptan, benzodiazepines such as alprazolam, analgesics such as ibuprofen, ergots such as ergotamine, opioids such as morphine, recreational drugs such as caffeine, nicotine, alcohol, e.g., hormone replacement therapy containing estrogen), etc. Further examples of disorders or conditions associated with head pain also include various headaches without organic lesions, headaches associated with nonvascular intracranial diseases, headaches associated with infections other than the head, headaches associated with metabolic diseases, headaches associated with diseases of the skull, neck, eyes, nose, sinuses, teeth, mouth, or other facial or cranial tissues, nerve trunk pain, and post-denervation pain.

[0034] composition The present invention also features a pharmaceutical composition comprising the psilocin salt form of the present invention and a pharma- ceutically acceptable excipient. Examples of pharma-ceutically acceptable excipients include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents that allow the composition to be used as a dosage form. Examples of other excipients include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0035] The pharmaceutical compositions of the present invention may contain one or more solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, 18th Edition, EW Martin (Mack Publishing Co., Easton, PA, 1990) discloses various excipients used in formulating pharmaceutical compositions and known techniques for their manufacture. Except insofar as any conventional excipient medium is incompatible with the compounds of the present invention, for example, by causing undesirable biological effects or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of the present invention. Some examples of substances which can serve as pharma- ceutically acceptable excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; soybean and egg yolk phosphatides, lecithin, hydrogenated Natural and synthetic phospholipids such as soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, distearoylphosphatidylethanolamine (DSPE) and its pegylated esters, e.g., DSPE-PEG750 and DSPE-PEG2000, phosphatidic acid, phosphatidylglycerol, and phosphatidylserine; and hydroxypropyl-beta-cyclodextrin and sulfonate-substituted cyclodextrins (e.g., CAPTISOL TM), but is not limited to these. Suitable commercial grades of lecithins include those available under the tradename Phosal® or Phospholipon®, including Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G, and Phospholipon 90 NG; soybean-phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly suitable; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; 5% dextrose solution and combinations of the foregoing in aqueous solutions; ethyl alcohol, and phosphate buffers, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents and perfuming agents, preservatives, and antioxidants can also be included in the composition according to the judgment of the formulator.

[0036] The composition can be used in any of the above forms for the treatment of the diseases or conditions described herein. An effective amount refers to the amount of active compound / drug required to produce a therapeutic effect in the treated subject. The effective dose will vary depending on the type of disease being treated, the route of administration, the use of excipients, and the possibility of co-administration with other therapies, as will be appreciated by those skilled in the art. The pharmaceutical composition of the present invention can be administered parenterally, orally, intranasally, rectally, topically, or bucally. As used herein, the term "parenteral" refers to subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable injection technique.

[0037] For use in the methods and compositions of the present invention, the pharma- ceutically acceptable psilocin salt may be contained in any suitable amount in any suitable carrier material formulated for intravenous infusion (infusion). In general, it is present in an amount of 0.01-95% by weight of the total weight of the composition. In particular embodiments, the pharma-ceutically acceptable psilocin salt is present in an amount of 0.01-5% by weight of the total weight of the composition. In some embodiments, an aqueous solution suitable for intravenous infusion containing a pharma-ceutically acceptable psilocin salt may be formulated in saline. The formulation of infusion solutions is well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy (23rd ed.), AR Gennaro, Ed., Lippincott Williams & Wilkins, 2000, and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and JC Boylan, Ed., 1988-1999, Marcel Dekker, New York). Compositions for injection can be provided in unit dosage form (e.g., single dose ampoules) or in vials containing several doses (to which suitable preservatives can be added). Pharmaceutically acceptable solutions of psilocin salts suitable for intravenous injection can have a pH of about 3 to about 9 (e.g., 3±1, 4±1, 5±1, 6±1, 7±1, 8±1, and 9±1). Additionally, pharma- ceutically acceptable solutions of psilocin salts suitable for intravenous infusion may be used in the form of a solution having a concentration of from about 0.1 mg / mL to about 50 mg / mL (e.g., 0.1±0.1 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.5 mg / mL, 1±0.5 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, In some embodiments, the psilocysin salt may comprise a concentration of 9±1 mg / mL, 10±1 mg / mL, 11±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, 15±1 mg / mL, 16±1 mg / mL, 17±1 mg / mL, 18±1 mg / mL, 19±1 mg / mL, 25±5 mg / mL, 30±5 mg / mL, 35±5 mg / mL, 40±5 mg / mL, 45±5 mg / mL, and 50±5 mg / mL) of a pharma- ceutically acceptable psilocin salt.In some embodiments, the aqueous solution comprises from about 1 mg / mL to about 15 mg / mL (e.g., 1±1 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, and 15±1 mg / mL) of any one of the pharma- ceutically acceptable psilocin salts described herein. In particular embodiments, the aqueous solution comprises from about 0.1 mg / mL to about 1 mg / mL (e.g., 0.1±0.1 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.1 mg / mL, 0.6±0.1 mg / mL, 0.7±0.1 mg / mL, 0.8±0.1 mg / mL, 0.9±0.1 mg / mL, and 1±0.1 mg / mL) of any one of the pharma- ceutically acceptable psilocin salts described herein.

[0038] Sterile injectable compositions may be solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Such solutions include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally used as solvents or suspending media (e.g., synthetic mono- or diglycerides). Fatty acids, such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, or their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as, but not limited to, carboxymethylcellulose, or similar dispersants. Other commonly used surfactants, such as, but not limited to, Tweens or Spans or other similar emulsifiers or bioavailability enhancers, commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0039] The composition for oral administration can be any orally acceptable dosage form, such as capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.For tablets, commonly used excipients include, but are not limited to, lactose and cornstarch.Lubricants, such as, but are not limited to, magnesium stearate, are also typically added.For oral administration in capsule form, useful diluents include, but are not limited to, lactose and dried cornstarch.When aqueous suspensions or emulsions are orally administered, the active ingredient can be suspended or dissolved in the oil phase in combination with emulsifiers or suspending agents.If desired, certain sweeteners, flavors, or colorants can also be added.

[0040] The compositions in any of the above forms can be stored in a light-proof container. For example, the compositions described herein can be stored in an amber bottle. EXAMPLES

[0041] The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform, make, and evaluate the methods and compounds claimed herein, and are intended to be purely illustrative of the invention and are not intended to limit the scope of what the inventors regard as their invention.

[0042] Example 1. Salt Screening Dissolved silocin was separately combined with 24 organic and inorganic acids in three different solvent systems, see Table 1.

[0043] [Table 1]

[0044] For some combinations, no solid product could be obtained even after cooling or addition of countersolvent. For other combinations, crystals formed, which were analyzed by X-ray powder diffraction (XPRD). XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Kα radiation (λ=1.54 Å, 40 kV, 40 mA) and a θ-2θ goniometer with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit, followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit before reaching the Lynxeye detector. The software used for data collection and analysis were Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively. Samples were measured under ambient conditions as flat specimens using the as-received powder. Samples were prepared on polished zero-background (510) silicon wafers by gently pressing them onto a flat surface or packing them into cut cavities. The samples were rotated in their own plane. Standard data collection method details are: (i) angle range: 2-42° 2θ; (ii) step size: 0.05° 2θ; and (iii) collection time: 0.5 s / step (total collection time: 6.40 min).

[0045] Crystalline materials with novel XRPD patterns were isolated from the experiment and characterized for 13 counterions. Acetate (ACE) Pattern 2, Adipic (ADI) Pattern 1, ADI Pattern 2, Fumaric (FUM) Pattern 1, FUM Pattern 2, 1,5-Naphthalenedisulfonic (NAP) Pattern 2, Oxalate (OX) Pattern 1, OX Pattern 2, Phosphonic (PHO) Pattern 1, PHO Pattern 2, Propionic (PRO) Pattern 1, Succinic (SUC) Pattern 1, SUC Pattern 2, Salicylic (SAL) Pattern 1, SAL Pattern 2 were shown to convert or partially convert to novel XRPD patterns after storage at 40°C / 75% RH for 7 days, indicating that these salt forms are not stable. For this reason, these patterns were rejected. Thermal data for silosin pamoate (PAM) pattern 1 showed significant mass loss in TGA and several endothermic events in DSC making it undesirable to proceed further. A limited number of combinations did indeed yield solid products and were further evaluated for stability (HPLC), crystallinity (XRPD), and counterion stoichiometry (NMR) and polymorphism and stability (XRPD). From this screen, only three silosin / acid combinations were deemed worthy of scale-up and more detailed evaluation.

[0046] Screening of various silosin salts was completed in acetone, 2-methyltetrahydrofuran, and ethanol:H2O (9:1), yielding 22 crystalline forms. These were characterized by X-ray powder diffraction (XRPD), high pressure liquid chromatography (HPLC), and NMR. 1The salts were characterized using H-NMR, thermogravimetric analysis / differential scanning calorimetry (TGA / DSC). They were also evaluated using XRPD and HPLC after 7 days of static storage at 40°C and 75% relative humidity, and the results are summarized in Table 2. Samples stored at 40°C and 75% relative humidity are indicated by numbers 40-75 after the sample number. Solid state stability, improved purity upon crystallization, minimal polymorphism, and the absence of hydrates, alcoholates, or solvent inclusions, as well as the solubility of the salt in saline were identified as important parameters for selecting the most suitable salt form. As a result, small-scale scale-up experiments were performed on seven salts, allowing the collection of solubility data. See Example 2.

[0047] Salt screening was performed by adding the appropriate counterion, either as a solution or as a solid, to a solution of silosin free base in a suitable solvent system at room temperature. This was then stirred at room temperature for 1 hour, before being cooled to 5°C and stirred at 5°C overnight. If a solid was isolated at this point, it was separated by filtration. If a solution or gum was isolated at this point, further processing was carried out as necessary by the addition of an additional 0.5 molar equivalent of counterion, temperature cycling from 5 to 25°C, and / or the addition of anti-solvent.

[0048] [Table 2-1]

[0049] [Table 2-2]

[0050] [Table 2-3]

[0051] The salts of silosin benzoate, silosin succinate, and silosin tartrate were all examined in their anhydrous forms. Silosin benzoate salt with BEN pattern 1 exhibited the lowest solubility and intrinsic dissolution rate (IDR) of the three forms, but was still significant and pharmacologic consistent. Silosin benzoate salt with BEN pattern 1 also exhibited substantial increases in solubility and IDR over the free base form. Silosin benzoate salt with BEN pattern 1 was also shown to be stable, not exhibit polymorphism, and non-hygroscopic (Table 3).

[0052] Siloxane succinate salt with SUC pattern 3 had the highest IDR as well as high solubility. This form was a hemi-salt and was stable to static storage. Although the material was hygroscopic (2.1% reversible mass change from 0 to 90% RH), this did not appear to result in a change in morphology, with most water uptake occurring between 80% and 90% RH.

[0053] Silosin tartrate salt with TAR pattern 1 contained some residual solvent, which was removed by storage at 40°C / 75% RH. It had high solubility and the second highest IDR. It transformed to TAR pattern 3 under storage at 25°C / 97%.

[0054] A summary of the properties of the silosin salts is provided in Table 4.

[0055] [Table 3]

[0056] [Table 4]

[0057] Example 2. Scale-up to 100 mg for solubility evaluation Each solid of interest was obtained by adapting the procedure from the small scale screening and analyzing XRPD, as shown in Table 5. 1Characterization was performed using H-NMR and HPLC. The solvents used were purged with N2 for at least 30 min before use. The solid obtained was dried in a vacuum oven at room temperature for 2 h.

[0058] Silosin salicylate was prepared by mixing 100 mg of silosin free base with 30 volumes of acetone in a 4 mL vial at 25° C. To this solution was added 1.1 molar equivalents of salicylic acid (1M in THF). Crystallization was carried out by cooling the solution to 5° C. at a rate of 0.25° C. / min and holding at 5° C. for 2 hours, at which point an additional 0.5 molar equivalents of salicylic acid was added. The crystallization solution was held at 5° C. for an additional 10 hours, after which 10 volumes of heptane were added to the clear solution and stirring was continued for an additional 24 hours. The white suspension was isolated using a fritted (sintered) filter cartridge using positive pressure, giving a yield of 86.38 mg.

[0059] Silosin succinate was prepared by mixing 100 mg of silosin free base with 30 volumes of acetone in a 4 mL vial at 25° C. To this solution was added 1.1 molar equivalents of succinic acid (1M in methanol). Crystallization was carried out by cooling the solution to 5° C. at a rate of 0.25° C. / min and holding at this temperature for 12 hours. The white suspension was isolated using a fritted filter cartridge with positive pressure, giving a yield of 89.96 mg.

[0060] Psilosin tartrate was prepared by mixing 100 mg of silosin free base with 30 volumes of 2-methyltetrahydrofuran in a 4 mL vial at 25° C. To this solution was added 1.1 molar equivalents of L-tartaric acid (1M in THF). Crystallization was carried out by cooling the solution to 5° C. at a rate of 0.25° C. / min and holding at this temperature for 12 hours. The off-white suspension was isolated using a fritted filter cartridge with positive pressure, giving a yield of 160.30 mg.

[0061] 1,5-Naphthalenedisulfonic acid silosin was prepared by mixing 100 mg of silosin free base with 30 volumes of 2-methyltetrahydrofuran in a 4 mL vial at 25° C. To this solution was added 1.1 molar equivalents of 1,5-naphthalenedisulfonic acid (1M in THF). Crystallization was carried out by cooling the solution to 5° C. at a rate of 0.25° C. / min and holding at this temperature for 12 hours. The white suspension was isolated using a fritted filter cartridge with positive pressure, giving a yield of 154.37 mg.

[0062] Silosin salicylate was prepared by mixing 100 mg of silosin free base with 30 volumes of 2-methyltetrahydrofuran in a 4 mL vial at 25° C. To this solution was added 1.1 molar equivalents of salicylic acid (1M in THF). Crystallization was carried out by cooling the solution to 5° C. at a rate of 0.25° C. / min. After this time crystallization occurred and no further salicylic acid was added. Crystallization was held at 5° C. for an additional 12 hours. The white suspension was isolated using a fritted filter cartridge using positive pressure, giving a yield of 101.99 mg.

[0063] Psilosin benzoate was prepared by mixing 100 mg of silosin free base with 30 volumes of 2-methyltetrahydrofuran in a 20 mL vial at 25° C. To this solution was added 1.1 molar equivalents of benzoic acid (0.5 M in isopropyl alcohol). Crystallization was then carried out by cooling the solution to 5° C. at 0.25° C. / min and holding at this temperature for 12 hours. The white suspension was isolated using a fritted filter cartridge with positive pressure, giving a yield of 135.81 mg.

[0064] Psilosin tartrate was prepared by mixing 100 mg of silosin free base with 40 volumes of EtOH:water (9:1) in a 20 mL vial at 25° C. To this solution was added 1.1 molar equivalents of L-tartaric acid (1M in tetrahydrofuran). Crystallization was carried out by cooling the solution to 5° C. at a rate of 0.25° C. / min and holding at this temperature for 12 hours. The white suspension was isolated using a fritted filter cartridge with positive pressure, giving a yield of 103.67 mg.

[0065] Silosin hydrochloride was prepared by mixing 100 mg of silosin free base with 40 volumes of acetonitrile in a 20 mL vial at 25° C. To this solution was added 1.1 molar equivalents of hydrochloride salt (1M in tetrahydrofuran). Crystallization was carried out by cooling the solution to 5° C. at a rate of 0.25° C. / min, at which point 10 volumes of methyl tert-butyl ether were added and the reaction stirred at 5° C. for an additional 12 hours. Only a small amount of brown material was found on the walls of the vial, so an additional 5 volumes of methyl tert-butyl ether were added and the crystallization solution was stirred at 5° C. for 72 hours. The off-white material that crystallized at the vial-solvent interface was knocked down and then isolated using a fritted filter cartridge using positive pressure, giving a yield of 32.51 mg.

[0066] Addition of 25 volumes of methyl tert-butyl ether, a small amount of seed material, and 0.55 molar equivalents of hydrochloride (1M in tetrahydrofuran) and stirring at 5° C. for 72 hours gave a second crop yield of 20-30 mg of light brown material, the results of which are summarized in Table 6.

[0067] [Table 5]

[0068] [Table 6]

[0069] A second attempt was made at 100 mg scale-up for solubility evaluation. The results are summarized in Tables 7 and 8. These attempts were made because the first attempt did not produce the desired morphology (Table 5). Psilosin succinate was prepared by dissolving 100 mg of silosin free base in a 20 mL vial in 30 volumes of acetone at 25° C. To this solution, 1.1 molar equivalents of succinic acid (1M in THF) were added. The crystallization solution was then cooled to 5° C. at a rate of 0.25° C. / min, resulting in a white suspension. To this suspension was added an additional 0.55 molar equivalents of succinic acid. The suspension was stirred at 5° C. for 12 hours. The resulting white suspension was isolated using a fritted filter cartridge using positive pressure, resulting in a yield of 65.8 mg.

[0070] Silosin salicylate was prepared by dissolving 100 mg of silosin free base in a 20 mL vial in 30 volumes of 2-MeTHF at 25° C. To this solution was added 1.1 molar equivalents of salicylic acid (1M in THF). The crystallization solution was then cooled to 5° C. at a rate of 0.25° C. / min. At 23° C. crystallization began and appeared cloudy, so approximately 2 mg of seed material was added. Desupersaturation to a thick white suspension was observed. An additional 0.55 molar equivalents of salicylic acid was added at 5° C., and the crystallization solution was held at 5° C. for 12 hours. The white suspension was isolated using a fritted filter cartridge with positive pressure, giving a yield of 90.35 mg.

[0071] Psilosin tartrate was prepared by dissolving 100 mg of silosin free base in 40 volumes of EtOH:water (9:1) at 25°C in a 20 mL vial. To this solution was added 1.1 molar equivalents of L-tartaric acid (1M in THF). Approximately 2 mg of seed material was added and gentle desupersaturation was maintained. The crystallization solution was cooled to 5°C at a rate of 0.25°C / min and held at that temperature for 12 hours. The white suspension was isolated using a fritted filter cartridge with positive pressure, yielding 107.18 mg.

[0072] [Table 7]

[0073] [Table 8]

[0074] Example 3. Solubility of silosin salts in saline A sufficient amount of sample was suspended in 0.5 mL of medium to obtain a maximum expected concentration of 10 mg / mL of psilocin free base. The resulting suspension was then shaken at 25°C and 750 rpm for 5 hours. After equilibration, the appearance was recorded and the pH of the saturated solution was measured. The sample was then centrifuged at 13,400 rpm for 2 minutes before being diluted with buffer as appropriate.

[0075] Quantitation was performed by HPLC with reference to a standard solution of approximately 0.15 mg / mL. Various amounts of standard, diluted, and undiluted sample solutions were injected. Solubility was calculated using the peak area determined by integrating the peak found at the same retention time as the major peak of the standard injection.

[0076] Solid residues from samples that did not completely dissolve were analyzed by XRPD to assess whether they had changed morphology. The appearance of each sample, pH after 5 hours, XRPD of any residue, solubility, and average solubility were evaluated for each salt and are summarized in Tables 9 and 10.

[0077] [Table 9]

[0078] [Table 10]

[0079] For silosin tartrate, TAR pattern 1 was obtained from acetone. 1H-NMR spectroscopy suggests that TAR Pattern 1 is the mono-L-tartrate salt. This form was stable to storage at 40°C / 75%RH. Solubility in saline is >10mg / mL. The purity gain of psilocin from the formation of TAR Pattern 1 is the lowest among the scaled-up salt forms.

[0080] For silosin succinate, a total of 1.65 molar equivalents of succinic acid were used, and SUC pattern 3 was obtained from acetone. 1 According to H-NMR spectroscopy, this solid form contains only 0.5 molar equivalents of the succinate salt. Thermal data suggests that this form is anhydrous. Both SUC Pattern 1 and SUC Pattern 2 have been observed to convert to SUC Pattern 3 under static storage conditions of elevated temperature and humidity, and DSC data also shows possible conversion to SUC Pattern 3 at elevated temperatures, as evidenced by an endotherm common to all three forms at approximately 185 °C. The solubility of SUC Pattern 3 has been shown to be >10 mg / mL in saline.

[0081] TAR Pattern 3 and HCl Pattern 1 show high solubility (>10mg / mL) but are not stable when stored at 40°C / 75%RH and are not recommended for further use. SAL Pattern 1, NAP Pattern 1 and BEN Pattern 1 all show substantial increases in solubility compared to the free forms, but are less soluble than the other salt forms. All are stable at high temperature and humidity and show good HPLC purity build-up.

[0082] SAL Pattern 1 and BEN Pattern 1 are anhydrous, while NAP Pattern 1 appears to be a hemihydrate. Only one solid form of the benzoate salt was identified throughout this screen (two for NAP and two for SAL).

[0083] The peaks observed from XRPD for TAR pattern 1 from silosin tartrate (Figure 6), SUC pattern 3 from silosin succinate (Figure 11), and BEN pattern 1 from silosin benzoate (Figure 8) are summarized in Table 11.

[0084] [Table 11]

[0085] Example 4. Photostability of psilocin salts Light stability studies were performed on approximately 3 mm thick solid silosin salt materials (including silosin tartrate, silosin benzoate, and silosin succinate) and 0.2 mg / mL free base solutions in water. Prior to dissolution, the water was purged with nitrogen for 30 minutes to prevent oxidative degradation. Two vials of each sample were prepared, one exposed to light and the other wrapped in foil for the duration of the experiment to act as a control. Light stability studies were performed using an Atlas Suntest CPS+. Samples were exposed to light at 500 W / m 2 The samples were exposed to 1000 nm iridescence levels (300-800 nm) for a period equivalent to one week of Miami sunlight, for a total exposure of 6.9 hours. Observations were performed on the free base psilocinate, tartrate, succinate, and benzoate salts before and after exposure (Table 12). Purity analysis was performed on all samples after exposure at 0.2 mg / mL of free base using an Agilent 1260 Series HPLC and OpenLab software. X-ray powder diffraction was performed on the solid psilocinate samples before and after exposure.

[0086] The purity and stability of the solid samples after light exposure were unchanged compared to those before exposure. XRPD analysis also showed that the crystalline form of all the samples remained unchanged after the light stability experiment. The benzoate, tartrate, and succinate salts of psilocin all showed greater stability in the presence of light when tested after dissolution in solution compared to the free base psilocin. The psilocin salt solutions were observed to discolor upon exposure to light. Additionally, the free base in solution after exposure was 34.1% pure by HPLC, while the salt forms retained >75% purity by HPLC after exposure to light. The L-tartrate salt form was the most photostable psilocin salt in solution, with a purity of 93.2% by HPLC after exposure. The tartrate salt performed best with respect to photostability in solution, with benzoate and succinate performing better than the free base.

[0087] Example 5. Forced decomposition of silosin salt A study was developed to evaluate the stability of psilocin salts and free base psilocin against oxidative degradation. Forced degradation of psilocin salts was performed in 0.3% H2O2 to test the oxidative stability of each salt form. An appropriate amount of 0.3% H2O2 was added to pre-weighed psilocin salt samples in amber vials to achieve a maximum concentration of 0.2 mg / mL psilocin (free base equivalent). Samples were stored at 25°C and the purity of each sample was evaluated at 0, 1, 6, and 24 hours (Table 12). Purity analysis was performed using an Agilent 1260 Series HPLC and OpenLab software.

[0088] [Table 12]

[0089] In 0.3% (v / v) H2O2, the decomposition rate of the salt forms of psilocin was slower compared to the free base psilocin. Of the three psilocin salts tested, the L-tartrate salt decomposed faster than the succinate and benzoate salts. After 6 hours of exposure to oxidizing conditions, the benzoate salt showed the highest stability against oxidative degradation.

[0090] These data suggest that sylocin benzoate and sylocin succinate are suitable salt forms for preparing pharmaceutical compositions with excellent storage stability and resistance to oxidative degradation.

[0091] Other Aspects All publications, patents, and patent applications mentioned in this specification are incorporated by reference herein to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. This application claims the benefit of U.S. Provisional Application No. 63 / 148,052, filed February 10, 2021, and U.S. Provisional Application No. 63 / 276,096, filed November 5, 2021, each of which is incorporated by reference in its entirety.

[0092] While the invention has been described in relation to particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any variation, use, or adaptation of the invention in accordance with the principles of the invention, including such departures from the present disclosure as fall within known practice or custom in the art to which the invention pertains and as are applicable to the essential features disclosed herein, in accordance with the scope of the appended claims.

[0093] Other aspects are within the scope of the claims.

Claims

1. A pharma- ceutically acceptable salt of psilocin, said pharma-ceutically acceptable salt being a 1:1 benzoate salt.

2. A pharma- ceutically acceptable salt of psilocin, said pharma-ceutically acceptable salt being a 1:1 tartrate salt.

3. A pharma- ceutically acceptable salt of psilocin, said pharma-ceutically acceptable salt being a 2:1 succinate salt.

4. A pharma- ceutically acceptable salt of psilocin, said pharma-ceutically acceptable salt being a 2:1 salt of 1,5-naphthalenedisulfonic acid, a 1:1 salt of 1,5-naphthalenedisulfonic acid, or a mixture thereof.

5. A pharmaceutical composition comprising the silosin salt of any one of claims 1 to 4 and a pharma- ceutically acceptable excipient.

6. 10. A pharmaceutical composition comprising: (i) an aqueous solution having a pH of from about 3 to about 9; and (ii) from about 0.1 mg / mL to about 50 mg / mL of a psilocin salt according to any one of claims 1 to 4, wherein the pharmaceutical composition is suitable for injection.

7. 7. The pharmaceutical composition of claim 6, wherein the aqueous solution has a concentration of from about 1 mg / mL to about 15 mg / mL.

8. A crystalline form of the 2:1 succinate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as measured by X-ray powder diffractometry, as provided in Figure 4 (SUC pattern 4).

9. A crystalline form of 1,5-naphthalenedisulfonate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as shown in FIG. 7 or FIG. 14 (NAP pattern 1) when measured by X-ray powder diffraction.

10. A crystalline form of the 1:1 tartrate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as measured by X-ray powder diffraction as provided in FIG. 9 or FIG. 12 (TAR pattern 3).

11. A crystalline form of the 1:1 tartrate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) as measured by X-ray powder diffractometry, as provided in FIG. 10 (TAR pattern 4).

12. A crystalline form of the 1:1 tartrate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) selected from 6.7±0.5, 12.6±0.5, 13.4±0.5, 14.7±0.5, 15.8±0.5, 16.2±0.5, 17.2±0.5, 18.8±0.5, 19.9±0.5, 20.8±0.5, 21.8±0.5, 22.5±0.5, 23.4±0.5, 23.7±0.5, 24.7±0.5, 25.5±0.5, 26.5±0.5, 27.0±0.5, 28.5±0.5, and 29.4±0.5 (TAR pattern 1) as measured by X-ray powder diffraction.

13. A crystalline form of the 2:1 succinate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) selected from 9.7±0.5, 11.2±0.5, 12.3±0.5, 13.8±0.5, 15.9±0.5, 16.4±0.5, 19.4±0.5, 20.0±0.5, 21.3±0.5, 22.6±0.5, 23.3±0.5, 23.5±0.5, 23.8±0.5, 24.5±0.5, 24.7±0.5, 25.0±0.5, 28.0±0.5, 28.3±0.5, 29.0±0.5, and 29.4±0.5 (SUC pattern 3) as measured by X-ray powder diffraction.

14. The results of X-ray powder diffraction analysis were: 9.4±0.5, 10.9±0.5, 12.3±0.5, 13.3±0.5, 14.5±0.5, 15.3±0.5, 16.3±0.5, 16.4±0.5, 18.2±0.5, 18.9±0.5, 19.3±0.5, 19.7±0.5, 20.0±0.5, 20.8±0.5, 21.3±0.5, 21.9±0.5, 22.6±0.5, A crystalline form of the 1:1 benzoate salt of psilocin having at least 4, 5, 6, or 7 peaks at diffraction angles 2θ (°) selected from 22.9±0.5, 23.8±0.5, 24.1±0.5, 24.9±0.5, 25.6±0.5, 26.0±0.5, 26.3±0.5, 26.5±0.5, 26.9±0.5, 27.5±0.5, and 28.5±0.5 (BEN pattern 1).

15. A pharmaceutical composition comprising the crystalline form of any one of claims 8 to 14 and a pharma- ceutically acceptable excipient.

16. The pharmaceutical composition of any one of claims 1 to 6 or 15, wherein the pharmaceutical composition is stored in an amber bottle.

17. A pharmaceutical composition according to any one of claims 5 to 7 or 15 for treating a disease or condition in a subject in need thereof.

18. 18. The pharmaceutical composition of claim 17, wherein the disease or condition is nerve damage, a neurodegenerative disease, an inflammatory disease, chronic pain, or a psychiatric disorder.

19. 18. The pharmaceutical composition of claim 17, wherein the disease or condition is an inflammatory disease.

20. 20. The pharmaceutical composition of claim 19, wherein the inflammatory disease is pulmonary inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn's disease, multiple sclerosis, and / or sepsis.

21. The pharmaceutical composition according to claim 19, wherein the inflammatory disease is chronic obstructive pulmonary disease (COPD) or Alzheimer's disease.

22. 18. The pharmaceutical composition of claim 17, wherein the disease or condition is nerve damage.

23. 23. The pharmaceutical composition of claim 22, wherein the neurological injury is stroke, traumatic brain injury, or spinal cord injury.

24. 18. The pharmaceutical composition of claim 17, wherein the disease or condition is chronic pain.

25. 25. The pharmaceutical composition of claim 24, wherein the chronic pain is caused by post-operative pain, tension headache, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica.

26. 26. The pharmaceutical composition of claim 25, wherein the chronic pain condition is caused by trigeminal autonomic cephalopathy.

27. 27. The pharmaceutical composition according to claim 26, wherein the trigeminal autonomic cephalopathy is selected from episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).

28. 28. The pharmaceutical composition of claim 27, wherein the trigeminal autonomic cephalopathy is episodic or chronic CH.

29. The pharmaceutical composition of claim 17, wherein the disease is a psychiatric disorder.

30. 30. The pharmaceutical composition of claim 29, wherein the psychiatric disorder is depression, anxiety, addiction, post-traumatic stress disorder, eating disorders, or obsessive-compulsive behavior.

31. 31. The pharmaceutical composition of claim 30, wherein the psychiatric disorder is depression.

32. 30. The pharmaceutical composition of claim 29, wherein the psychiatric disorder is anxiety.

33. 18. The pharmaceutical composition of claim 17, wherein the disease or condition is a neurodegenerative disease selected from Alzheimer's disease, Huntington's disease, and Parkinson's disease.

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