Psilocybin and O-acetylpsilocin, salts and solid state forms thereof
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Publication Number
US-11945832-B2
Publication Date
2024-04-02
Expiration Date
Abstract
Disclosed herein are salts and solid-state forms of psilocybin, including psilocybin HCl, and salts and solid forms of O-acetylpsilocin, including O-acetylpsilocin fumarate. Also disclosed are methods for making the salts and solid forms and methods for administering the salts and solid forms. The salts and solid forms disclosed herein are useful for treating neurological disease and/or a psychiatric disorder in a subject.
Core Innovation
The invention relates to solid-state forms and salts of psilocybin and O-acetylpsilocin, including psilocybin edisylate Form A, psilocybin mesylate Form A, psilocybin·HCl, O-acetylpsilocin fumarate, and O-acetylpsilocin salt/maleate Form A. The crystalline form of psilocybin edisylate is characterized by X-ray powder diffraction diffractograms with characteristic peaks measured with Cu Kα radiation.
The disclosure also includes extensive characterization of psilocybin forms and related crystalline materials using XRPD, DSC, TG, DVS, and NMR. The document additionally characterizes polymorph Form B of O-acetylpsilocin phosphate by XRPD matched to single-crystal data, with reported unit cell parameters and a monoclinic C2/c (15) space group.
The selected solid-state forms and salts are intended to provide improved properties, including thermal stability, solubility, hygroscopicity, dissolution, and bioavailability. The disclosure further relates to pharmaceutical compositions comprising the solid-state forms or salts together with pharmaceutically acceptable excipients, and to administration for treating neurological and psychiatric disorders and increasing neuronal plasticity and/or neurotrophic factor expression.
In addition, the document describes combination schedules for a serotonin receptor modulator and psilocybin or O-acetylpsilocin, including pretreatment and post-treatment paradigms. The serotonin receptor modulators include 5-HT2A modulators such as eplivanserin, ketanserin, volinanserin, and pimavanserin, as well as ritanserin, nelotanserin, pruvanserin, flibanserin, olanzapine, risperidone, and quetiapine.
Claims Coverage
The provided claims focus on crystalline forms of psilocybin edisylate (Form A) defined by XRPD peak fingerprints measured with Cu Kα radiation, with three independent XRPD characterizations across claims 1–3. Additional claim coverage includes pharmaceutical compositions and treatment methods involving administration of an amount equivalent to psilocybin, with oral administration and narrowed disorder scope in dependent claims.
Psilocybin edisylate Form A defined by XRPD peak set using Cu Kα radiation (7.0°–13.4° peaks)
A crystalline form of psilocybin edisylate (Form A) characterized as having an XRPD diffractogram with characteristic peaks at 7.0±0.2°, 9.1±0.2°, 11.6±0.2°, 13.1±0.2°, and 13.4±0.2° 2-Theta, as measured with Cu Kα radiation.
Psilocybin edisylate Form A defined by XRPD peak set using Cu Kα radiation (9.0°–18.5° peaks)
A crystalline form of psilocybin edisylate (Form A) characterized as having an XRPD diffractogram with characteristic peaks at 9.0±0.2°, 11.6±0.2°, 13.0±0.2°, 16.4±0.2°, and 18.5±0.2° 2-Theta, as measured with Cu Kα radiation.
Pharmaceutical composition containing crystalline psilocybin edisylate (Form A)
A pharmaceutical composition comprising the crystalline form together with a pharmaceutically acceptable excipient.
Method of treating neurological and/or psychiatric disorders
A method of treating neurological and/or psychiatric disorders in a human by administering the crystalline Form A in amounts equivalent to psilocybin within defined ranges, including narrowed disorder categories and oral administration.
Overall, the claim coverage centers on defining psilocybin edisylate Form A through XRPD diffractogram characteristic peaks measured with Cu Kα radiation. The claim set also links the crystalline form to pharmaceutical compositions and treatment methods, including administering an amount equivalent to about 10 mg to about 50 mg of psilocybin and narrowed disorder scope such as treatment resistant depression and major depressive disorder.
Stated Advantages
Improved thermal stability of selected solid-state forms/polymorphs.
Improved solubility.
Reduced or controlled hygroscopicity.
Improved dissolution.
Improved bioavailability.
Attenuation of serotonin receptor activation via the use of a serotonin receptor modulator and timing/modified-release strategies with O-acetylpsilocin.
Attenuating serotonin receptor activation associated with psilocybin through temporal administration/release of a serotonin receptor modulator.
Documented Applications
Treatment of neurological and psychiatric disorders, including depression and treatment resistant depression.
Treatment of addiction or substance use disorder.
Treatment of anxiety.
Treatment of post-traumatic stress disorder and suicidal ideation.
Treatment of major depressive disorder, bipolar disorder, and schizophrenia.
Treatment of stroke and traumatic brain injury.
Methods that increase neuronal plasticity and/or neurotrophic factor expression.
Combination therapy with serotonin receptor modulators, including 5-HT2A modulators.
Combination regimen use in which a serotonin receptor modulator is administered as pretreatment or post-treatment relative to administration or release of an O-acetylpsilocin psychedelic, including O-acetylpsilocin salt/maleate Form A and O-acetylpsilocin fumarate.
Use of modified-release strategies with O-acetylpsilocin fumarate combinations to enable sequential exposure and attenuation of serotonin receptor activation.
Combination use cases involving serotonin receptor modulators with psilocybin mesylate Form A or other psilocybin salts/solids under specified pretreatment and post-treatment timing paradigms.
Co-administration schedules involving a serotonin receptor modulator and O-acetylpsilocin salt/solid forms using specified release/ordering concepts to achieve temporal control relative to psychedelic dosing.
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