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EP4587426A1 - Formes cristallines de psilocine - Google Patents

Formes cristallines de psilocine

Info

Publication number
EP4587426A1
EP4587426A1 EP23864880.2A EP23864880A EP4587426A1 EP 4587426 A1 EP4587426 A1 EP 4587426A1 EP 23864880 A EP23864880 A EP 23864880A EP 4587426 A1 EP4587426 A1 EP 4587426A1
Authority
EP
European Patent Office
Prior art keywords
crystalline form
acid
psilocin
crystalline
peaks
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23864880.2A
Other languages
German (de)
English (en)
Inventor
Jim GILLIGAN
Peter Guzzo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tryp Therapeutics Inc
Original Assignee
Tryp Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tryp Therapeutics Inc filed Critical Tryp Therapeutics Inc
Publication of EP4587426A1 publication Critical patent/EP4587426A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/124—Acids containing four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to psilocin crystalline forms.
  • the present invention relates to psilocin crystalline forms having improved physical properties such as aqueous solubility and stability.
  • Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a psychoactive compound which is naturally- occurring, and may be isolated from psilocybin mushrooms. In vivo psilocybin is rapidly dephosphorylated to psilocin which is the psychoactive compound. Research into the therapeutic benefits of psilocybin and its active metabolite psilocin has led to the use of these psychoactives for the treatment of a variety of conditions including drug dependence, anxiety, depression, PTSD and eating disorders and chronic pain.
  • Both psilocin and psilocybin have limited stability in aqueous solutions and such solutions rapidly degrade on exposure to light.
  • the active agent psilocin has a relatively low solubility in aqueous media, which limits its ability to be used in, for example a dosage form suitable for intravenous or subcutaneous injection.
  • microdosing i.e., administering psilocin or psilocybin in quantities much lower than typical therapeutic or recreational doses
  • microdosing i.e., administering psilocin or psilocybin in quantities much lower than typical therapeutic or recreational doses
  • psilocin formulations which can reliably be used to accurately administer low doses, for example maintenance doses.
  • Crystalline or amorphous solid forms of a pharmaceutically active agents can exist as singlecomponent and multiple-component solids.
  • Single-component solids consist essentially of the agent in the absence of other substances.
  • Single-component crystalline materials may exist as different polymorphs, which have different three-dimensional arrangements of the component.
  • different polymorphs may have differing properties such as stability, solubility, melting point, reactivity, and other processability variations.
  • Multiple-component solids comprising two or more ionic species are referred to as salts.
  • a pharmaceutical active or its salt may also exist in forms such as hydrates, solvates or cocrystals.
  • Multiple- component crystal forms may also exhibit polymorphism if the components exist in more than one three- dimensional crystalline arrangement, with each form exhibiting potentially different physical properties.
  • Cocrystals are crystalline molecular complexes of two or more compounds bound together in a crystal lattice by non-ionic interactions.
  • Pharmaceutical cocrystals are cocrystals of an active agent and one or more compounds referred to as coformers.
  • Typical coformers include non-toxic pharmaceutically acceptable substances, such as a food additives, preservatives, pharmaceutical excipients, or other active agents.
  • the acid or coformer may be selected from one or more of acetic acid, aconitic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, erythorbic acid, fumaric acid, gentisic acid, glutamic acid, glycolic acid, hydrochloric acid, maleic acid, phosphoric acid, pyroglutamic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, arginine, lysine, methyl paraben, nicotinamide and ethyl acetate.
  • Besylate Form A is characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 4.
  • butyrate Form A may be characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 7.
  • Figure 3 shows an 1 H NMR spectrum of psilocin free base.
  • Figure 11 shows an indexing solution for psilocin gentisate Form A with the following characteristics:
  • Figure 12 shows an 1 H NMR spectra of psilocin gentisate Form A before drying (top middle) and after drying (bottom middle), including reference spectra for psilocin free base (top) and gentisic acid (bottom).
  • MTBE refers to Methyl tert-butyl ether
  • THF Tetrahydrofuran
  • agg refers to aggregates/agglomerates
  • B/E refers to birefringence/extinction
  • IV refers to intravenous
  • LIMS refers to laboratory information management system
  • min refers to minute(s)
  • N2 refers to nitrogen
  • API Material X refers to material confirmed to contain the API but of unknown crystalline form.
  • Single crystalline phase refers to circumstances where an XRPD pattern is judged to contain evidence of a single crystalline phase if all the Bragg peaks can be indexed with a single unit cell.
  • X-ray amorphous refers to circumstances where diffuse scatter is present, but no evidence for Bragg peaks in an XRPD pattern.
  • X-ray amorphous materials may be:
  • thermodynamic amorphous material • thermodynamic amorphous material or a combination of the above. Additional analysis may differentiate among these options.
  • the crystalline forms described herein may provide enhanced physical properties, such as solubility, dissolution rate, bioavailability, physical stability, chemical stability, flowability, fractability, or compressibility.
  • a given API may form different cocrystals with one or more different counter-molecules, and some of these cocrystals may exhibit enhanced solubility or stability.
  • crystalline form of psilocin is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt may be selected from any pharmaceutically acceptable salt known in the art.
  • the pharmaceutically acceptable salt is a base form of an acid.
  • the acid may be selected from the group consisting of acetic acid, aconitic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, erythorbic acid, fumaric acid, gentisic acid, glutamic acid, glycolic acid, hydrochloric acid, maleic acid, phosphoric acid, pyrogluamic acid, sorbic acid, succinic acid, sulfuric acid and tartaric acid.
  • the crystalline form of a pharmaceutically acceptable salt of psilocin is a cocrystal comprising a coformer.
  • the coformer may be any pharmaceutically acceptable coformer known in the art.
  • the coformer is arginine, acetylsalicylic acid, glucose, nicotinic acid, aconitic acid, glutamic acid, oxalic acid, adipic acid, glutaric acid, proline, 4-aminosalicylic acid, glycine, propyl gallate, ascorbic acid, glycolic acid, pyroglutamic acid, benzoic acid, hippuric acid, saccharin, camphoric acid, 1- hydroxy-2-naphthoic acid, salicylic acid, capric acid, ketoglutaric acid, sebacic acid, cinnamic acid, lysine, sodium lauryl sulfate, citric acid, magnesium bromide, sorbic acid,
  • the coformer is selected from the group consisting of arginine, lysine, methyl paraben, nicotinamide and ethyl acetate.
  • the coformer is ethyl acetate.
  • a crystal form comprising (a) psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof and (b) a coformer.
  • an amorphous form comprising (a) psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof and (b) a coformer.
  • the ratio of psilocin to acid is 1 :5, 1 :4, 1 :3, 1 :2, 1 :1 , 2:1 , 3:1 , 4:1 , or 5:1 mol/mol.
  • the solvent may be selected from ethyl acetate or acetone.
  • the reaction between psilocin with the pharmaceutically acceptable acid is conducted at a lowered temperature, preferably from about 2-8 °C. In some embodiments, the drying is conducted under vacuum at ambient temperature.
  • the present invention provides use of the crystalline form or pharmaceutical composition, as described herein, in the manufacture of a medicament for treating or preventing a disease or condition.
  • Materials exhibiting unique crystalline XRPD patterns are assigned sequential alphabetical characters as the default designation, if no other character types already pertain to the compound. Each uniquely identified material is assigned a new designation, which includes the chemical name of the guest used. The designation is tentatively associated with the term "Material” until the phase purity and chemical composition is determined through further characterization. Presence of psilocin, composition determination, and verification of phase uniformity are necessary before the term "Form" is used.
  • Besylate Form A was generated from a salt formation experiment in EtOAc using 1 :1 mol/mol psilocin and benzenesulfonic acid, followed by drying.
  • the XRPD pattern ( Figure 4) was successfully indexed ( Figure 5).
  • the indexing solution is consistent with an unsolvated mono-salt.
  • Tracrium® Atracurium Besylate
  • Cleviprex® Clevidipine Butyrate
  • AZEDRA® iobenguane I 131 injection, for IV use, contains sodium gentisate as an excipient (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209607s000lbl.pdf).
  • Acetate Form A was generated from a reaction between psilocin and acetic acid (1 :1 mol/mol) in EtOAc. The solids were dried under vacuum at ambient temperature before analysis. The XRPD pattern ( Figure 13) was successfully indexed ( Figure 14). Based on the indexing solution, Acetate Form A can be an unsolvated material.
  • the 1 H NMR spectrum of Acetate Form A ( Figure 15) is consistent with psilocin chemical structure, containing 1 mole of acetic acid and 0.03 moles of EtOAc. Peak shifts were observed compared with the spectrum of psilocin free base, indicative of salt formation. Therefore Acetate Form A is likely an unsolvated mono-salt.
  • Fumarate Form A was dried under vacuum at ambient temperature for 1 day, and the sample converted to a mixture of Fumarate Form B and minor unknown secondary phase(s). The 1 H NMR spectrum of this mixture is consistent with that of Fumarate Form A, containing 0.2 moles of acetone. From an additional salt experiment with fumaric acid in IPA, followed by drying under vacuum, a single phase of Fumarate Form B was generated. This XRPD pattern was successfully indexed and the indexing solution is consistent with an unsolvated hemi-fumarate.
  • Psilocin Tartrate Form A was generated from a reaction between psilocin and tartaric acid (1 :1 mol/mol) in acetone. The solids were dried under vacuum at ambient temperature before analysis. The XRPD pattern ( Figure 23) was successfully indexed ( Figure 24). Based on the indexing solution, Tartrate Form A can be unsolvated for a 1 :1 salt. The 1 H NMR spectrum of Tartrate Form A ( Figure 25) is consistent with psilocin chemical structure, containing 1 mole of tartaric acid and 0.1 moles of acetone. Peak shifts were observed compared with the spectrum of psilocin free base, indicative of salt formation.
  • Succinate Material A To complete the salt reaction and remove residual psilocin and acid, the mixture was re-slurried in EtOAc. In the re-slurried material, psilocin and succinic acid are not present. However an additional phase is observed. This mixture was not further analyzed.
  • the wavelength used to calculate d-spacings was 1 .5405929A, the Cu-Ka1 wavelength (Phys. Rev. A56(6) 4554-4568 (1997)). Variability associated with d-spacing estimates was calculated from the USP recommendation, at each d-spacing, and provided in the respective data tables.
  • variable hydrates and solvates may display peak variances greater than 0.2° 20 and therefore peak variances of 0.2° 20 are not applicable to these materials.
  • peak tables contain data identified only as "Prominent Peaks”. These peaks are a subset of the entire observed peak list. Prominent peaks are selected from observed peaks by identifying preferably non-overlapping, low-angle peaks, with strong intensity.
  • assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Reproducibility among XRPD patterns from multiple samples analyzed on a single diffractometer indicates that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks”.
  • Example 4 Comparison of psilocin salt and psilocin free base solubility in saline
  • Psilocin besylate, psilocin butyrate, psilocin gentisate, and psilocin free base were prepared at 1 .0 mg/mL in saline. Psilocin free base was also prepared at 0.1 mg/mL. Solubility of material in solution was observed and pH was recorded (Table 13)
  • Example 5 Psilocin salt and psilocin free base stability in saline
  • Solid-state stability may be assessed using a temperature/humidity control chamber.
  • a sample of each crystalline form is placed in the chamber and exposed to various temperatures and humidities, for example 25° C/60% RH, 40° C/75% RH, 70° C./75% RH, and/or irradiated with a Xenon lamp.
  • the crystalline form, thermal behavior, purity and/or weight change of the resultant sample after the exposure or irradiation may be evaluated by using one or more of XRPD, thermogravity/differential thermal analysis, differential scanning calorimetry, high performance liquid chromatography, or a microbalance.
  • each crystalline form will be stable.
  • the solid-state stability study after storage at 25° C/60% RH, or 40° C/75% RH, or 70° C./75% RH for one week, two weeks, one month, or two months the crystalline forms described herein will be chemically and physically stable
  • Example 7 Prophetic Example - Photostability
  • Example 8 Prophetic Example - Forced Degradation
  • a test will be carried out to assess the stability of the psilocin crystalline forms and free base psilocin to oxidative degradation. Forced degradation of the psilocin salts will be performed in H2O2, for example 0.3 % H202to test the oxidative stability of each crystalline form.
  • the appropriate volume of H2O2 will be added to a pre-weighed sample of the crystalline form in an amber vial (or other vial shieled from light) to give a maximum concentration of, for example 0.2 mg/mL of psilocin (free base equivalent).
  • the samples will be stored at 25°C and the purity of each sample was assessed periodically thereafter by HPLC. For example the samples may be assessed at 0, 1 , 6, and 24 hours using HPLC.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes cristallines de sels ou de co-cristaux de psilocine (4-hydroxy-N,N-diméthyltryptamine), ainsi que des compositions, des procédés de préparation et des procédés d'utilisation correspondants. La présente invention concerne également lesdites formes cristallines ayant des propriétés physiques améliorées telles que la solubilité aqueuse et la stabilité, les formes cristallines et leurs compositions étant appropriées pour une administration orale, sous-cutanée, intraveineuse ou intramusculaire.
EP23864880.2A 2022-09-12 2023-09-12 Formes cristallines de psilocine Pending EP4587426A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263375305P 2022-09-12 2022-09-12
PCT/IB2023/059011 WO2024057193A1 (fr) 2022-09-12 2023-09-12 Formes cristallines de psilocine

Publications (1)

Publication Number Publication Date
EP4587426A1 true EP4587426A1 (fr) 2025-07-23

Family

ID=90274467

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23864880.2A Pending EP4587426A1 (fr) 2022-09-12 2023-09-12 Formes cristallines de psilocine

Country Status (6)

Country Link
EP (1) EP4587426A1 (fr)
JP (1) JP2025530158A (fr)
AU (1) AU2023343417A1 (fr)
CA (1) CA3267523A1 (fr)
IL (1) IL319227A (fr)
WO (1) WO2024057193A1 (fr)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB912715A (en) * 1958-02-21 1962-12-12 Sandoz Ltd 4-hydroxytryptamines
US20080293695A1 (en) * 2007-05-22 2008-11-27 David William Bristol Salts of physiologically active and psychoactive alkaloids and amines simultaneously exhibiting bioavailability and abuse resistance
CA3210966A1 (fr) * 2021-02-10 2022-08-18 Eleusis Therapeutics Us, Inc. Sels de psilocine de qualite pharmaceutique et leurs utilisations
CN117177959A (zh) * 2021-03-18 2023-12-05 赛本爱尔兰有限公司 裸头草碱类似物、盐、组合物和使用方法
WO2022251169A1 (fr) * 2021-05-24 2022-12-01 Canna-Chemistries Llc Sels cristallins de psilocine
EP4486448A1 (fr) * 2022-03-04 2025-01-08 Reset Pharmaceuticals, Inc. Co-cristaux ou sels comprenant de la psilocine
US11667607B1 (en) * 2022-06-30 2023-06-06 Zylorion Health Inc. Crystalline forms of compositions comprising psilocin and psilocybin

Also Published As

Publication number Publication date
AU2023343417A1 (en) 2025-03-13
WO2024057193A1 (fr) 2024-03-21
JP2025530158A (ja) 2025-09-11
IL319227A (en) 2025-04-01
CA3267523A1 (fr) 2024-03-21

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