WO2022123232A1 - Pharmaceutical composition comprising psilocybin or its polymorphs - Google Patents

Pharmaceutical composition comprising psilocybin or its polymorphs Download PDF

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Publication number
WO2022123232A1
WO2022123232A1 PCT/GB2021/053199 GB2021053199W WO2022123232A1 WO 2022123232 A1 WO2022123232 A1 WO 2022123232A1 GB 2021053199 W GB2021053199 W GB 2021053199W WO 2022123232 A1 WO2022123232 A1 WO 2022123232A1
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Prior art keywords
composition
psilocybin
polymorph
peaks
xrpd
Prior art date
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PCT/GB2021/053199
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French (fr)
Inventor
Fiona DUNBAR
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Beckley Psytech Limited
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Priority claimed from GBGB2019237.3A external-priority patent/GB202019237D0/en
Priority claimed from GBGB2101638.1A external-priority patent/GB202101638D0/en
Priority claimed from GBGB2105858.1A external-priority patent/GB202105858D0/en
Priority claimed from GBGB2114043.9A external-priority patent/GB202114043D0/en
Application filed by Beckley Psytech Limited filed Critical Beckley Psytech Limited
Publication of WO2022123232A1 publication Critical patent/WO2022123232A1/en
Priority to PCT/GB2022/053123 priority Critical patent/WO2023105222A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • This invention relates to pharmaceutically acceptable compositions of psilocybin, psilocin or a prodrug thereof.
  • the invention relates to formulations and uses of the same as a medicament.
  • Psilocybin [3-(2-Dimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate
  • Psilocybin is a pharmacologically active compound of the tryptamine class and has the chemical formula:
  • Psilocybin is a psychoactive/psychedelic prodrug substance found in nature. Psilocybin is rapidly dephosphorylated in the body to psilocin, which is a partial agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. It is believed that psilocin binds with high affinity to 5-HT 2 receptors and low affinity to 5-HTi receptors, including 5-HTIA and 5-HTw; effects are also mediated via 5-HT2C receptors.
  • psilocybin is not well understood and uses of this compound have not been well explored. Further, psilocybin is not easy to handle, and is often taken with the consumption of mushrooms containing the substance, and there are challenges in formulating it for effective delivery in a controlled way in pharmaceutically useful compositions.
  • composition comprising a pharmaceutically effective amount of psilocybin, psilocin or a prodrug thereof, wherein the psilocybin, psilocin or a prodrug thereof, has been synthesised, or has been isolated from a naturally occurring substance or product.
  • compositions for use in a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)
  • the composition comprises a pharmaceutically effective amount of psilocybin, psilocin or a prodrug thereof, wherein the psilocybin, psilocin or a prodrug thereof, has been synthesised, or has been isolated from a naturally occurring substance or product.
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • the invention provides for improved formulations and uses of psilocybin, psilocin or a prodrug thereof.
  • Psilocybin is often taken in the form of mushrooms containing this substance. As such, this means it is difficult to regulate the amount ingested by a patient, and so this limits its use and effectiveness as a controlled and deliverable pharmaceutical product. Treatments using psilocybin are likewise detrimentally limited.
  • SUNHA Short lasting unilateral neuralgiform headaches
  • SUNCT short acting neuralgiform headaches with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • Lamotrigine has been associated with Stevens Johnson Syndrome, immune-complex mediated hypersensitivity reactions with high mortality and morbidity.
  • Commonly reported adverse events with gabapentin include: ataxia, dizziness, drowsiness, fatigue, fever, nystagmus disorder, sedated state, and viral infections.
  • Adverse events reported with topiramate include anxiety, arthralgia, asthenia, ataxia, confusion, diarrhea, diplopia, dizziness, drowsiness, dysphasia, fatigue, lack of concentration, memory impairment, nausea, nervousness, paresthesia, psychomotor disturbance, speech disturbance, depression, visual disturbance, weight loss, renal calculi dysgeusia, mood changes, and anorexia.
  • hypothalamus plays a major role in generating SUNHA and that psilocybin's therapeutic effects are exerted via the hypothalamus.
  • the posterior hypothalamus has a modulatory role in the nociceptive and autonomic pathways, specifically the trigeminovascular nociceptive pathways. It is proposed that central disinhibition of the trigemino-autonomic reflex by the posterior hypothalamus accounts for the occurrence of cranial autonomic symptoms together with the pain of SUNHA.
  • the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.05mg to lOOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of O.lmg to 50mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.5mg to lOmg.
  • the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of lmg to lOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.005mg to lOOmg.
  • the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of O.OOlmg to lOOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.0005mg to lOOmg. In an embodiment the composition comprises a dosage amount of psilocybin of 5mg, 7.5mg or lOmg. In an embodiment the composition comprises a dosage amount of 5mg, 7.5mg or lOmg of polymorph A' of psilocybin.
  • the purity of the psilocybin, psilocin or a prodrug thereof has a chemical purity greater than 90, 95, 97, 99 or 99.5%, and no single impurity of greater than 1%, as determined by HPLC analysis, is present.
  • the composition has a chemical purity greater than 90, 95, 97, 99 or 99.5% and no single impurity of greater than 1%, as determined by HPLC analysis, is present.
  • the composition is substantially free of polymorph A.
  • the composition is substantially free of hydrate A.
  • the composition is substantially free of polymorph A and hydrate A.
  • the composition does not comprise more than 0.5% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 0.5% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 1% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 1% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 1.5% of any other polymorph of psilocybin other than polymorph A'.
  • the composition does not comprise more than 1.5% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 2% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 2% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 2.5% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 2.5% of any other polymorph of psilocybin, such as polymorph A or hydrate A.
  • the level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the condition(s) being treated.
  • composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. In an embodiment the composition is formulated in an oral dosage form.
  • composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
  • the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • the powder comprises particles, the particles having a median diameter of less than 2000pm, 1000pm, 500pm, 250pm, 100pm, 50pm, or 1pm.
  • the powder comprises particles, the particles having a median diameter of greater than 500pm, 250pm, 100pm, 50pm, 1pm or 0.5pm.
  • the nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.
  • the psilocybin is crystalline.
  • the psilocybin is in a polymorphic crystalline form, optionally psilocybin is Polymorph A.
  • the psilocybin is in a polymorphic crystalline form, optionally psilocybin is not Polymorph A.
  • the psilocybin is in a polymorphic crystalline form, optionally psilocybin is Polymorph A' (i.e. Polymorph A prime or form A prime).
  • the psilocybin is amorphous.
  • Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties.
  • a crystalline psilocybin Polymorph A' characterised by one or more of: a. Peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5’20 + O.l°20; b. Peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5°20 + O.l°20, but absent or substantially absent of a peak at 17.5’20 + 0.1’20; c.
  • peaks in an XRPD diffractogram may be ⁇ 0.1’20, ⁇ 0.2’20 or ⁇ 0.3’20.
  • the peak has a relative intensity, compared to a peak at 14.5’20 ⁇ 0.1’20, of less than 5%, of less than 4%, of less than 3%, of less than 2%, or of less than 1% or less.
  • psilocybin Polymorph A' exhibits an XRPD diffractogram characterised by the diffractogram summarised in anyone of Tables 1, 2 or 3.
  • psilocybin Polymorph A' exhibits an XRPD diffractogram characterised by the diffractogram summarised in anyone of Tables la, 2a or 3a.
  • XRPD Data Ambient temperature XRD (30 deg. C) was performed. Data was collected using a copper x- ray anode tube, 2-Theta range from 4-40 degrees, with step size 0.02, 1 second per step. All samples have identical patterns, with crystallinity > 95%. The data shows that the samples are polymorph A'. It is noted that Polymorph A has a characteristic small peak at 17.5 deg. 2-Theta, but this peak is absent in the XRPD for the measured samples. These samples have a peak at 10.1 deg. 2-Theta, which is absent from Polymorph A. Polymorphs A' in the prior art is thought to only form in small scale recrystallizations. However, it was found that it was possible to make polymorph A' on a large scale.
  • the psilocybin Polymorph A' comprises at least a peak at 1O.1°20 + O.l°20 in the XRPD.
  • the psilocybin Polymorph A' does not have, or does not substantially have, a peak at 17.5°20 + O.l°20 in the XRPD.
  • the peak at 17.5°20 ⁇ O.l°20 is characteristic of psilocybin Polymorph A.
  • the psilocybin Polymorph A' comprises at least 4 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A' comprises at least 5 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A' comprises at least 6 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.l°20.
  • the psilocybin Polymorph A' comprises at least 7 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + 0.1’20.
  • the psilocybin Polymorph A' comprises at least 8 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A’ comprises at least 9 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A' comprises at least 10 peaks ( ⁇ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ⁇ O.l°20.
  • the psilocybin Polymorph A' comprises at least 11, 12, 13, 14, 15 or 16 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.V20.
  • the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 3.
  • the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 4.
  • the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 5.
  • the polymorph is polymorph A' as characterised by an XRPD diffractogram as substantially illustrated in Figure 6.
  • the psilocybin Polymorph A' exhibits peaks in an XRPD diffractogram at 10.1, 14.9, 18.7, 19.4, 21.1, 25.1, 26.3 and 28.6 + 0.1 °20.
  • the polymorph is polymorph A' as characterised by a DSC thermograph as substantially illustrated in Figure 7.
  • the polymorph is polymorph A' as characterised by a minor endotherm peaking at 155.43 °C (10.767 J/g) with a preceding shoulder peaking at 142.49°C and a main endotherm peaking at 221.09°C (79.782 J/g) in a DSC thermograph.
  • the polymorph is polymorph A' as characterised by a endotherm peaking at ca. 155°C with a preceding shoulder peaking at around 142 °C and a main endotherm peaking at ca. 221°C in a DSC thermograph.
  • the polymorph is polymorph A' as characterised by optical microscopy images as substantially illustrated in any one of Figures 8 to 13.
  • the polymorph is polymorph A' as characterised by an onset of melt during hot stage microscopy from 227°C.
  • the polymorph is polymorph A' as characterised by a completion of melt during hot stage microscopy by 234°C.
  • polymorph is polymorph A' as characterised by a DSC thermograph as substantially illustrated in Figure 15.
  • the polymorph is polymorph A' as characterised by a DVS isotherm profile as substantially illustrated in Figure 18.
  • the composition comprises an anhydrous form of psilocybin.
  • the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 19
  • the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 20.
  • the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 23.
  • the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 24.
  • the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 27.
  • the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 28.
  • the composition comprises a form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 21.
  • composition comprises a form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 25. In an embodiment, the composition comprises a form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 29.
  • the composition comprises a form of psilocybin as characterised by a DVS isotherm profile a substantially illustrated in Figure 26.
  • the composition comprises a form of psilocybin as characterised by a DVS isotherm profile a substantially illustrated in Figure 22.
  • the peaks in an XRPD diffractogram according to polymorph A' are within the scope of experimental error based on conditions and device used for 20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ O.O5°20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.1’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.15’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.2’20.
  • the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.25’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.3’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.4’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 0.5’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are + 1’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ⁇ 1.5’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are + 2’20.
  • composition comprises one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
  • the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N- dimethyl chitosan, chitosan chloride), -cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean TMC
  • composition disclosed herein above for use in a method of treatment of a human or animal subject by therapy.
  • the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, treatment resistant depression anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
  • sleep regulation such as insomnia
  • analgesics such as chronic pain
  • migraines migraines
  • trigeminal autonomic cephalgias such as short-lasting
  • Treatment of the above conditions may be beneficially improved by taking the invention.
  • the method of treatment is a method of treatment of alcohol-related diseases and disorders, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, benzodiazepine abuse or dependence related disorders, and/or opioid-related disorders.
  • the method of treatment is a method of treatment of tobacco addiction. In an embodiment, the method is a method of reducing tobacco use. In an embodiment, the method of treatment is a method of treatment of nicotine addiction. In an embodiment, the method is a method of reducing nicotine use.
  • the method of treatment is a method of treating alcohol abuse and/or addiction. In an embodiment, the method of treatment is a method of reducing alcohol use.
  • the method of treatment is a method of treating or preventing heavy drug use.
  • the method of treatment is a method of treating or preventing heavy drug use, including, but not limited to, alcohol, tobacco, nicotine, cocaine, methamphetamine, other stimulants, phencyclidine, other hallucinogens, marijuana, sedatives, tranquilizers, hypnotics, and opiates. It will be appreciated by one of ordinary skill in the art that heavy use or abuse of a substance does not necessarily mean the subject is dependent on the substance.
  • the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
  • the method of treatment excludes the treatment of cluster headache or migraine; and/or the treatment of any headache-related disorder not disclosed in this application.
  • the composition is to be administered one or more times a year. In an embodiment the composition is to be administered one or more times a month. In an embodiment the composition is to be administered one or more times a week. In an embodiment the composition is to be administered one or more times a day. In an embodiment the composition is to be administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is to be administered together with a complementary treatment and/or with a further active agent. In an embodiment the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent.
  • the further active agent is a psychedelic compound, optionally a tryptamine.
  • the further active agent is lysergic acid diethylamide (LSD), or 5-methoxy-N,N-dimethyltryptamine (SMeODMT) or a salt thereof.
  • the further active agent is selected from: nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetaminophen (Excedrin, Tylenol), aspirin, diclofenac (Cataflam), ibuprofen (Advil, Motrin), ketorolac (Toradol), naproxen (Aleve); Ergotamines such as dihydroergotamine (DHE-45, Migranal), ergotamine (Ergomar), ergotamine and caffeine (Cafatine, cafergot, cafetrate, Ercaf, Migergot, Wigraine), methysergide (Sansert), methylergonovine (Methergine); Triptans such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), naratriptan (Amerge), rizatriptan (Maxalt, Maxalt-MLT), sumatriptan
  • the further active agent is an antidepressant compound.
  • the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.
  • the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Ami
  • the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline).
  • the complementary treatment is psychotherapy. In an embodiment the complementary treatment is supported by an app, program, digital assistant and/or digital diary. In an embodiment, the complementary treatment is a prescription digital therapeutic (PDT). In an embodiment, PDTs are evidence-based therapeutic interventions driven by high quality software programs to prevent, manage, or treat a medical disorder or disease.
  • Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; also these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day.
  • a composition as herein described for the manufacture of a medicament for the treatment of trigeminal autonomic cephalgias optionally wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a method of treating trigeminal autonomic cephalgias optionally wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA) in a patient by the administration of a composition as described herein.
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a composition for use in a method of treatment of trigeminal autonomic cephalgias wherein the composition comprises 5-10mg of a polymorph of psilocybin, and wherein the polymorph is not polymorph A; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a composition for use in a method of treatment of trigeminal autonomic cephalgias wherein the composition comprises 5-10mg of a polymorph of psilocybin, and wherein the polymorph is polymorph A'; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a composition for use in a method of treatment of trigeminal autonomic cephalgias wherein the composition comprises 7.5-10mg of a polymorph of psilocybin, and wherein the polymorph is not polymorph A; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a composition for use in a method of treatment of trigeminal autonomic cephalgias (, wherein the composition comprises 7.5-10mg of a polymorph of psilocybin, and wherein the polymorph is polymorph A'; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
  • a composition for use in a method of treatment of trigeminal autonomic cephalgias wherein the composition comprises a pharmaceutically effective amount of a polymorph of psilocybin which is not polymorph A; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • the polymorph is polymorph A'.
  • the polymorph is polymorph A' as disclosed herein.
  • compositions as defined in herein for the manufacture of a medicament for the treatment of trigeminal autonomic cephalgias; wherein the trigeminal autonomic cephalgias is shortlasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
  • SUNCT conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • Figure 1 is a schematic route for the synthesis of psilocybin and psilocin.
  • Figure 2 is a schematic route for the preparation of a powder form of psilocybin or psilocin.
  • Figure 3 is an XRPD diffractogram of Polymorph A' of Psilocybin.
  • Figure 4 is an XRPD diffractogram of Polymorph A' of Psilocybin.
  • Figure 5 is an XRPD diffractogram of Polymorph A' of Psilocybin.
  • Figure 6 shows an XRPD diffractogram of Psilocybin batch PSC.40(3)0820 of Psilocybin.
  • Figure 7 shows a DSC and TGA thermograph overlay of Psilocybin batch PSC.40(3)0820, acquired at 10°C min 1 heating rate.
  • Figure 8 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x4 objective lens; no immersion oil; non-polarised light.
  • Figure 9 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the xlO objective lens; no immersion oil; non-polarised light.
  • Figure 10 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x4 objective lens; dispersed in immersion oil; non-polarised light.
  • Figure 11 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the xlO objective lens; dispersed in immersion oil; non-polarised light.
  • Figure 12 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x50 objective lens; dispersed in immersion oil; non-polarised light.
  • Figure 13 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x50 objective lens; dispersed in immersion oil; polarised light.
  • Figure 14 shows hot stage microscopy stills of Psilocybin batch PSC.40(3)0820.
  • Figure 15 shows a DSC thermograph overlay of Psilocybin batch PSC.40(3)0820 pre- and post-185°C thermal manipulation.
  • Figure 16 shows a XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 pre- and post-185°C thermal manipulation.
  • Figure 17 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 post-185°C thermal manipulation.
  • Figure 18 shows a DVS isothermal plot of Psilocybin batch PSC.40(3)0820.
  • Figure 19 shows an XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 input and ex-DVS 90 %RH.
  • Figure 20 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 ex-DVS 90 %RH.
  • Figure 21 shows a DSC thermograph for Psilocybin batch PSC.40(3)0820 ex-DVS (90 %RH).
  • Figure 22 shows a DVS staggered isothermal plot of Psilocybin batch PSC.40(3)0820.
  • Figure 23 shows an XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 input and ex-DVS 0 %RH.
  • Figure 24 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 ex-DVS 0 %RH.
  • Figure 25 shows a DSC thermograph overlay of Psilocybin batch PSC.40(3)0820 ex-DVS at 0%RH.
  • Figure 26 shows a DVS 1 cycle isothermal plot of Psilocybin batch PSC.40(3)0820.
  • Figure 1 shows an XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 input, ex-DVS 0 %RH 1 cycle and ex-DVS 0 %RH 3 cycles.
  • Figure 28 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 ex-DVS 0 %RH 1 cycle.
  • Figure 29 shows a DSC thermograph overlay of Psilocybin batch PSC.40(3)0820, ex-DVS at 0 %RH 1 cycle and ex-DVS at 0 %RH 3 cycles.
  • Figure 30 shows an optical micrograph of psilocybin particles.
  • Figure 31 shows an optical micrograph of psilocybin particles.
  • Figure 32 shows an optical micrograph of psilocybin particles.
  • Figure 1 shows reagent and reaction conditions as follows: (i) Ac2O, pyridine, CH2CI2, 0°C to room temperature; (ii) (COCI)2, ether, 0°C, n-hexane, then -20°C; (iii) (CH3)2NH, THF; (iv) LiAIH4, THF, A; (v) [(BnO)2PO]2O, n-BuLi, THF, -78°C to 0°C; (vi) H2, Pd/C, (vii) MeOH, room temperature.
  • FIG. 2 shows the schematic route for the formation of a powder form of psilocybin using a spray drying process.
  • SUNHA short lasting unilateral neuralgiform headaches
  • IRC International Classification of Headache Disorders
  • SUNCT/SUNHA are distinct from cluster headache and migraines.
  • TACs are divided into five subtypes: cluster headaches, paroxysmal hemicrania, SUNHA, hemicranias continua and probable autonomic cephalalgia as detailed more below.
  • SUNHA As with the other primary headache disorders, diagnosis of SUNHA is clinical.
  • the pain is paroxysmal in nature and occasionally will come in waves during one attack.
  • the severity of the pain is generally severe to excruciating.
  • the pain is usually described as stabbing, burning, pricking or electric shock-like in character.
  • Common triggers include any irritation of the trigeminal nerve such as with chewing, touching the face, brushing teeth, temperature, or loud noise.
  • the pain is usually very severe.
  • a chronic headache pattern is more common than an episodic pattern in both SUNCT and SUNA.
  • SUNHA is a rare condition, with one study showing a SUNCT prevalence of 6.6/100,000 and an incidence of 1.2/100,000. SUNHA may occur at any age and has been reported from childhood through advanced years. A male preponderance is generally reported in SUNCT but a cohort study found that it was more common in women. SUNA occurs predominantly in females.
  • SUNHA is an extremely painful and highly debilitating condition with very limited pharmacological treatment options. There is a clear need for new pharmacological treatment options for SUNHA that:
  • Psilocybin (IUPAC name [3-(2-Dimethylarninoethyl)-lH-indol-4-yl] dihydrogen phosphate) is a naturally occurring psychoactive compound found in the fruiting bodies and sclerotia of mushrooms of the Psilocybe genus.
  • psilocybin As a tryptamine compound, psilocybin has an indole ring structure, which is linked to a phosphoric acid group. In mammals it is rapidly dephosphorylated in the acidic environment of the stomach, or by alkaline phosphatase in the intestine, to produce psilocin, a phenol compound which easily crosses the bloodbrain barrier and acts as an agonist of a number of serotonin receptors. Psilocin has a high affinity for the 5-HT2A receptor, which antagonist studies indicate is responsible for its most striking behavioural and mental effects.
  • Psilocybin possesses relatively low physiological toxicity and has not been shown to result in organ damage or neuropsychological deficits. Some physiological symptoms may occur during hallucinogen action, such as dizziness, weakness, tremors, nausea, drowsiness, paresthesia, blurred vision, dilated pupils, and increased tendon reflexes. In addition, psilocybin can moderately increase pulse and both systolic and diastolic blood pressure. However, these somatic effects are usually mild without long term sequelae.
  • Psilocybin was first synthesized by Swiss chemist Albert Hofmann in the laboratories of Sandoz AG, the synthesis process followed is described in US 3075992, the disclosure thereof is incorporated by reference in its entirety.
  • reaction mixture was then diluted with ethyl acetate and filtered through an aminopropyl silica gel laminated Celite pad by suction. The pad was washed with ethyl acetate. The organic solution was quickly concentrated in vacuo, and the resulting crystals were briefly washed with MeOH to afford psilocin (14.3g, 87.5%) as white crystals.
  • the precipitated white substance was collected by filtration and washed with CH 2 CI 2 to obtain ⁇ Benzyl[2-(4-oxyindol-3- yl)ethyl]dimethylammonio ⁇ -4-O-benzyl Phosphate (10.5g, 85.2%) as a white powder.
  • Psilocin can be obtained according to the experimental procedure described above for psilocybin by following the first three steps only.
  • a schematic route for the preparation of a powder form of psilocybin or psilocin is shown in Figure 2.
  • the three main steps in the process are: 1. Spray drying a solution containing the substance(s) of interest (e.g. psilocybin inclusive of any excipients). This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.
  • Thermal examination of batch PSC.40(3)0820 demonstrated an (moderate) endotherm peaking at 155.43°C (ca. 155°C) and a main endotherm peaking at 221.09°C (ca. 221°C), which is believed to be the main melt-endotherm.
  • TGA examination revealed a minor weight reduction of 0.27 wt% from ca. 25 to 100°C which is believed to be due to residual solvent and/or water and no other events until the onset degradation that coincided with what is believed to be the main melt endotherm from ca. 210°C.
  • the DSC thermograph for batch PSC.40(3)0820 is considered to be substantially similar to that reported for Form A prime, and is believed to be influenced by the crystallinity of the solids under examination.
  • Optical microscopy examination of batch PSC.40(3)0820 revealed a particle habit of needles and batons (typically ca. 20 to 150 pm in length) that formed weak aggregates which dispersed readily under immersion oil.
  • PSC.40(3)0820 demonstrated a well-resolved crystalline diffraction pattern.
  • a list of the diffraction positions and relative intensities are shown in the table below.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 6.
  • a method of treatment as described elsewhere in this application.
  • a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)
  • SAUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table below.
  • a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application.
  • use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)).
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table above.
  • a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application.
  • use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUN A)).
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUN A short-lasting neuralgiform headaches with cranial autonomic symptoms
  • Thermal examination of batch PSC.40(3)0820 is shown in Figure 7.
  • a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 7.
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • the DSC thermograph revealed a minor endotherm peaking at 155.43°C (10.767 J/g) with a preceding shoulder peaking at 142.49°C and a main endotherm peaking at 221.09°C (79.782 J/g) that is believed to be the main melt-endotherm. Additional events above 240°C are believed to relate to thermal decomposition.
  • the minor event at ca. 100°C is an artefact of the DSC instrument used.
  • the TGA thermograph revealed a minor weight reduction of 0.270 wt% from ca. 25 to 100°C that was potentially due to residual solvent and/or water. There were no other events until the onset of degradation that coincided with the melt endotherm by DSC from ca. 210°C.
  • Optical microscopy of batch PSC.40(3)0820 revealed a particle habit of needles and batons that formed weak agglomerates that dispersed readily under immersion oil and demonstrated birefringence under polarised light.
  • the needles and batons demonstrated a visual particle length of typically ca. 20 to 150 pm, although few smaller fine needles and larger batons were observed.
  • a crystalline form of psilocybin as substantially illustrated in any one of Figures 8 to 13.
  • a method of treatment as described elsewhere in this application.
  • a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)).
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a crystalline form of psilocybin as substantially illustrated by the hot stage microscopy stills of Figure 14.
  • a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application.
  • use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)).
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 15.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 16.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 17.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table below.
  • a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application.
  • use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • Batch PSC.40(3)0820 demonstrates similar behaviour under thermal manipulation and converts to Form B.
  • an anhydrous form of psilocybin there is provided an anhydrous form of psilocybin. In an embodiment, there is provided the use of such an anhydrous form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such an anhydrous form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such an anhydrous form of psilocybin in a method of treatment of SUNCT and/or SUNA.
  • trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches
  • a crystalline form of psilocybin as characterised by a DVS isotherm as substantially illustrated in Figure 18.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 19.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table above.
  • a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 21.
  • a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application.
  • use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • DVS examination was repeated with additional RH steps during sorption and desorption with 5 %RH intervals at 0-5-10 and 70-75-80-85 %RH to assess whether a gradual desorption would afford a stable weight at 0 %RH (i.e. not demonstrate a significant drop to co. 6 wt% less than that of the input) and determine the extent of water uptake from 70 to 85 %RH (shown in Figure 22). Following isothermal cycling, the sample was equilibrated at 0 %RH for co. 20 hours before isolation and examination.
  • a water content of about 6, 11 and 16 wt% is required for a mono-, di- and tri-hydrate respectively.
  • a crystalline form of psilocybin as characterised by a DVS isotherm as substantially illustrated in Figure 22.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 23.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 24.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the tables above or below.
  • a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 25.
  • a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application.
  • use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias such as shortlasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and shortlasting neuralgiform headaches with cranial autonomic symptoms (SUN A)).
  • SUNCT shortlasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUN A shortlasting neuralgiform headaches with cranial autonomic symptoms
  • DVS examination was repeated with one isothermal cycle applied, starting with additional RH steps during sorption with 5 %RH intervals at 70-75-80-85 %RH and an additional RH step during desorption with 5 %RH intervals at 0-5-10 %RH and equilibrating at 0 %RH for ca. 14 hours to assess the impact of a reduced water uptake upon sorption and subsequent desorption upon the solid form characteristics of the material.
  • DVS examination revealed a relatively stable weight from 40 to 80 %RH during the sorption cycle until a water uptake of ca. 9 wt% upon holding at 85 %RH. This was not as significant as observed up to 90 %RH during the first DVS examination (ca. 20 wt% observed from 70 to 90 %RH) but was greater than observed following the first sorption during the second DVS examination (ca. 7.3 wt% at 85 %RH). The potentially hydrated version was stable upon desorption from 75 to 10 %RH before drying to afford what is believed to be the anhydrous version.
  • a water content of about 6 and 11 wt% is required for a mono- and di-hydrate respectively.
  • XRPD examination of the solid isolated at 0 %RH after 1 cycle revealed a crystalline diffraction pattern that matched the input ( Figure 27, Figure 28 and the table below).
  • a crystalline form of psilocybin as characterised by a DVS isotherm as substantially illustrated in Figure 26.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 27.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 28.
  • a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the tables above or below.
  • a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application.
  • use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)).
  • SUNCT short-lasting unilateral neuralgiform headache with conjunctival injection and tearing
  • SUNA cranial autonomic symptoms
  • Eligible patients - are required to have chronic SUNHA (either SUNCT/ SUNA) and experience a mean headache frequency of at least five attacks per day during the two weeks prior to the first dosing day. They are required to be on a stable dose of prescribed SUNHA medication for one month before dosing and willing to remain on this stable dose throughout the study; or to have not received prescribed SUNHA medication for at least one month prior to the psilocybin dosing.
  • Screening period - of a minimum of two-weeks will be given to all patients to confirm their eligibility including recording the frequency, duration and intensity of their headache attacks.
  • At least one preparation session will be scheduled to inform the patient about the potential effects of psilocybin as a psychedelic. Up to two further sessions, as determined necessary by the patient and/or therapist can be scheduled prior to the first dosing visit.
  • the patients After each dose, and before being discharged, the patients are to be asked if they would be willing to receive the same dose or a higher dose at the next dosing visit. If they are unwilling to receive a higher dose, they will return for the next dosing day and receive the same dose as at the last visit.
  • Cognitive tests - will be completed three times per dose level, pre-dose as a baseline, at 90 to 100 minutes post dose, and at 360 minutes post dose. This will determine psychomotor speed, visual episodic memory and learning, sustained attention, and working memory strategy.
  • the tests will include:
  • Changes in consciousness will be assessed via the five dimension-Altered States of Consciousness Scale. Changes in headache parameters will be assessed using the headache diary and the Headache Impact Test -6 (HIT-6). A Clinical Global Impression of Change (CGIC) and a Patient Global Impression of Change (PGIC) will also be performed.
  • CGIC Clinical Global Impression of Change
  • PGIC Patient Global Impression of Change
  • the below measurements are directed to efficacy assessments of the treatment, and include the patient reported headache diary record of the number and severity of daily headaches, HIT-6, PGIC and CGIC:
  • Headache severity is rated from 0 -10, with 0 being pain free and 10 being excruciating pain.
  • the Headache Impact Test-6 assesses the impact of headaches on the person's ability to function. It covers six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. The patient answers each of the six related questions using one of the following five responses: “never”, “rarely”, “sometimes”, “very often”, or “always”.
  • the HIT-6 questions are:
  • the PGIC is a seven-item scale to self-rate total improvement.
  • the patient compares their current condition to that at screening and reports change on the following scale:
  • the CGIC is a seven-item scale to rate total improvement whether or not, in the investigator's judgment, it is due entirely to drug treatment.
  • Dose 1 5mg Psilocybin
  • Dose 2 7.5mg Psilocybin
  • Dose 3 lOmg Psilocybin.
  • Psilocybin was Polymorph A'.
  • headache frequency was reduced by 50% and the overall reduction of all 3 treatment weeks compared to screening was 28%.
  • the HIT-6 score reflects the severe impact of the headache attacks on the patient's daily life. At least 2 of the 6 items on the HIT-6 improved after each dose compared to baseline, indicating that the negative impact of the headaches on daily life was lessened with the psilocybin treatment.
  • psilocybin reduced the mean number of daily headaches by 28%, reduced the percentage of days with severely painful headaches by 38% and also, significantly, resulted in the occurrence of headache free days.
  • the negative impact of the headaches on daily life was lessened with the psilocybin treatment in view of both the patient and clinician.
  • the method of treatment does not include a method of treatment of cluster headaches. In an embodiment, the method of treatment does not include a method of treatment of any headache conditions or trigeminal autonomic cephalgias, other than SUNCT or SUNA (or SUNHA).
  • Drying the hydrated particles in a vacuum oven afforded irregular shaped particles ranging from ca. 7 to 170 microns with a maximum aspect ratio of ca. 9:1, but achieving a low water content e.g. >0.5% required a prolonged period. Drying the hydrated particles under a relative humidity of 1% also afforded irregular shaped particles ranging from ca. 4 to 260 microns with a maximum aspect ratio of ca. 13:1.
  • polymorph A' is obtained from hydrate A.
  • polymorph A' is obtained from dehydration of hydrate A.
  • polymorph A' is obtained from dehydration under vacuum of hydrate A.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of an inert atmosphere, of hydrate A.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere, of hydrate A.
  • the vacuum pressure is lmbar.
  • the vacuum pressure is between lmbar and lOmbar.
  • the vacuum pressure is between 0.5mbar and lOmbar.
  • the vacuum pressure is between 0.25mbar and 20mbar.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of 50ml/min, of hydrate A.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 40 to 60ml/min, of hydrate A.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 30 to 70ml/min, of hydrate A.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 20 to 80ml/min, of hydrate A. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 10 to 90ml/min, of hydrate A.
  • polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 10 to lOOml/min, of hydrate A.
  • high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from hydrate A.
  • high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from hydrate A by promoting the formation of large hydrated psilocybin particles prior to drying under a (mild) vacuum.
  • high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from hydrate A by promoting the formation of large hydrated psilocybin particles prior to drying under a (mild) vacuum accompanied by a flow of nitrogen gas.
  • the flow rate is between 10 to lOOml/min.
  • the flow rate is 50ml/min.
  • a process of controlled crystallization to produce psilocybin or a polymorph thereof for direct use in a pharmaceutical product.
  • psilocybin particles with a particle size range suitable for direct use in a pharmaceutical product.
  • psilocybin polymorph A' particles with a particle size range suitable for direct use in a pharmaceutical product.

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Abstract

A composition for use in a method of treatment of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA), wherein the composition comprises a pharmaceutically effective amount of psilocybin, psilocin or a prodrug thereof, wherein the psilocybin, psilocin or a prodrug thereof, has been synthesised, or has been isolated from a naturally occurring substance or product.

Description

PHARMACEUTICAL COMPOSITION COMPRISING PSILOCYBIN OR ITS POLYMORPHS
Field of the invention
This invention relates to pharmaceutically acceptable compositions of psilocybin, psilocin or a prodrug thereof. In particular, though not exclusively, the invention relates to formulations and uses of the same as a medicament.
Background of the invention
Psilocybin ([3-(2-Dimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate) is a pharmacologically active compound of the tryptamine class and has the chemical formula:
Figure imgf000002_0001
Psilocybin is a psychoactive/psychedelic prodrug substance found in nature. Psilocybin is rapidly dephosphorylated in the body to psilocin, which is a partial agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. It is believed that psilocin binds with high affinity to 5-HT2 receptors and low affinity to 5-HTi receptors, including 5-HTIA and 5-HTw; effects are also mediated via 5-HT2C receptors. However, psilocybin is not well understood and uses of this compound have not been well explored. Further, psilocybin is not easy to handle, and is often taken with the consumption of mushrooms containing the substance, and there are challenges in formulating it for effective delivery in a controlled way in pharmaceutically useful compositions.
There remains a need in the art for improved formulations and uses of psilocybin.
Summary of the invention
Herein disclosed, there is provided a composition comprising a pharmaceutically effective amount of psilocybin, psilocin or a prodrug thereof, wherein the psilocybin, psilocin or a prodrug thereof, has been synthesised, or has been isolated from a naturally occurring substance or product.
Herein disclosed, there is provided a composition for use in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), wherein the composition comprises a pharmaceutically effective amount of psilocybin, psilocin or a prodrug thereof, wherein the psilocybin, psilocin or a prodrug thereof, has been synthesised, or has been isolated from a naturally occurring substance or product.
Herein disclosed, there is provided a composition for use in a method of treatment of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA), wherein the composition comprises a pharmaceutically effective amount of psilocybin, psilocin or a prodrug thereof, wherein the psilocybin, psilocin or a prodrug thereof, has been synthesised, or has been isolated from a naturally occurring substance or product. In a first aspect of the invention, there is provided a composition for use in a method of treatment of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) or shortlasting neuralgiform headaches with cranial autonomic symptoms (SUNA), wherein the composition comprises a pharmaceutically effective amount of psilocybin.
The invention provides for improved formulations and uses of psilocybin, psilocin or a prodrug thereof. Psilocybin is often taken in the form of mushrooms containing this substance. As such, this means it is difficult to regulate the amount ingested by a patient, and so this limits its use and effectiveness as a controlled and deliverable pharmaceutical product. Treatments using psilocybin are likewise detrimentally limited.
Short lasting unilateral neuralgiform headaches (SUNHA) are rare primary headache disorders. There are two types of SUNHA, short acting neuralgiform headaches with conjunctival injection and tearing (SUNCT), and short acting neuralgiform headaches with cranial autonomic symptoms (SUNA), both may occur in episodic or chronic forms.
Due to the rarity of SUNHA treatment recommendations are based primarily on case reports. No treatments have been specifically developed and approved by regulatory authorities for SUNHA. Among the treatments tried to date lamotrigine is generally considered the most effective while gabapentin and topiramate are also regarded to be effective.
Lamotrigine has been associated with Stevens Johnson Syndrome, immune-complex mediated hypersensitivity reactions with high mortality and morbidity. Commonly reported adverse events with gabapentin include: ataxia, dizziness, drowsiness, fatigue, fever, nystagmus disorder, sedated state, and viral infections. Adverse events reported with topiramate include anxiety, arthralgia, asthenia, ataxia, confusion, diarrhea, diplopia, dizziness, drowsiness, dysphasia, fatigue, lack of concentration, memory impairment, nausea, nervousness, paresthesia, psychomotor disturbance, speech disturbance, depression, visual disturbance, weight loss, renal calculi dysgeusia, mood changes, and anorexia.
The pathophysiology of SUNCT/SUNA is largely unknown. Without wishing to be bound by theory, it is proposed that the hypothalamus plays a major role in generating SUNHA and that psilocybin's therapeutic effects are exerted via the hypothalamus. The posterior hypothalamus has a modulatory role in the nociceptive and autonomic pathways, specifically the trigeminovascular nociceptive pathways. It is proposed that central disinhibition of the trigemino-autonomic reflex by the posterior hypothalamus accounts for the occurrence of cranial autonomic symptoms together with the pain of SUNHA.
In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.05mg to lOOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of O.lmg to 50mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.5mg to lOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of lmg to lOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.005mg to lOOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of O.OOlmg to lOOmg. In an embodiment the composition comprises a dosage amount of psilocybin, psilocin or a prodrug thereof, in the range of 0.0005mg to lOOmg. In an embodiment the composition comprises a dosage amount of psilocybin of 5mg, 7.5mg or lOmg. In an embodiment the composition comprises a dosage amount of 5mg, 7.5mg or lOmg of polymorph A' of psilocybin. In an embodiment, the purity of the psilocybin, psilocin or a prodrug thereof, has a chemical purity greater than 90, 95, 97, 99 or 99.5%, and no single impurity of greater than 1%, as determined by HPLC analysis, is present. In an embodiment, the composition has a chemical purity greater than 90, 95, 97, 99 or 99.5% and no single impurity of greater than 1%, as determined by HPLC analysis, is present. In an embodiment, the composition is substantially free of polymorph A. In an embodiment, the composition is substantially free of hydrate A. In an embodiment, the composition is substantially free of polymorph A and hydrate A. In an embodiment, the composition does not comprise more than 0.5% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 0.5% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 1% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 1% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 1.5% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 1.5% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 2% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 2% of any other polymorph of psilocybin, such as polymorph A or hydrate A. In an embodiment, the composition does not comprise more than 2.5% of any other polymorph of psilocybin other than polymorph A'. In an embodiment, the composition does not comprise more than 2.5% of any other polymorph of psilocybin, such as polymorph A or hydrate A.
The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the condition(s) being treated.
In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. In an embodiment the composition is formulated in an oral dosage form.
It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
In an embodiment the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
In an embodiment the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
In an embodiment the powder comprises particles, the particles having a median diameter of less than 2000pm, 1000pm, 500pm, 250pm, 100pm, 50pm, or 1pm.
In an embodiment the powder comprises particles, the particles having a median diameter of greater than 500pm, 250pm, 100pm, 50pm, 1pm or 0.5pm.
In an embodiment the powder comprises particles, and wherein the powder has a particle size distribution of dl0=20-60pm, and/or d50=80-120pm, and/or d90=130-300pm.
The nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet. In an embodiment the psilocybin is crystalline.
In an embodiment the psilocybin is in a polymorphic crystalline form, optionally psilocybin is Polymorph A.
In an embodiment the psilocybin is in a polymorphic crystalline form, optionally psilocybin is not Polymorph A.
In an embodiment the psilocybin is in a polymorphic crystalline form, optionally psilocybin is Polymorph A' (i.e. Polymorph A prime or form A prime).
In an embodiment the psilocybin is amorphous.
Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties.
In an embodiment, there is provided a crystalline psilocybin Polymorph A' characterised by one or more of: a. Peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5’20 + O.l°20; b. Peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5°20 + O.l°20, but absent or substantially absent of a peak at 17.5’20 + 0.1’20; c. Peaks in an XRPD diffractogram at 11.5, 12.0 and 14.5’20 + 0.1’20, but absent or substantially absent of a peak at 17.5’20 ± 0.1’20, further characterised by at least one further peak at 19.7, 21.0, 22.2, 24.3 or 27.7’20 ± 0.1’20; or d. An XRPD diffractogram as substantially illustrated in Fig. 3, 4, 5, 6 and/or 7.
In an embodiment, peaks in an XRPD diffractogram may be ± 0.1’20, ± 0.2’20 or ± 0.3’20.
It is considered that within the scope of the invention, numbers expressed to two decimal places can be rounded to one decimal place or to whole numbers.
In an embodiment, if a peak is present at 17.5’20 + 0.1’20, then the peak has a relative intensity, compared to a peak at 14.5’20 ± 0.1’20, of less than 5%, of less than 4%, of less than 3%, of less than 2%, or of less than 1% or less.
In an embodiment, psilocybin Polymorph A' exhibits an XRPD diffractogram characterised by the diffractogram summarised in anyone of Tables 1, 2 or 3.
Figure imgf000005_0001
Figure imgf000006_0001
In an embodiment, psilocybin Polymorph A' exhibits an XRPD diffractogram characterised by the diffractogram summarised in anyone of Tables la, 2a or 3a.
Figure imgf000006_0002
XRPD Data: Ambient temperature XRD (30 deg. C) was performed. Data was collected using a copper x- ray anode tube, 2-Theta range from 4-40 degrees, with step size 0.02, 1 second per step. All samples have identical patterns, with crystallinity > 95%. The data shows that the samples are polymorph A'. It is noted that Polymorph A has a characteristic small peak at 17.5 deg. 2-Theta, but this peak is absent in the XRPD for the measured samples. These samples have a peak at 10.1 deg. 2-Theta, which is absent from Polymorph A. Polymorphs A' in the prior art is thought to only form in small scale recrystallizations. However, it was found that it was possible to make polymorph A' on a large scale.
In an embodiment, the psilocybin Polymorph A' comprises at least a peak at 1O.1°20 + O.l°20 in the XRPD.
In an embodiment, the psilocybin Polymorph A' does not have, or does not substantially have, a peak at 17.5°20 + O.l°20 in the XRPD. The peak at 17.5°20 ± O.l°20 is characteristic of psilocybin Polymorph A.
In an embodiment, the psilocybin Polymorph A' comprises at least 4 peaks (± O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ± O.l°20.
In an embodiment, the psilocybin Polymorph A' comprises at least 5 peaks (± O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ± O.l°20.
In an embodiment, the psilocybin Polymorph A' comprises at least 6 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.l°20.
In an embodiment, the psilocybin Polymorph A' comprises at least 7 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + 0.1’20.
In an embodiment, the psilocybin Polymorph A' comprises at least 8 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ± O.l°20.
In an embodiment, the psilocybin Polymorph A’ comprises at least 9 peaks (± O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ± O.l°20.
In an embodiment, the psilocybin Polymorph A' comprises at least 10 peaks (± O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ± O.l°20.
In an embodiment, the psilocybin Polymorph A' comprises at least 11, 12, 13, 14, 15 or 16 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.V20.
In an embodiment, the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 3.
In an embodiment, the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 4.
In an embodiment, the psilocybin Polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram of Figure 5.
In an embodiment, the polymorph is polymorph A' as characterised by an XRPD diffractogram as substantially illustrated in Figure 6.
In an embodiment, the psilocybin Polymorph A' exhibits peaks in an XRPD diffractogram at 10.1, 14.9, 18.7, 19.4, 21.1, 25.1, 26.3 and 28.6 + 0.1 °20. In an embodiment, the polymorph is polymorph A' as characterised by a DSC thermograph as substantially illustrated in Figure 7.
In an embodiment, the polymorph is polymorph A' as characterised by a minor endotherm peaking at 155.43 °C (10.767 J/g) with a preceding shoulder peaking at 142.49°C and a main endotherm peaking at 221.09°C (79.782 J/g) in a DSC thermograph.
In an embodiment, the polymorph is polymorph A' as characterised by a endotherm peaking at ca. 155°C with a preceding shoulder peaking at around 142 °C and a main endotherm peaking at ca. 221°C in a DSC thermograph.
In an embodiment, the polymorph is polymorph A' as characterised by optical microscopy images as substantially illustrated in any one of Figures 8 to 13.
In an embodiment, the polymorph is polymorph A' as characterised by an onset of melt during hot stage microscopy from 227°C.
In an embodiment, the polymorph is polymorph A' as characterised by a completion of melt during hot stage microscopy by 234°C.
In an embodiment, polymorph is polymorph A' as characterised by a DSC thermograph as substantially illustrated in Figure 15.
In an embodiment, the polymorph is polymorph A' as characterised by a DVS isotherm profile as substantially illustrated in Figure 18.
In an embodiment, the composition comprises an anhydrous form of psilocybin.
In an embodiment, the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 19
In an embodiment, the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 20.
In an embodiment, the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 23.
In an embodiment, the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 24.
In an embodiment, the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 27.
In an embodiment, the composition comprises a form of psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as substantially illustrated in Figure 28.
In an embodiment, the composition comprises a form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 21.
In an embodiment, composition comprises a form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 25. In an embodiment, the composition comprises a form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 29.
In an embodiment, the composition comprises a form of psilocybin as characterised by a DVS isotherm profile a substantially illustrated in Figure 26.
In an embodiment, the composition comprises a form of psilocybin as characterised by a DVS isotherm profile a substantially illustrated in Figure 22.
In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are within the scope of experimental error based on conditions and device used for 20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± O.O5°20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 0.1’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 0.15’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 0.2’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 0.25’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 0.3’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 0.4’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 0.5’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are + 1’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are ± 1.5’20. In an embodiment, the peaks in an XRPD diffractogram according to polymorph A' are + 2’20.
In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients.
In an embodiment the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
In an embodiment the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N- dimethyl chitosan, chitosan chloride), -cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
In an embodiment the composition disclosed herein above for use in a method of treatment of a human or animal subject by therapy.
In an embodiment the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, treatment resistant depression anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
Treatment of the above conditions may be beneficially improved by taking the invention.
In an embodiment, the method of treatment is a method of treatment of alcohol-related diseases and disorders, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, benzodiazepine abuse or dependence related disorders, and/or opioid-related disorders.
In an embodiment, the method of treatment is a method of treatment of tobacco addiction. In an embodiment, the method is a method of reducing tobacco use. In an embodiment, the method of treatment is a method of treatment of nicotine addiction. In an embodiment, the method is a method of reducing nicotine use.
In an embodiment, the method of treatment is a method of treating alcohol abuse and/or addiction. In an embodiment, the method of treatment is a method of reducing alcohol use.
In an embodiment, the method of treatment is a method of treating or preventing heavy drug use.
In an embodiment, the method of treatment is a method of treating or preventing heavy drug use, including, but not limited to, alcohol, tobacco, nicotine, cocaine, methamphetamine, other stimulants, phencyclidine, other hallucinogens, marijuana, sedatives, tranquilizers, hypnotics, and opiates. It will be appreciated by one of ordinary skill in the art that heavy use or abuse of a substance does not necessarily mean the subject is dependent on the substance.
In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
In an embodiment the method of treatment excludes the treatment of cluster headache or migraine; and/or the treatment of any headache-related disorder not disclosed in this application.
In an embodiment the composition is to be administered one or more times a year. In an embodiment the composition is to be administered one or more times a month. In an embodiment the composition is to be administered one or more times a week. In an embodiment the composition is to be administered one or more times a day. In an embodiment the composition is to be administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is to be administered together with a complementary treatment and/or with a further active agent. In an embodiment the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent.
In an embodiment the further active agent is a psychedelic compound, optionally a tryptamine. In an embodiment the further active agent is lysergic acid diethylamide (LSD), or 5-methoxy-N,N-dimethyltryptamine (SMeODMT) or a salt thereof.
In an embodiment the further active agent is selected from: nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetaminophen (Excedrin, Tylenol), aspirin, diclofenac (Cataflam), ibuprofen (Advil, Motrin), ketorolac (Toradol), naproxen (Aleve); Ergotamines such as dihydroergotamine (DHE-45, Migranal), ergotamine (Ergomar), ergotamine and caffeine (Cafatine, Cafergot, Cafetrate, Ercaf, Migergot, Wigraine), methysergide (Sansert), methylergonovine (Methergine); Triptans such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt, Maxalt-MLT), sumatriptan (Imitrex), sumatriptan and naproxen (Treximet), zolmitriptan (Zomig); Antinausea drugs such as dimenhydrinate (Gravol), metoclopramide (Reglan), prochlorperazine (Compazine), promethazine (Phenergan), trimethobenzamide (Tigan); Opioids such as codeine, meperidine (Demerol), morphine, oxycodone (OxyContin); CGRP antagonists such as erenumab (Aimovig), fremanezumab (Ajovy); Betablockers such as atenolol (Tenormin), metoprolol (Toprol XL), nadolol (Corgard), propranolol (Inderal), timolol (Blocadren); Calcium channel blockers such as diltiazem (Cardizem, Cartia XT, Dilacor, Tiazac), nimodipine (Nimotop), verapamil (Calan, Covera, Isoptin, Verelan); Anticonvulsants such as lamotrigine (Lamictal), divalproex-sodium (Depakote, Depakote ER), gabapentin (Neurontin), levetiracetam (Keppra), pregabalin (Lyrica), tiagabine (Gabitril), topiramate (Topamax), valproate (Depakene), zonisamide (Zonegran); Botulinum toxin type A (Botox). In an embodiment the further active agent is selected from gabapentin (Neurontin), lamotrigine (Lamictal) and topiramate (Topamax).
In an embodiment the further active agent is an antidepressant compound.
In an embodiment the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.
In an embodiment the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen/Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4), Triiodothyronine (T3).
In an embodiment the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline).
In an embodiment the complementary treatment is psychotherapy. In an embodiment the complementary treatment is supported by an app, program, digital assistant and/or digital diary. In an embodiment, the complementary treatment is a prescription digital therapeutic (PDT). In an embodiment, PDTs are evidence-based therapeutic interventions driven by high quality software programs to prevent, manage, or treat a medical disorder or disease.
Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; also these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day.
In an embodiment, the use of a composition as herein described for the manufacture of a medicament for the treatment of trigeminal autonomic cephalgias; optionally wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
In an embodiment, a method of treating trigeminal autonomic cephalgias; optionally wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA) in a patient by the administration of a composition as described herein.
In an embodiment, a composition for use in a method of treatment of trigeminal autonomic cephalgias, wherein the composition comprises 5-10mg of a polymorph of psilocybin, and wherein the polymorph is not polymorph A; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
In an embodiment, a composition for use in a method of treatment of trigeminal autonomic cephalgias, wherein the composition comprises 5-10mg of a polymorph of psilocybin, and wherein the polymorph is polymorph A'; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
In an embodiment, a composition for use in a method of treatment of trigeminal autonomic cephalgias, wherein the composition comprises 7.5-10mg of a polymorph of psilocybin, and wherein the polymorph is not polymorph A; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
In an embodiment, a composition for use in a method of treatment of trigeminal autonomic cephalgias (, wherein the composition comprises 7.5-10mg of a polymorph of psilocybin, and wherein the polymorph is polymorph A'; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA). In an embodiment, a composition for use in a method of treatment of trigeminal autonomic cephalgias, wherein the composition comprises a pharmaceutically effective amount of a polymorph of psilocybin which is not polymorph A; wherein the trigeminal autonomic cephalgias is short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
In an embodiment, the polymorph is polymorph A'.
In an embodiment, the polymorph is polymorph A' as disclosed herein.
Herein disclosed is use of a composition as defined in herein for the manufacture of a medicament for the treatment of trigeminal autonomic cephalgias; wherein the trigeminal autonomic cephalgias is shortlasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA).
The present invention will now be further described with reference to the accompanying drawings, of which:
Brief description of the drawings
Figure 1 is a schematic route for the synthesis of psilocybin and psilocin.
Figure 2 is a schematic route for the preparation of a powder form of psilocybin or psilocin.
Figure 3 is an XRPD diffractogram of Polymorph A' of Psilocybin.
Figure 4 is an XRPD diffractogram of Polymorph A' of Psilocybin.
Figure 5 is an XRPD diffractogram of Polymorph A' of Psilocybin.
Figure 6 shows an XRPD diffractogram of Psilocybin batch PSC.40(3)0820 of Psilocybin.
Figure 7 shows a DSC and TGA thermograph overlay of Psilocybin batch PSC.40(3)0820, acquired at 10°C min 1 heating rate.
Figure 8 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x4 objective lens; no immersion oil; non-polarised light.
Figure 9 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the xlO objective lens; no immersion oil; non-polarised light.
Figure 10 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x4 objective lens; dispersed in immersion oil; non-polarised light.
Figure 11 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the xlO objective lens; dispersed in immersion oil; non-polarised light.
Figure 12 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x50 objective lens; dispersed in immersion oil; non-polarised light.
Figure 13 shows a micrograph of Psilocybin batch PSC.40(3)0820 under the x50 objective lens; dispersed in immersion oil; polarised light. Figure 14 shows hot stage microscopy stills of Psilocybin batch PSC.40(3)0820.
Figure 15 shows a DSC thermograph overlay of Psilocybin batch PSC.40(3)0820 pre- and post-185°C thermal manipulation.
Figure 16 shows a XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 pre- and post-185°C thermal manipulation.
Figure 17 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 post-185°C thermal manipulation.
Figure 18 shows a DVS isothermal plot of Psilocybin batch PSC.40(3)0820.
Figure 19 shows an XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 input and ex-DVS 90 %RH.
Figure 20 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 ex-DVS 90 %RH.
Figure 21 shows a DSC thermograph for Psilocybin batch PSC.40(3)0820 ex-DVS (90 %RH).
Figure 22 shows a DVS staggered isothermal plot of Psilocybin batch PSC.40(3)0820.
Figure 23 shows an XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 input and ex-DVS 0 %RH.
Figure 24 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 ex-DVS 0 %RH.
Figure 25 shows a DSC thermograph overlay of Psilocybin batch PSC.40(3)0820 ex-DVS at 0%RH.
Figure 26 shows a DVS 1 cycle isothermal plot of Psilocybin batch PSC.40(3)0820.
Figure 1 shows an XRPD pattern comparison of Psilocybin batch PSC.40(3)0820 input, ex-DVS 0 %RH 1 cycle and ex-DVS 0 %RH 3 cycles.
Figure 28 shows an XRPD pattern of Psilocybin batch PSC.40(3)0820 ex-DVS 0 %RH 1 cycle.
Figure 29 shows a DSC thermograph overlay of Psilocybin batch PSC.40(3)0820, ex-DVS at 0 %RH 1 cycle and ex-DVS at 0 %RH 3 cycles.
Figure 30 shows an optical micrograph of psilocybin particles.
Figure 31 shows an optical micrograph of psilocybin particles.
Figure 32 shows an optical micrograph of psilocybin particles.
Detailed description of the invention
Figure 1 shows reagent and reaction conditions as follows: (i) Ac2O, pyridine, CH2CI2, 0°C to room temperature; (ii) (COCI)2, ether, 0°C, n-hexane, then -20°C; (iii) (CH3)2NH, THF; (iv) LiAIH4, THF, A; (v) [(BnO)2PO]2O, n-BuLi, THF, -78°C to 0°C; (vi) H2, Pd/C, (vii) MeOH, room temperature.
Figure 2 shows the schematic route for the formation of a powder form of psilocybin using a spray drying process. As outlined hereinabove, short lasting unilateral neuralgiform headaches (SUNHA) are rare primary headache disorders. SUNCT was first described in 1978. The International Classification of Headache Disorders (ICHD) includes SUNHA within the group of Trigeminal Autonomic Cephalalgias (TAC). SUNCT/SUNHA are distinct from cluster headache and migraines. TACs are divided into five subtypes: cluster headaches, paroxysmal hemicrania, SUNHA, hemicranias continua and probable autonomic cephalalgia as detailed more below.
Figure imgf000015_0001
1. Cluster headache
1.1 Episodic cluster headache
1.2 Chronic cluster headache
2. Paroxysmal hemicrania
2.1 Episodic paroxysmal hemicrania
2.2 Chronic paroxysmal hemicrania (CPH)
3. Short-lasting unilateral neuralgiform headache attacks
3.1 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
3.1.1 Episodic SUNCT
3.1.2 Chronic SUNCT
3.2 Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA)
3.2.1 Episodic SUNA
3.2.2 Chronic SUNA
4. Hemicrania continua
4.1 Hemicrania continua, remitting subtype
4.2 Hemicrania continua, unremitting subtype
5. Probable trigeminal autonomic cephalalgia
5.1 Probable cluster headache
The diagnostic criteria for SUNHA are detailed below:
SUNHA Diagnostic Criteria
A. At least 20 attacks fulfilling criteria B-D
B. Moderate or severe unilateral head pain, with orbital, supraorbital, temporal and/or other trigeminal distribution, lasting for 1-600 seconds and occurring as single stabs, series of stabs or in a saw-tooth pattern.
C. At least one of the following cranial autonomic symptoms or signs, ipsilateral to the pain:
1. conjunctival injection and/or lacrimation
2. nasal congestion and/or rhinorrhoea
3. eyelid edema
4. forehead and facial sweating
5. forehead and facial flushing 6. sensation of fullness in the ear
7. miosis and/or ptosis
D. Attacks have a frequency of at least one a day for more than half of the time when the disorder is active
E. Not better accounted for by another ICHD-3 diagnosis.
SUNCT Diagnostic Criteria
A. Attacks fulfilling criteria for SUNHA
B. Both of conjunctival injection and lacrimation (tearing).
SUNA Diagnostic Criteria
A. Attacks fulfilling criteria for SUNHA, and criterion B below
B. Only one or neither of conjunctival injection and lacrimation (tearing).
As with the other primary headache disorders, diagnosis of SUNHA is clinical. The pain is paroxysmal in nature and occasionally will come in waves during one attack. The severity of the pain is generally severe to excruciating. The pain is usually described as stabbing, burning, pricking or electric shock-like in character. Common triggers include any irritation of the trigeminal nerve such as with chewing, touching the face, brushing teeth, temperature, or loud noise. The pain is usually very severe. The majority of patients experience attacks during both waking and sleep hours. A chronic headache pattern is more common than an episodic pattern in both SUNCT and SUNA.
SUNHA is a rare condition, with one study showing a SUNCT prevalence of 6.6/100,000 and an incidence of 1.2/100,000. SUNHA may occur at any age and has been reported from childhood through advanced years. A male preponderance is generally reported in SUNCT but a cohort study found that it was more common in women. SUNA occurs predominantly in females.
Due to the rarity of SUNHA treatment recommendations are based primarily on case reports. No treatments have been specifically developed and approved by regulatory authorities for SUNHA. Among the treatments tried to date lamotrigine is generally considered the most effective while gabapentin and topiramate are also regarded to be effective. In order to reduce the incidence of adverse events it is recommended and standard clinical practice to gradually titrate up the dose to an effective level. It may take several weeks before the drugs are effective.
SUNHA is an extremely painful and highly debilitating condition with very limited pharmacological treatment options. There is a clear need for new pharmacological treatment options for SUNHA that:
1. Are not associated with life-threatening adverse events such as Stevens Johnson Syndrome with lamotrigine or cardiac arrhythmias with intravenous lidocaine
2. Are not associated with severe adverse events with high morbidity such as diabetes with steroids, metabolic acidosis and renal calculi with topiramate and multiorgan hypersensitivity reported with gabapentin
3. Are better tolerated with fewer adverse events than the anticonvulsants currently used
4. Are more reliably effective at reducing the severity, frequency and duration of SUNHA attacks than any the available treatment options
5. Are easier to administer without the need for ECG monitoring required with intravenous lidocaine and the need for prolonged drug titration required with anticonvulsants Psilocybin (IUPAC name [3-(2-Dimethylarninoethyl)-lH-indol-4-yl] dihydrogen phosphate) is a naturally occurring psychoactive compound found in the fruiting bodies and sclerotia of mushrooms of the Psilocybe genus.
As a tryptamine compound, psilocybin has an indole ring structure, which is linked to a phosphoric acid group. In mammals it is rapidly dephosphorylated in the acidic environment of the stomach, or by alkaline phosphatase in the intestine, to produce psilocin, a phenol compound which easily crosses the bloodbrain barrier and acts as an agonist of a number of serotonin receptors. Psilocin has a high affinity for the 5-HT2A receptor, which antagonist studies indicate is responsible for its most striking behavioural and mental effects.
The classical psychedelic drugs, including psilocybin were used extensively in psychiatry before they were placed in Schedule I of the United Nations Convention on Drugs in 1967. With the Controlled Substance Act of 1970 in the US and related policies in most countries, clinical studies with psychedelics essentially ceased. In 1992, the National Institute on Drug Abuse worked with a US Food and Drug Administration advisory committee that ultimately allowed for the resumption of research of psychedelic agents. Studies of psilocybin have been undertaken in psychiatric diseases and substance use disorders. It has a well-established physiological and psychological safety profile in human laboratory and clinical research, is not known to be addictive and it is believed to have anti-addictive properties. Psilocybin possesses relatively low physiological toxicity and has not been shown to result in organ damage or neuropsychological deficits. Some physiological symptoms may occur during hallucinogen action, such as dizziness, weakness, tremors, nausea, drowsiness, paresthesia, blurred vision, dilated pupils, and increased tendon reflexes. In addition, psilocybin can moderately increase pulse and both systolic and diastolic blood pressure. However, these somatic effects are usually mild without long term sequelae.
Examples
Figure imgf000017_0001
Psilocybin was first synthesized by Swiss chemist Albert Hofmann in the laboratories of Sandoz AG, the synthesis process followed is described in US 3075992, the disclosure thereof is incorporated by reference in its entirety.
An improved synthesis process has been developed and a schematic representation of this reaction is shown in Figure 1, and involves the following steps:
4-Acetylindole:
To a solution of 4-hydroxyindole (Tokyo Kasei Kogyo Co., Ltd.; >25g/bottle, >185mmol) in anhydrous CH2CI2 (200mL) with stirring in an ice bath was added pyridine (20mL, 246mmol) and acetic anhydride (20mL, 210mmol). After the mixture was stirred for 2h at room temperature, H2O was added, and the mixture was evaporated in vacuo. The resulting concentrate was dissolved in ethyl acetate and washed twice with H2O and once with saturated NaCI. The organic phase was dried over anhydrous Na2SO and the volume reduced by evaporation to form a crystalline material, which was collected by filtration and successively washed with H2O and ethyl acetate to afford 4-acetylindole (34g; constant) as ivory white crystals.
3-Dimethylaminooxalyl-4-acetylindole:
To a solution of 4-Acetylindole (17.6g, lOOmmol) in anhydrous diethyl ether (lOOmL) with stirring in an ice bath was added oxalyl chloride (13mL, 146mmol). After stirring for 15min, n-hexane (200mL) was added, and the reaction flask was placed in a freezer and stored overnight. The resulting yellow crystals were separated from the solution by filtration and dissolved in anhydrous tetrahydrofuran (lOOmL). To this solution with stirring in an ice bath was added a 2M dimethylamine tetrahydrofuran solution (60mL, 120mmol) and pyridine (lOmL, 123mmol) over 15min. Additional anhydrous ether was added to the mixture because of solidification, and then it was stirred for 15 min at room temperature. The reaction product was separated from the solution by filtration and successively washed with n-hexane, ethyl acetate, and H2O to afford 3-dimethylaminooxalyl-4-acetylindole (22.0g, 80.0%) as an ivory white crystalline powder.
Psilocin:
To a suspension of lithium aluminium hydride (ca. 12g) in anhydrous tetrahydofuran (300mL) under an argon atmosphere was dropwise added a solution of 3-Dimethylaminooxalyl-4-acetylindole (22.0g, 80mmol) in anhydrous tetrahydofuran (250mL) over 2h, and then the reaction mixture was refluxed for 2h. After cooling, anhydrous Na2SO4 powder (ca. 10g) was added, and then a solution of saturated Na2SO4 (ca. 12mL) was dropwise added over lh with stirring at room temperature. After the reaction was stopped, additional anhydrous Na2SO4 powder (ca. 10g) was added. The reaction mixture was then diluted with ethyl acetate and filtered through an aminopropyl silica gel laminated Celite pad by suction. The pad was washed with ethyl acetate. The organic solution was quickly concentrated in vacuo, and the resulting crystals were briefly washed with MeOH to afford psilocin (14.3g, 87.5%) as white crystals.
{Benzyl[2-(4-oxyindol-3-yl)ethylldimethylammonio}-4-O-benzyl Phosphate.
To a solution of psilocin (5.4g, 26.4mmol) in anhydrous tetrahydofuran (255mL) with stirring at -78°C was added 2.6M n-butyllithiumin n-hexane (11.5mL, 29.9mmol). After stirring for 5min, tetrabenzylpyrophosphate (18.0g, 33.4mmol), which was prepared in almost 100% yield from dibenzyl phosphate using a literature procedure with some modification (Almeida, M. V. d.; Dubreuil, D.; Cleophax, J.; Verre-Sebrie ', C; Pipelier,M.; Prestat, G.; Vass, G.; Gero, S. D. Tetrahedron 1999, 55, 7251-7270), was added all at once to the mixture.
Stirring was continued for lh while the temperature was allowed to warm to 0°C. After checking the production of bis(boranylamino) [3-(2-dimethylaminoethyl)-3H-indol-4-yl] phosphate, instead of the disappearance of psilocin, aminopropyl silica gel (ca. 20g) was added to the reaction mixture, and then the mixture was diluted with ethyl acetate and filtered through a Celite pad by suction. The filtrate was concentrated in vacuo, redissolved in CH2CI2, and stored overnight. The precipitated white substance was collected by filtration and washed with CH2CI2 to obtain {Benzyl[2-(4-oxyindol-3- yl)ethyl]dimethylammonio}-4-O-benzyl Phosphate (10.5g, 85.2%) as a white powder.
Psilocybin
To a solution of {benzyl[2-(4-oxyindol-3-yl)ethyl]dimethylammonio}-4-O-benzyl phosphate (10.5g, 22.5mmol) in methanol (225mL) was added 10% palladium-activated carbon (ca. 1g) under an argon atmosphere, and the suspension was stirred under a hydrogen atmosphere at room temperature for 2 hours. Water (ca. 50mL) was then added and the mixture was stirred for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through a Celite pad by suction, and the volume was reduced by evaporation to form a crystalline material. The product was collected by filtration and washed with ethanol; to afford psilocybin as a white needle crystalline powder (5.6g, 87.5%).
Synthesis of psilocin
Psilocin can be obtained according to the experimental procedure described above for psilocybin by following the first three steps only.
Psilocybin powder
A schematic route for the preparation of a powder form of psilocybin or psilocin is shown in Figure 2. The three main steps in the process are: 1. Spray drying a solution containing the substance(s) of interest (e.g. psilocybin inclusive of any excipients). This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.
2. Drying of the atomized droplets (e.g. with nitrogen gas, optionally at an elevated temperature).
3. Separating and collecting the dried particles from the gas stream (e.g. using a cyclone separator to capture the required size fraction).
Characterisation of a batch of polymorph J ' (prime) of Psilocybin
Solid state characterisation of Psilocybin, batch PSC.40(3)0820, was performed. PSC.40(3)0820 demonstrated a well-resolved crystalline XRPD pattern. Comparison against existing XRPD patterns and reported diffraction lists suggested the material to be Form A prime.
Thermal examination of batch PSC.40(3)0820 demonstrated an (moderate) endotherm peaking at 155.43°C (ca. 155°C) and a main endotherm peaking at 221.09°C (ca. 221°C), which is believed to be the main melt-endotherm. TGA examination revealed a minor weight reduction of 0.27 wt% from ca. 25 to 100°C which is believed to be due to residual solvent and/or water and no other events until the onset degradation that coincided with what is believed to be the main melt endotherm from ca. 210°C.
The DSC thermograph for batch PSC.40(3)0820 is considered to be substantially similar to that reported for Form A prime, and is believed to be influenced by the crystallinity of the solids under examination.
Optical microscopy examination of batch PSC.40(3)0820 revealed a particle habit of needles and batons (typically ca. 20 to 150 pm in length) that formed weak aggregates which dispersed readily under immersion oil.
Thermal manipulation of batch PSC.40(3)0820 with heating to 185°C induced solid form conversion from Form A prime to Form B. This matched reported observations during thermal manipulation of Form A. No observations of the thermal manipulation of Form A prime are reported in the literature.
DVS examination of batch PSC.40(3)0820 revealed a water uptake of ca. 20 wt% from 70 to 90 %RH to afford a stable hydrate (ca. 20 % water required for a tetra-hydrate). XRPD and DSC examination of the ex-90 %RH material revealed diffraction patterns and thermographs representative of reported Hydrate A.
Isolation of DVS cycled batch PSC.40(3)0820 at 0 %RH afforded lower crystallinity material that was still characteristic of Form A' (as determined by XRPD), indicating the collapse of Hydrate A..
XRPD Examination
PSC.40(3)0820 (shown in Figure 6) demonstrated a well-resolved crystalline diffraction pattern. A list of the diffraction positions and relative intensities are shown in the table below.
In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 6. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table below. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
Figure imgf000020_0001
Differentiation between Form A and Form A prime reported in the prior art (Pattern H) show the presence of diffractions at 10.1, 14.9, 18.7, 19.4, 21.1, 25.1, 26.3 and 28.6 ± 0.1 °20, which are reportedly present in Form A prime but absent in Form A. The diffraction positions observed in batch PSC.40(3)0820 substantially match the diffraction pattern H reported in the literature. The differences in some of the peak intensities are considered to relate to the nature of the solids and their respective preferred orientations. It should also be noted that the diffraction at ca. 17.5 °20, which was reported for Form A and in pattern H of the prior art was absent in batch PSC.40(3)0820.
Figure imgf000021_0001
* Diffractions are visually evident on the diffraction pattern but were r ot detected during peak searching
In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table above. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUN A)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
Thermal Examination
Thermal examination of batch PSC.40(3)0820 is shown in Figure 7. In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 7. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
The DSC thermograph revealed a minor endotherm peaking at 155.43°C (10.767 J/g) with a preceding shoulder peaking at 142.49°C and a main endotherm peaking at 221.09°C (79.782 J/g) that is believed to be the main melt-endotherm. Additional events above 240°C are believed to relate to thermal decomposition.
The minor event at ca. 100°C is an artefact of the DSC instrument used.
The TGA thermograph revealed a minor weight reduction of 0.270 wt% from ca. 25 to 100°C that was potentially due to residual solvent and/or water. There were no other events until the onset of degradation that coincided with the melt endotherm by DSC from ca. 210°C.
Microscopy Examination
Optical microscopy of batch PSC.40(3)0820 (shown in Figure 8 to Figure 13) revealed a particle habit of needles and batons that formed weak agglomerates that dispersed readily under immersion oil and demonstrated birefringence under polarised light. The needles and batons demonstrated a visual particle length of typically ca. 20 to 150 pm, although few smaller fine needles and larger batons were observed.
In an embodiment, there is provided a crystalline form of psilocybin as substantially illustrated in any one of Figures 8 to 13. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
Thermal Manipulation Investiaations
Examination of the material by hot stage microscopy (HSM - stills shown in Figure 14) using 100 to 250°C at a heating rate of 20°C min-1, revealed no events up to ca. 150°C before the onset of significant particle excitement from ca. 155°C. Particle excitement reached a crescendo at ca. 163°C before the occurrence of excitement began to decrease from ca. 196°C and stopped by ca. 217°C. The onset of melt was observed from ca. 227°C with melt completion observed by ca. 234°C.
In an embodiment, there is provided a crystalline form of psilocybin as substantially illustrated by the hot stage microscopy stills of Figure 14. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
The prevalence of particle excitement so far above the temperature of the first DSC endotherm was noteworthy. As a result, a portion of batch PSC.40(3)0820 was subject to thermal manipulation by TGA, heating to 185°C and equilibrating at this temperature for 1 minute before cooling to ambient temperature.
Thermal examination of the post-185°C material compared against the input is shown in Figure 15. Thermal manipulation to 185°C successfully removed the first endotherm. It was observed that a minor event present at 142.52°C in the input remained relatively unchanged at 142.66°C in the thermally manipulated material.
In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 15. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 16. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 17. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table below. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA. XRPD examination of the post-185°C thermal manipulation revealed a different diffraction pattern from the input (as shown in Figure 16 and Figure 17; the peak list shown in the table below).
Figure imgf000023_0001
Batch PSC.40(3)0820 demonstrates similar behaviour under thermal manipulation and converts to Form B.
DVS Examination
DVS examination of Batch PSC.40(3)0820 (Figure 18) revealed stability from 0 to 70 %RH during the first desorption and sorption. However, a significant weight uptake of ca. 20 wt% was observed from 70 to 90 %RH, which is believed to afford a hydrated version of Psilocybin. The hydrate was stable upon desorption from 90 to 10 %RH before drying to afforded what is believed to be the anhydrous version. A water content of ca. 16 and 20 wt% is believed to be necessary for the tri- and tetra-hydrate forms respectively.
In an embodiment, there is provided an anhydrous form of psilocybin. In an embodiment, there is provided the use of such an anhydrous form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such an anhydrous form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such an anhydrous form of psilocybin in a method of treatment of SUNCT and/or SUNA.
XRPD examination of the solid isolated at 90 %RH revealed a different diffraction pattern to the input (Figure 19, Figure 20 and the table below) which was a close match with the reported diffraction pattern and peak lists for Hydrate A and believed to be Hydrate A.
Figure imgf000024_0001
Thermal examination of ex-DVS 90 %RH material (Figure 21) revealed a similar DSC thermograph to that of Hydrate A as detailed in the literature, although the primary endotherm was presented as a broad, bimodal endotherm with shoulders rather than two separate endotherms.
According to the form diagrams reported in the literature, equilibration of Pattern A, Pattern A prime and Pattern B in water will afford Hydrate A. It is believed that equilibration in 90 %RH has afforded a similar form version change.
In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DVS isotherm as substantially illustrated in Figure 18. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 19. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the table above. In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 21. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
DVS examination was repeated with additional RH steps during sorption and desorption with 5 %RH intervals at 0-5-10 and 70-75-80-85 %RH to assess whether a gradual desorption would afford a stable weight at 0 %RH (i.e. not demonstrate a significant drop to co. 6 wt% less than that of the input) and determine the extent of water uptake from 70 to 85 %RH (shown in Figure 22). Following isothermal cycling, the sample was equilibrated at 0 %RH for co. 20 hours before isolation and examination.
DVS examination of Batch PSC.40(3)0820 revealed a relatively stable weight from 0 to 75 %RH during the first desorption and sorption. The extent of weight uptake was not as significant as previously observed up to 90 %RH (ca. 20 wt% observed from 70 to 90 %RH), with the first sorption affording a total weight uptake of co. 7.3 wt% and the second sorption affording a total weight uptake of ca. 24.5 wt% that settled to co. 15.0 wt%, believed to be a hydrated version of Psilocybin during the third desorption. The hydrate was stable upon desorption from 75 to 10 %RH before drying to afford what is believed to be anhydrous version with no apparent overshoot in the weight loss at 0 %RH as previously observed.
A water content of about 6, 11 and 16 wt% is required for a mono-, di- and tri-hydrate respectively.
XRPD examination of the solid isolated at 0 %RH revealed a low crystallinity, low resolution diffraction pattern (Figure 23, Figure 24 and the table below).
Figure imgf000026_0001
In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DVS isotherm as substantially illustrated in Figure 22. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 23. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 24. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the tables above or below. In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 25. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as shortlasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and shortlasting neuralgiform headaches with cranial autonomic symptoms (SUN A)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA.
Upon initial comparison against the Form A prime input, most key diffraction peaks appeared to be present but at significantly reduced intensity and resolution. However, comparison of the peak list against Form A and Form A prime reported in the literature revealed the absence of diffractions at 18.7-18.8 and 25.1 °20; some of the diffractions characteristic of Form A prime but absent in Form A.
DVS cycling of Form A prime input afforded Hydrate A upon isolation at 90 %RH. Repeat DVS examination revealed formation of a stable hydrate before desorption to give a reduction in the material crystallinity and resolution that has an impact on the crystal lattice, having swelled to accommodate water as Hydrate A during sorption, collapsing and contracting to an anhydrous version during desorption from 10 to 0 %RH.
DVS examination was repeated with one isothermal cycle applied, starting with additional RH steps during sorption with 5 %RH intervals at 70-75-80-85 %RH and an additional RH step during desorption with 5 %RH intervals at 0-5-10 %RH and equilibrating at 0 %RH for ca. 14 hours to assess the impact of a reduced water uptake upon sorption and subsequent desorption upon the solid form characteristics of the material.
DVS examination (Figure 26) revealed a relatively stable weight from 40 to 80 %RH during the sorption cycle until a water uptake of ca. 9 wt% upon holding at 85 %RH. This was not as significant as observed up to 90 %RH during the first DVS examination (ca. 20 wt% observed from 70 to 90 %RH) but was greater than observed following the first sorption during the second DVS examination (ca. 7.3 wt% at 85 %RH). The potentially hydrated version was stable upon desorption from 75 to 10 %RH before drying to afford what is believed to be the anhydrous version.
A water content of about 6 and 11 wt% is required for a mono- and di-hydrate respectively. XRPD examination of the solid isolated at 0 %RH after 1 cycle revealed a crystalline diffraction pattern that matched the input (Figure 27, Figure 28 and the table below).
Figure imgf000028_0001
In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DVS isotherm as substantially illustrated in Figure 26. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 27. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in Figure 28. In an embodiment, there is provided a crystalline form of psilocybin as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in the tables above or below. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA. Comparison of the diffraction list of the sample against Form A and Form A prime reported in the literature revealed the presence of all diffractions reportedly characteristic of Form A prime.
T1
Figure imgf000029_0001
* Diffractions are visually evident on the diffraction pattern but not detected during peak searching
DVS cycling of Form A prime input afforded Hydrate A upon isolation at 90 %RH. Repeat DVS examination revealed formation of a stable hydrate before desorption to afford a reduction in the material crystallinity and resolution as shown by XRPD. In an embodiment, there is provided a crystalline form of psilocybin as characterised by a DSC thermograph as substantially illustrated in Figure 29. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment, as described elsewhere in this application. In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)). In an embodiment, there is provided the use of such a crystalline form of psilocybin in a method of treatment of SUNCT and/or SUNA. Ascending dose study to evaluate the effects of oral administration of on cognition in asting unilateral headache attacks
Figure imgf000030_0001
Figure imgf000030_0002
Eligible patients - are required to have chronic SUNHA (either SUNCT/ SUNA) and experience a mean headache frequency of at least five attacks per day during the two weeks prior to the first dosing day. They are required to be on a stable dose of prescribed SUNHA medication for one month before dosing and willing to remain on this stable dose throughout the study; or to have not received prescribed SUNHA medication for at least one month prior to the psilocybin dosing.
Screening period - of a minimum of two-weeks will be given to all patients to confirm their eligibility including recording the frequency, duration and intensity of their headache attacks.
During the screening period at least one preparation session will be scheduled to inform the patient about the potential effects of psilocybin as a psychedelic. Up to two further sessions, as determined necessary by the patient and/or therapist can be scheduled prior to the first dosing visit.
Active treatment - will be given to the eligible patients, and they will receive psilocybin and complete cognitive tests on each of the three dosing visits:
Day 1 (+2 day) - 5mg psilocybin polymorph A'
Day 6 (+2 day) - 7.5mg psilocybin polymorph A'
Day 11 (±2 day) - lOmg psilocybin polymorph A'
Day 16 (±2 day) a follow up visit will be conducted
After each dose, and before being discharged, the patients are to be asked if they would be willing to receive the same dose or a higher dose at the next dosing visit. If they are unwilling to receive a higher dose, they will return for the next dosing day and receive the same dose as at the last visit.
Familiarisation with the cognitive tests will also be conducted at the screening visit.
The day after each dosing visit patients will have a follow up telephone call to assess their need for further support.
Cognitive tests - will be completed three times per dose level, pre-dose as a baseline, at 90 to 100 minutes post dose, and at 360 minutes post dose. This will determine psychomotor speed, visual episodic memory and learning, sustained attention, and working memory strategy. The tests will include:
Reaction Time Index (RTI)
Paired Associates learning (PAL)
Rapid Visual Information Processing (RVP)
Spatial working memory (SWM)
Changes in consciousness will be assessed via the five dimension-Altered States of Consciousness Scale. Changes in headache parameters will be assessed using the headache diary and the Headache Impact Test -6 (HIT-6). A Clinical Global Impression of Change (CGIC) and a Patient Global Impression of Change (PGIC) will also be performed.
Patients discharged - from the clinic after an assessment by a psychiatrist. Patients reports - on the frequency, duration and intensity of the headache attacks will be collected in patient diaries, which will be completed daily from screening until the last follow-up visit.
Measurements/assessments
The below measurements are directed to efficacy assessments of the treatment, and include the patient reported headache diary record of the number and severity of daily headaches, HIT-6, PGIC and CGIC:
Headache Diary:
Patients record the number, duration and severity of headache attacks. Headache severity is rated from 0 -10, with 0 being pain free and 10 being excruciating pain.
HIT-6
The Headache Impact Test-6 (HIT-6) assesses the impact of headaches on the person's ability to function. It covers six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. The patient answers each of the six related questions using one of the following five responses: "never", "rarely", "sometimes", "very often", or "always".
The HIT-6 questions are:
1. When you have headaches, how often is the pain severe?
2. How often do headaches limit your ability to do usual daily activities including household work, work, school, or social activities?
3. When you have a headache, how often do you wish you could lie down?
4. In the past week, how often have you felt too tired to do work or daily activities because of your headaches?
5. In the past week, how often have you felt fed up or irritated because of your headaches?
6. In the past week, how often did headaches limit your ability to concentrate on work or daily activities?
PGIC
The PGIC is a seven-item scale to self-rate total improvement. The patient compares their current condition to that at screening and reports change on the following scale:
0 = Not assessed
1 = Very much improved
2 = Much improved
3 = Minimally improved
4 = No change
5 = Minimally worse
6 = Much worse
7 = Very much worse
GIC
The CGIC is a seven-item scale to rate total improvement whether or not, in the investigator's judgment, it is due entirely to drug treatment. The investigator compares the patient's current condition to that at screening and reports how much the patient has changed on the following scale: 0 = Not assessed
1 = Very much improved
2 = Much improved
3 = Minimally improved
4 = No change
5 = Minimally worse
6 = Much worse
7 = Very much worse
Efficacy evaluation
The below results are in respect of a 56-year-old female patient with a six-year history of the SUNHA condition and is under the care of a headache specialist.
In each case. Dose 1 = 5mg Psilocybin, Dose 2 = 7.5mg Psilocybin, and Dose 3 = lOmg Psilocybin. Psilocybin was Polymorph A'.
Table 1 Number of daily headaches
Figure imgf000032_0001
Table 2 Headache free days
Figure imgf000032_0002
Table 3 Number of days with at least one headaches rated >8 on pain rating scale
Figure imgf000032_0003
Table 4 HIT-6 Scores (6-7 days post dose)
Figure imgf000032_0004
* Improvements vs screening
Table 5 Patient Global Impression of Change (6-7 days post dose)
Figure imgf000033_0001
Table 6 Clinical Global Impression of Change (6-7 days post dose)
Figure imgf000033_0002
Discussion
During the above 14-day screening period the mean number of headaches was 21.7 with a range of 10-44 headaches per day and no headache free days were observed.
Following 2 of the 3 psilocybin administrations, headache frequency was reduced by 50% and the overall reduction of all 3 treatment weeks compared to screening was 28%.
The occurrence of headache free days following psilocybin treatment is particularly noteworthy. During the screening period no headache free days was observed, but in each of the treatment weeks at least one day was completely without SUNHA headaches.
During the screening period severely painful headaches (8 or greater score on 0-10 pain scale) occurred on 93% of the days, following psilocybin this was reduced to 55% of days (38% reduction).
The HIT-6 score reflects the severe impact of the headache attacks on the patient's daily life. At least 2 of the 6 items on the HIT-6 improved after each dose compared to baseline, indicating that the negative impact of the headaches on daily life was lessened with the psilocybin treatment.
Further evidence of a positive treatment effect was the assessment of the patient's condition as much improved by both the Investigator and the Patient herself.
In summary, psilocybin reduced the mean number of daily headaches by 28%, reduced the percentage of days with severely painful headaches by 38% and also, significantly, resulted in the occurrence of headache free days. The negative impact of the headaches on daily life was lessened with the psilocybin treatment in view of both the patient and clinician.
In an embodiment, the method of treatment does not include a method of treatment of cluster headaches. In an embodiment, the method of treatment does not include a method of treatment of any headache conditions or trigeminal autonomic cephalgias, other than SUNCT or SUNA (or SUNHA).
A method of synthesizing polymorph A'
Production of hydrate A resulted in large needles and acicular particles of varying length which ranged from co. 300 microns to co.1.7mm and fines of co. 15-18 microns, as shown in Figure 30. The aspect ratio of the particles ranged from 6.5:1 up to 35:1. Such particle morphologies may not be suitable for the manufacture of a pharmaceutical product, causing powder flow related issues, filtration issues and a lack of ability to uniformly dose the drug substance into a drug product. Attempts to reduce the particle size by grinding were not successful and afforded a large degree of amorphicity.
Attempts to reduce the particle size by altering the agitation rate during production of the hydrate A resulted in particles of a smaller size, as shown in Figure 31, with irregular shaped rod particles of between ca. 40 to 170 microns and with an aspect ratio of 6:1 to 1:1. However, the resultant mixture was not of high polymorphic purity and was a mixture of the hydrated and unhydrated particles.
Drying the hydrated particles in a vacuum oven afforded irregular shaped particles ranging from ca. 7 to 170 microns with a maximum aspect ratio of ca. 9:1, but achieving a low water content e.g. >0.5% required a prolonged period. Drying the hydrated particles under a relative humidity of 1% also afforded irregular shaped particles ranging from ca. 4 to 260 microns with a maximum aspect ratio of ca. 13:1.
Surprisingly, it was found that a controlled crystallization process was successful in producing psilocybin particles with high polymorphic purity and desired particle size/morphology characteristics. In such a process, the formation of large hydrated psilocybin particles is promoted prior to drying under a mild vacuum accompanied with an addition flow of nitrogen gas over the sample. Such a process combining a mild vacuum accompanied with a flow of nitrogen gas affords the production of large scale psilocybin particles of high polymorphic purity, desired particle size and limited accretions. Such particles being suitable for commercial pharmaceutical formulation and manufacture. See Figure 32.
In an embodiment, polymorph A' is obtained from hydrate A.
In an embodiment, polymorph A' is obtained from dehydration of hydrate A.
In an embodiment, polymorph A' is obtained from dehydration under vacuum of hydrate A.
In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of an inert atmosphere, of hydrate A.
In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere, of hydrate A.
In an embodiment, the vacuum pressure is lmbar.
In an embodiment, the vacuum pressure is between lmbar and lOmbar.
In an embodiment, the vacuum pressure is between 0.5mbar and lOmbar.
In an embodiment, the vacuum pressure is between 0.25mbar and 20mbar.
In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of 50ml/min, of hydrate A.
In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 40 to 60ml/min, of hydrate A.
In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 30 to 70ml/min, of hydrate A.
In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 20 to 80ml/min, of hydrate A. In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 10 to 90ml/min, of hydrate A.
In an embodiment, polymorph A' is obtained from dehydration under vacuum, in the presence of a nitrogen atmosphere with a flow rate of between 10 to lOOml/min, of hydrate A.
In an embodiment, high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from hydrate A.
In an embodiment, high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from hydrate A by promoting the formation of large hydrated psilocybin particles prior to drying under a (mild) vacuum.
In an embodiment, high purity polymorph A' with a particle size and morphology which is suitable for direct use in a pharmaceutical product is obtained from hydrate A by promoting the formation of large hydrated psilocybin particles prior to drying under a (mild) vacuum accompanied by a flow of nitrogen gas.
In an embodiment, the flow rate is between 10 to lOOml/min. Optionally, the flow rate is 50ml/min.
In an embodiment, there is provided a process of controlled crystallization to produce psilocybin or a polymorph thereof for direct use in a pharmaceutical product.
In an embodiment, there is provided a process of controlled crystallization to produce psilocybin particles with high polymorphic purity and morphology suitable for direct use in a pharmaceutical product.
In an embodiment, there is provided a process of controlled crystallization to produce psilocybin particles with high polymorphic purity and morphology suitable for direct use in a pharmaceutical product wherein the psilocybin is A'.
In an embodiment, there is provided a process of controlled crystallization to produce highly crystalline psilocybin particles with a particle size range suitable for direct use in a pharmaceutical product.
In an embodiment, there is provided a process of controlled crystallization to produce highly crystalline psilocybin polymorph A' particles with a particle size range suitable for direct use in a pharmaceutical product.
In an embodiment, there is provided psilocybin particles with a particle size range suitable for direct use in a pharmaceutical product.
In an embodiment, there is provided psilocybin polymorph A' particles with a particle size range suitable for direct use in a pharmaceutical product.
In an embodiment, there is provided highly crystalline psilocybin polymorph A'.
In an embodiment, there is provided highly crystalline psilocybin polymorph A' with a particle size range suitable for direct use in a pharmaceutical product.
In an embodiment, there is provided highly crystalline psilocybin polymorph A' as substantially illustrated in Figure 32. In an embodiment, there is provided a process that employs nitrogen or another suitable inert gas under a pressure to produce psilocybin polymorph A'.
In an embodiment, there is provided a process that employs nitrogen or another suitable inert gas under a pressure in combination with vacuum to produce psilocybin polymorph A'.

Claims

Claims
1. A composition for use in a method of treatment of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) or short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA), wherein the composition comprises a pharmaceutically effective amount of psilocybin.
2. The composition of claim 1, wherein the composition comprises polymorph A' of psilocybin.
3. The composition of claim 2, wherein polymorph A' is characterised by an XRPD diffractogram as illustrated in Figure 6.
4. The composition of claim 2, wherein polymorph A' is characterised by at least a peak at 1O.1°20 ± 0.1°26 in an XRPD diffractogram.
5. The composition of claim 3 or claim 4, wherein the polymorph does not have, or does not substantially have, a peak at 17.5°20 + O.l°20 in an XRPD diffractogram.
6. The composition of any one of claims 2, 3, 4 or 5, wherein the polymorph comprises at least 4 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.l°20.
7. The composition of any one of claims 2 to 6, wherein the polymorph comprises at least 5 peaks (± O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ± O.l°20.
8. The composition of any one of claims 2 to 7, wherein the polymorph comprises at least 6 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.l°20.
9. The composition of any one of claims 2 to 8, wherein the polymorph comprises at least 7 peaks (+ O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 + O.l°20.
10. The composition of any one of claims 2 to 9, wherein the polymorph comprises at least 8 peaks (± O.l°20) in the XRPD of any one of Tables 1, 2 or 3, and optionally absent or substantially absent of a peak at 17.5°20 ± O.l°20.
11. The composition of any one of claims 2 to 10, wherein the polymorph is characterised by a DSC thermograph as illustrated in Figure 7.
12. The composition of any one of claims 2 to 11, wherein the polymorph is characterised by an endotherm peaking at ca. 155°C (10.767 J/g) with a preceding shoulder peaking at ca. 142 °C and a main endotherm peaking at ca. 221°C (79.782 J/g) in a DSC thermograph.
13. The composition of any one of claims 2 to 12, wherein the polymorph is characterised by optical microscopy images as illustrated in any one of Figures 8 to 13.
14. The composition of any one of claims 2 to 13, wherein the polymorph is characterised by an onset of melt during hot stage microscopy from 227°C.
36 The composition of any one of claims 2 to 14, wherein the polymorph is characterised by a completion of melt during hot stage microscopy by 234°C. The composition of any one of claims 2 to 15, wherein the polymorph is characterised by a DSC thermograph as illustrated in Figure 15. The composition of any one of claims 2 to 16, wherein the polymorph is characterised by a DVS isotherm profile as illustrated in Figure 18. The composition of any one preceding claim, wherein the composition comprises an anhydrous form of psilocybin. The composition of claim 1, wherein the composition comprises psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as illustrated in Figure 19. The composition of claim 1, wherein the composition comprises psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as illustrated in Figure 20. The composition of claim 1, wherein the composition comprises psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as illustrated in Figure 23. The composition of claim 1, wherein the composition comprises psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as illustrated in Figure 24. The composition of claim 1, wherein the composition comprises psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as illustrated in Figure 27. The composition of claim 1, wherein the composition comprises psilocybin as characterised by one or more peaks in an XRPD diffractogram pattern as illustrated in Figure 28. The composition of any one of claims 18 to 24, wherein the composition comprises psilocybin as characterised by a DSC thermograph as illustrated in Figure 21. The composition of any one of claims 18 to 24, wherein the composition comprises psilocybin as characterised by a DSC thermograph as illustrated in Figure 25. The composition of any one of claims 18 to 24, wherein the composition comprises psilocybin as characterised by a DSC thermograph as illustrated in Figure 29. The composition of any one of claims 18 to 27, wherein the composition comprises psilocybin as characterised by a DVS isotherm profile as illustrated in Figure 26. The composition of any one of claims 18 to T1 , wherein the composition comprises psilocybin as characterised by a DVS isotherm profile as illustrated in Figure 22. The composition of any one of the preceding claims, wherein the composition comprises a dosage amount of psilocybin in the range of 0.05mg to lOOmg.
37 The composition of any one of the preceding claims, wherein the composition comprises a dosage amount of psilocybin in the range of O.lmg to 50mg.
The composition of any one of the preceding claims, wherein the composition comprises a dosage amount of psilocybin in the range of 0.5mg to 25mg.
The composition of any one of the preceding claims, wherein the composition comprises a dosage amount of psilocybin of 5mg, 7.5mg or lOmg.
The composition of any one of the preceding claims, wherein the composition is formulated in an oral dosage form.
The composition of any one of the preceding claims, wherein the composition comprises one or more pharmaceutically acceptable carriers or excipients.
The composition of any one of the preceding claims, wherein the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
The composition of any one of the preceding claims, wherein the composition is to be administered one or more times a year.
The composition of any one of the preceding claims, wherein the composition is to be administered one or more times a month.
The composition of any one of the preceding claims, wherein the composition is to be administered one or more times a week.
The composition of any one of the preceding claims, wherein the composition is to be administered one or more times a day.
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