WO2023135595A1 - Combinations with psilocybin for treating gastrointestinal diseases or disorders - Google Patents

Combinations with psilocybin for treating gastrointestinal diseases or disorders Download PDF

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Publication number
WO2023135595A1
WO2023135595A1 PCT/IL2023/050030 IL2023050030W WO2023135595A1 WO 2023135595 A1 WO2023135595 A1 WO 2023135595A1 IL 2023050030 W IL2023050030 W IL 2023050030W WO 2023135595 A1 WO2023135595 A1 WO 2023135595A1
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Prior art keywords
psilocybin
active agent
pharmaceutical composition
psilocin
analogs
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PCT/IL2023/050030
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French (fr)
Inventor
Asher Holzer
Noam BARNEA-YGAEL
Yaacov BUXDORF
Itai HECHT
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Psyrx Ltd.
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Publication of WO2023135595A1 publication Critical patent/WO2023135595A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • 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
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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

Definitions

  • the present invention relates to compositions and methods for treating gastrointestinal diseases or disorders.
  • the present invention relates to pharmaceutical compositions and combinations comprising psilocybin and an additional therapeutic agent for use in treating bowel diseases, such as Crohn and colitis, and immune-related gastrointestinal diseases or disorders.
  • Gastrointestinal, or stomach disorders are very common and are responsible for a significant amount of suffering and morbidity in the population.
  • Gastrointestinal disorders comprise a variety of ailments including, inter alia, constipation, irritable bowel syndrome, diverticular disease, colon polyps, and colitis.
  • Gastrointestinal disorders can be triggered by various factors, including functional changes after surgery, inherited disorders, neurologic diseases, connective tissue disorders, metabolic abnormalities, and infections.
  • Psilocybin is a small compound, naturally occurring tryptamine known for its psychedelic properties. Over 100 species of mushrooms have been found to contain psilocybin, many falling within the genus Psilocybe. Psilocybin is a prodrug metabolized through in vivo dephosphorylation to psilocin, which is presumed to be the active agent in the central nervous system. Like other classic psychedelics, the behavioral effects of psilocybin appear to be mediated primarily by agonist activity at the 5 -hydroxy tryptamine (HT)2A receptor; however, 5-HT2A activity does not appear to account fully for its effects. Psilocybin is characterized by low physiological toxicity and low abuse liability (Johnson et al. Neurotherapeutics. 2017 Jul;14(3):734-740).
  • compositions and methods comprising a psilocybin derivative.
  • 2018/0221396 discloses the use of the compositions in a method of regulating a neurotransmitter receptor, e.g., a serotonin receptor.
  • US Publication No. 2019/0192498 discloses methods and compositions for enhancing neurogenesis, resolving neuropathy and improving neurological health and functioning using fungal extracts and their active ingredients, including species of mushrooms and mycelia containing psilocybin and psilocin, combined with erinacines and hericenones or fungal extracts containing those active ingredients, with the addition of nicotinic acid.
  • US Publication No. 2019/0350949 discloses cannabinoids and/or terpenes in combination with psilocybin and/or psilocin for use in the prevention or treatment of psychological or brain disorders.
  • compositions and methods which comprise a therapeutically effective amount of a first purified psilocybin derivative and a therapeutically effective amount of a second compound selected from the group consisting of a second purified psilocybin derivative, a purified terpene, a serotonergic drug, an adrenergic drug, a dopaminergic drug, a purified erinacine, and a purified hericenone.
  • the present invention provides psilocybin, or a derivative thereof, in combination with at least one additional therapeutic agent for treating gastrointestinal-related disease or disorder.
  • the present invention further provides in some embodiments methods of treating gastrointestinal disease or disorder, in particular irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), comprising administering psilocybin and an additional therapy selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, and immunotherapy agent.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • psilocybin has a therapeutic beneficial effect on gastrointestinal disease, in particular IBD, and acts effectively with other therapies for treating gastrointestinal-related diseases or disorders.
  • the psilocybin has a beneficial effect on the gut microbiome and may potentiate drugs that treat gastrointestinal diseases.
  • the combinations described herein enable the use of reduced amounts of the active agents, which reduces side effects while maintaining or even enhancing the drug's effectiveness against the disease.
  • pharmaceutical compositions disclosed herein may have beneficial therapeutic effects on additional diseases or conditions that have been shown to be affected by gastrointestinal state such as neurodegenerative or psychiatric diseases.
  • the present invention further provides pharmaceutical compositions or combinations comprising psilocybin or psilocin for use in treating gastrointestinal disorder related to primary sclerosing cholangitis (PSC).
  • PSC primary sclerosing cholangitis
  • the present invention provides a pharmaceutical combination or composition for use in treating a gastrointestinal-related disease or disorder, said pharmaceutical combination or composition comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
  • the gastrointestinal disease is inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • Crohn's disease the inflammatory bowel disease is Crohn's disease.
  • the inflammatory bowel disease is ulcerative colitis (UC) or indeterminate colitis.
  • the gastrointestinal disease or disorder is selected from the group consisting of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastrointestinal motility disorders, constipation, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, functional heartburn, dyspepsia, visceral pain, gastroparesis, and chronic intestinal pseudo-obstruction.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • GFD gastroesophageal reflux disease
  • duodenogastric reflux functional heartburn
  • dyspepsia visceral pain
  • gastroparesis gastroparesis
  • chronic intestinal pseudo-obstruction chronic intestinal pseudo-obstruction
  • the gastrointestinal disorder is inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC).
  • IBD inflammatory bowel disease
  • PSC primary sclerosing cholangitis
  • the at least one psilocybin, psilocin, or analogs thereof; and the at least one active agent are present in a single pharmaceutical composition. According to additional embodiments, the at least one psilocybin, psilocin, or analogs thereof; and the at least one active agent are present in separate pharmaceutical compositions.
  • the active agents or active ingredients disclosed herein are the sole active agents or active ingredients within the pharmaceutical composition or combination.
  • the use comprises administering of the psilocybin, psilocin, or analogs or derivatives thereof; and the least one active agent, substantially simultaneously, concurrently, alternately, sequentially or successively.
  • the active agent is an immunosuppressive medication.
  • the active agent is a probiotic.
  • the active agent is steroid.
  • the active agent is antibiotic.
  • the active agent is an antiinflammatory agent.
  • the active agent is an immunotherapy agent.
  • the immunosuppressive medication is selected from the group consisting of Azathioprine, calcineurin inhibitor, Methotrexate, and Mercaptopurine. Each possibility represents a separate embodiment of the invention.
  • the immunosuppressive medication is Azathioprine (Imuran).
  • the calcineurin inhibitor is cyclosporine.
  • the steroid is a corticosteroid.
  • the steroid is a corticosteroid selected from the group consisting of Budesonide, Hydrocortisone, Methylprednisolone, and Prednisone. Each possibility represents a separate embodiment of the invention.
  • the at least one active agent is quinuclidine or a derivative thereof.
  • the at least one active agent exhibits a therapy selected from the group consisting of anti-tumor necrosis factor-alpha therapy, anti- integrin therapy, and anti-interleukin- 12 and interleukin-23 therapy.
  • a therapy selected from the group consisting of anti-tumor necrosis factor-alpha therapy, anti- integrin therapy, and anti-interleukin- 12 and interleukin-23 therapy.
  • the at least one active agent is selected from the group consisting of adalimumab, certolizumab, infliximab, natalizumab, vedolizumab, ustekinumab and azulfidine.
  • adalimumab certolizumab
  • infliximab natalizumab
  • vedolizumab vedolizumab
  • ustekinumab azulfidine.
  • the probiotic is Lactobacillus or
  • the anti-inflammatory agent is 5- aminosalicylate (5-ASA).
  • the at least one active agent is selected from the group consisting of Humira, Remicade, mesalamine, Stelara, Entyvio, sulfasalazine, azathioprine, Cimzia, budesonide, infliximab, adalimumab, vedolizumab, Entocort EC, Inflectra, ustekinumab, certolizumab, Renflexis, Avsola, hyoscyamine, Imuran, Risankizumab, Skyrizi, cholestyramine, rifaximin, and Azasan.
  • Humira Humira, Remicade, mesalamine, Stelara, Entyvio, sulfasalazine, azathioprine, Cimzia, budesonide, infliximab, adalimumab, vedolizumab, Entocort EC,
  • the use comprises orally administration of the at least one psilocybin, psilocin, or analogs thereof; and/or the at least one active agent.
  • the use comprises administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent in different administration routes.
  • the use comprises administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent once a day, once a week, once in two weeks, once in three weeks or once a month.
  • the present invention provides a method of treating a gastrointestinal-related disease or disorder, comprising administering to a subject in need thereof a combination of: (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and anti-inflammatory agent.
  • the gastrointestinal-related disease or disorder and the at least one active agent is as described hereinabove.
  • the method comprising administering orally, or parenterally. According to specific embodiments, the method comprising administering orally.
  • the at least one psilocybin, psilocin, or analogs thereof; and at least one active agent are administered in different routes of administration.
  • the method comprising administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent once a day, once a week, once in two weeks, once in three weeks or once a month.
  • the method is used in combination with additional therapeutic agents for treatment or prevention of gastrointestinal diseases or disorders.
  • the treatment decreases abdominal pain in said patient compared to said patient prior to treatment with the psilocybin combinations described herein.
  • the gastrointestinal disease or disorder is immune-related disease.
  • a subject according to the present invention is typically a human subject. According to other embodiments, a subject according to the present invention is a nonhuman mammal.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (1) a psilocybin, psilocin, or analogs thereof; and (2) an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent, and an antiinflammatory agent; and a pharmaceutical acceptable excipient, carrier or diluent.
  • the active agent is an immunosuppressive medication.
  • the active agent is probiotic.
  • the active agent is steroid.
  • the active agent is antibiotic.
  • the active agent is an immunotherapy agent.
  • the active agent is an antiinflammatory agent.
  • the steroid is a corticosteroid selected from the group consisting of Budesonide, Hydrocortisone, Methylprednisolone, and Prednisone.
  • a corticosteroid selected from the group consisting of Budesonide, Hydrocortisone, Methylprednisolone, and Prednisone.
  • the immunosuppressive medication is selected from the group consisting of Azathioprine, calcineurin inhibitor, Methotrexate, and Mercaptopurine. Each possibility represents a separate embodiment of the invention.
  • the immunosuppressive medication is Azathioprine (Imuran).
  • the calcineurin inhibitor is cyclosporine.
  • the active agent exhibits a therapy selected from the group consisting of anti-tumor necrosis factor-alpha therapy, anti-integrin therapy, and anti-interleukin- 12 and interleukin-23 therapy.
  • a therapy selected from the group consisting of anti-tumor necrosis factor-alpha therapy, anti-integrin therapy, and anti-interleukin- 12 and interleukin-23 therapy.
  • the active agent is selected from the group consisting of adalimumab, certolizumab, infliximab, natalizumab, vedolizumab, and ustekinumab.
  • the probiotic is Lactobacillus or
  • the anti-inflammatory agent is 5- aminosalicylate (5-ASA).
  • the pharmaceutical composition comprises a psilocybin and immunosuppressive medication.
  • the pharmaceutical composition comprises a psilocybin and probiotic.
  • the pharmaceutical composition comprises a psilocybin and steroid.
  • the pharmaceutical composition comprises a psilocybin and antibiotic.
  • the pharmaceutical composition comprises a psilocybin and an immunotherapy agent.
  • the pharmaceutical composition comprises a psilocybin and antiinflammatory agent.
  • the present invention provides a pharmaceutical composition or combination comprising: at least one psilocybin, psilocin, or analogs thereof; and at least one compound or substance with therapeutic activity against a gastrointestinal disease or disorder, for use in treating a gastrointestinal disease or disorder.
  • the gastrointestinal disease is a Crohn disease.
  • the compound or substance with therapeutic activity is Indole. According to additional embodiments, the compound or substance with therapeutic activity is tryptophan.
  • the compound or substance with therapeutic activity against a gastrointestinal disease or disorder is selected from the group consisting of immunosuppressive medication, probiotic, steroid, antibiotic and immunotherapy agent.
  • immunosuppressive medication probiotic, steroid, antibiotic and immunotherapy agent.
  • the pharmaceutical composition further comprises an excipient selected from the group consisting of emulsifiers, buffering agents, pH adjusting agents, preservatives, antioxidants, stabilizers, and combinations thereof.
  • an excipient selected from the group consisting of emulsifiers, buffering agents, pH adjusting agents, preservatives, antioxidants, stabilizers, and combinations thereof.
  • the pharmaceutical composition further comprises electrolytes, vitamins, anti-oxidants, minerals, and/or flavoring agents.
  • the pharmaceutical composition is formulated in a form of a liquid or a gel.
  • the pharmaceutical composition further comprises triglycerides, fats, lipids, oils, fatty acids, solvents or mixtures thereof.
  • the present invention provides a method of modulating 5TH receptors in the gastrointestinal tract (GI), comprising administering to a subject in need thereof: at least one agonist of psilocybin receptor; and at least one compound or substance with therapeutic activity against a gastrointestinal disease or disorder.
  • GI gastrointestinal tract
  • the psilocybin and the compound or substance with therapeutic activity against the gastrointestinal disease or disorder are as described hereinabove.
  • the present invention provides a method of treating primary sclerosing cholangitis (PSC), comprising administering to a subject in need thereof a therapeutically effective amount of a psilocybin, psilocin, or analogs thereof.
  • the method further comprises administering to the subject an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and an antiinflammatory agent.
  • the immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and an anti-inflammatory agent are as described hereinabove.
  • the present invention a pharmaceutical combination or composition for use in treating a liver-related disease or disorder, said pharmaceutical combination or composition comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent suitable for use in treating liver-related disease or disorder.
  • the at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
  • the liver-related disease is primary sclerosing cholangitis (PSC).
  • the pharmaceutical combination or composition is for use in treating the bile duct.
  • the active agent is an anti-scar medication.
  • the anti-scar medication is a corticosteroid.
  • the active agent is paclitaxel (taxol) or rapamycin (sirolimus).
  • the present invention provides a pharmaceutical composition comprising psilocybin, psilocin, or analogs or derivatives thereof, for use in treating primary sclerosing cholangitis (PSC).
  • PSC primary sclerosing cholangitis
  • the pharmaceutical composition further comprises an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and an antiinflammatory agent.
  • the present invention provides methods of treating gastrointestinal diseases or disorders comprising administering to a subject in need thereof a therapeutic effective amount of psilocybin, psilocin, or analogs thereof in combination with at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, anti-inflammatory agent and immunotherapy agent.
  • autoimmune diseases AiD
  • NIH National Institute of Health
  • AARDA American Autoimmune Related Diseases Association
  • the NIH also calculates that over $100 billion in health care costs is spent annually in the United States on treating those with autoimmune diseases, compared to cancer which has an estimated cost of $50 billion annually.
  • Autoimmunity is defined as the loss of tolerance to self-antigens in which the immune system attacks healthy tissues in an individual. While there are different characteristics of expression and tissues affected amongst the autoimmune disorder types, there are many shared mechanisms of action and potential origins. Many diseases that were initially considered to be unrelated to autoimmunity are now being reexplored as autoimmune-related, especially in the field of psychiatry. This includes major depressive disorder (MDD), schizophrenia, Parkinson’s disease, Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis.
  • MDD major depressive disorder
  • AD Alzheimer’s disease
  • AD Amyotrophic Lateral Sclerosis
  • AiDs often encompass a variety of symptoms and features, but common characteristics observed among the various types of AiD include increased vascular and epithelial (e.g., intestinal) permeability, chronic inflammation, the presence of chronic infections, dysregulated Hypothalamic -pituitary- adrenal axis (HPA axis), mitochondrial dysfunction, and microbiome dysbiosis (Thompson, C. and A. Szabo, Immunology letters, 2020).
  • IBD inflammatory bowel disease
  • Crohn's disease mainly involves the gastrointestinal tract.
  • ulcerative colitis inflammation and sores are confined morphologically and microscopically to the mucosa, the innermost surface of the colon and the rectum.
  • Crohn’s disease the infection is granulomatous and transmural, affecting the entire gastrointestinal tract from the mouth to the anus, with the skip area in-between.
  • Crohn’s disease is a progressive disease that leads to bowel damage and disability that results from a complex interplay between genetic susceptibility, environmental factors, and altered gut microbiota, which leads to dysregulated innate and adaptive immune responses.
  • the intestinal microflora takes part in bidirectional communication between the gut and the brain.
  • scientists suggest that human gut microflora may even act as the “second brain” and be responsible for neurodegenerative disorders like AD.
  • This axis includes the enteric nervous system, consisting of neurons embedded in the lining of the gastrointestinal tract, the parasympathetic and sympathetic branches of the autonomous nervous system, and the neuroendocrine and neuro-immune system.
  • a key concept is the gut microbiome, a collection of microorganisms in the gut that is regarded as a critical node in the brain-gut axis.
  • microbiota can influence CNS function and vice versa via effects on the gastrointestinal tract.
  • scientific evidence of this gut-brain axis interaction was provided by an animal study in which gut microbiota-free rats, transplanted with microbiota from depressed patients, developed depression-like features.
  • the idea that alterations in the brain immunomodulation are critical for AD pathogenesis provides the most integrative view on this cognitive disorder, considering that converging research lines have revealed the involvement of inflammatory processes in AD (Maccioni, R.B. et al., Academy of Sciences, 2009. 1153(1): p. 240-246).
  • AD neuropathology is strongly associated with the activation of inflammatory pathways, and long-term use of antiinflammatory drugs reduces the risk of developing the disease (Currais, A. et al., Journal of ethnopharmacology, 2014. 155(1): p. 830-840).
  • Pharmacological management of Crohn’s disease and ulcerative colitis typically involves a stepwise approach, and remission induction usually includes antiinflammatory drugs such as 5-aminosalicylate (5-ASA) for mild diseases, and corticosteroids for moderate and severe disease, or immune modifying agents such as thiopurine (azathioprine, 6-mercaptopurine), methotrexate, with addition of or switching to biologies for refractory cases.
  • antiinflammatory drugs such as 5-aminosalicylate (5-ASA) for mild diseases, and corticosteroids for moderate and severe disease
  • immune modifying agents such as thiopurine (azathioprine, 6-mercaptopurine), methotrexate
  • antibodies with targeted action on inflammation proteins that are used in the treatment of IBD usually include antitumor necrosis factor (anti-TNF) such as adalimumab and infliximab, and non anti- TNF such as vedolizumab and ustekinumab (Ho, C. and C. Argaez, Sequencing of Pharmacological Management of Crohn’s Disease and Ulcerative Colitis: A Review of Guidelines. 2019).
  • anti-TNF antitumor necrosis factor
  • vedolizumab and ustekinumab Ho, C. and C. Argaez, Sequencing of Pharmacological Management of Crohn’s Disease and Ulcerative Colitis: A Review of Guidelines. 2019).
  • psilocybin includes any isoform, crystalline form, or salts thereof.
  • the psilocybin is in a crystalline form selected from the group consisting of Hydrate A, Polymorph A, Polymorph B, and any combination thereof.
  • the psilocybin described herein comprises more than one crystalline form.
  • the present invention provides a pharmaceutical combination or composition for use in treating a gastrointestinal-related disease or disorder, said pharmaceutical combination or composition comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
  • the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and an immunosuppressive medication.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and Azathioprine (Imuran).
  • the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and probiotic.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and steroid.
  • the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and antibiotic.
  • the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and an immunotherapy agent.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and quinuclidine or a derivative thereof.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Humira.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Remicade.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) mesalamine.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Stelara.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) sulfasalazine.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Entyvio.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) azathioprine.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Cimzia.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) budesonide.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) infliximab.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) adalimumab.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) vedolizumab.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Entocort EC.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Inflectra.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) ustekinumab.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) certolizumab.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Renflexis.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Avsola.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) hyoscyamine.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Imuran.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Risankizumab.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Skyrizi.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) cholestyramine.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Azasan.
  • the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) rifaximin.
  • the pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention provides a pharmaceutical combination comprising: (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, an antiinflammatory agent, antibiotic, and immunotherapy agent.
  • pharmaceutical combination refers to either a pharmaceutical composition comprising one or more active pharmaceutical ingredient and one or more second therapeutic compounds or a pharmaceutical composition comprising an active therapeutic ingredient co-administered with a second therapeutic compound. According to some embodiments, the terms pharmaceutical combination and pharmaceutical composition are used herein interchangeably.
  • compositions of the present invention may be artificially synthesized.
  • ingredients which are found in natural sources such as plant or fungi sources, may be extracted or purified from the natural sources.
  • the present invention encompasses artificially synthesized compounds as well as compounds extracted and/or purified from natural sources.
  • compositions according to the present invention may be in a form selected from the group consisting of a pill, a tablet, a caplet, a capsule, a softgel, a powder, and a lozenge. Additional suitable forms include sublingual and/or buccal administration compositions, sachets, bars, gummies, gummy caps, in yogurt and in functional foods and functional drinks. Compositions according to the present invention may be formulated for administration as a nasal spray. Compositions according to the present invention may also be formulated for administration via routs such as intravenous (IV), subcutaneous (SC), intramuscular (IM) and intraperitoneal (IP), or using inhalers and inhalation vaporizers. Each of the aforementioned possibilities represents a separate embodiment of the present invention. According to additional embodiments, the pharmaceutical composition is formulated for injectable administration.
  • IV intravenous
  • SC subcutaneous
  • IM intramuscular
  • IP intraperitoneal
  • the pharmaceutical composition or combination is formulated for an oral administration use.
  • the pharmaceutical composition or combination is formulated in a form of a liquid or a gel. According to other embodiments, the pharmaceutical composition or combination is a non-aqueous composition.
  • the pharmaceutical composition or combination is formulated as a capsule, a tablet, a liquid, or a syrup.
  • the dosage form is granules or pellets delivered in a sachet or filled into capsule or compressed into a tablet.
  • the pharmaceutical composition or combination further comprises triglycerides, fats, lipids, oils, fatty acids, co-solvents or mixtures thereof.
  • the pharmaceutical composition or combination comprises an edible oil or fat.
  • the pharmaceutical composition comprises an edible oil selected from the group consisting of copaiba oil, coconut oil, cottonseed oil, soybean oil, safflower oil, sesame oil, sunflower oil, castor oil, corn oil, olive oil, palm oil, peanut oil, and poppy seed oil.
  • the pharmaceutical composition further comprises electrolytes, vitamins, minerals, and/or flavoring agents.
  • the pharmaceutical composition is formulated for slow release of the active component. According to some embodiments, the pharmaceutical composition is formulated for slow release of psilocybin. In certain embodiments, the pharmaceutical composition further comprises a release retarding agent or a mixture of release retarding agents. According to some embodiments, the pharmaceutical composition is at least partly coated by an enteric-coating agent.
  • the composition is a gel, wherein the psilocybin component or the at least one active agent is entrapped in a gel matrix.
  • Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability for a given formulation provides an estimate of the relative fraction of the orally administered dose that is absorbed into the systemic circulation. Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs. Insufficient time for absorption in the gastrointestinal tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (e.g., if it is highly ionized and polar), time at the absorption site may be insufficient. Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver, both of which are common sites of first-pass metabolism (metabolism that occurs before a drug reaches systemic circulation).
  • the bioavailability enhancing agent is an edible oil or fat, a protective colloid, or both a protective colloid and an edible oil or fat.
  • the bioavailability enhancing agent is also a lipophilic active agent taste masking agent.
  • the bioavailability of the lipophilic active agent in a subject is at least about 2 times, 5 times, or 10 times greater than the bioavailability of the lipophilic active agent in the subject in the absence of the bioavailability enhancing agent.
  • the pharmaceutical composition or combination comprises at least one micelle-forming compound selected from the group consisting of a polyoxyethylene ether, ester or alcohol; an alkali metal alkyl sulfate; a bile acid; lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening of primrose oil, trihydroxy oxo-cholanylglycine, glycerin, poly glycerin, lysine, polylysine, triolein, salts thereof, and mixtures thereof.
  • a micelle-forming compound selected from the group consisting of a polyoxyethylene ether, ester or alcohol; an alkali metal alkyl sulfate; a bile acid; lecithin, hyaluronic acid, pharmaceutically acceptable
  • the pharmaceutical composition or combination comprises phospholipids.
  • the pharmaceutical composition comprises a phospholipid selected from the group consisting of naturally occurring phospholipids and synthetic phospholipids.
  • the synthetic phospholipid is selected from the group consisting of phosphocholines, phosphoethanolamines, phosphatidic acids, phosphoglycerols, phosphoserines, mixed chain phospholipids, lysophospholipids, pegylated phospholipids, and a combination thereof. Each possibility represents a separate embodiment of the invention.
  • the phospholipid may form micelles, emulsions or liposomes. According to some embodiments, the phospholipid forms liposomes. According to some embodiments, the pharmaceutical composition further comprises cholesterol.
  • the pharmaceutical composition or combination comprises cyclodextrins.
  • the cyclodextrin is selected from the group consisting of hydroxypropyl P-cyclodextrin, sulfobutylether P-cyclodextrin, and methyl-P-cyclodextrin (MpCD) and combinations thereof.
  • the pharmaceutical composition or combination comprises a pharmaceutically acceptable solvent, i.e, a non-toxic solvent that is suitable for administration to a mammal with no unacceptable adverse effects.
  • a pharmaceutically acceptable solvent i.e, a non-toxic solvent that is suitable for administration to a mammal with no unacceptable adverse effects.
  • the solvent may be an aqueous or non-aqueous solvent.
  • the pharmaceutical composition or combination may optionally contain a stabilizer and/or a preservative.
  • the pharmaceutically carrier is an aqueous carrier.
  • the pharmaceutical composition or combination may also comprise one or more of the following additional additives: inorganic salts, antioxidants, colorants and flavoring agents.
  • inorganic salts include sodium, potassium, calcium and zinc salts, especially sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate.
  • antioxidants include tocopherol, methyl paraben, ethyl paraben, ascorbic acid and mixtures thereof.
  • flavoring agents include menthol, sorbitol and fruit flavors.
  • Such additional additives may comprise between about 0.1 and 5 wt./wt. % of the composition.
  • Orally administered formulations such as tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • sustained refers to a composition which provides prolonged, long or extended release of the therapeutic agent. This term may further refer to a composition which provides prolonged, long or extended duration of action (pharmacokinetics) of the pharmaceutical composition of the present invention.
  • the pharmaceutical composition or combination may include additional ingredients including but not limited to the excipients described herein.
  • one or more therapeutic agents of the dosage unit may exist in an extended or control release formulation and additional therapeutic agents may not exist in extended release formulation.
  • the pharmaceutical composition or combination further comprises at least one pharmaceutically acceptable excipient.
  • the excipient is selected from the group consisting of emulsifiers, buffering agents, pH adjusting agents, tonicity modifiers, preservatives, antioxidants, stabilizers, and a combination thereof.
  • the pharmaceutically acceptable carrier is an aqueous carrier.
  • the aqueous carrier is a physiologically acceptable buffer having physiological or near-physiological pH.
  • the pharmaceutical composition or combination further comprises one or more vitamins including, but not limited to, vitamin A, vitamin C, vitamin D (e.g., vitamin DI, D2, D3, D4, and/or D5), vitamin E, vitamin Bl (thiamine), vitamin B2 (e.g., riboflavin), vitamin B3 (e.g., niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (e.g., folate or folic acid), vitamin B12 (cobalamin), and vitamin K (e.g., vitamin KI, K2, K3, K4, and Ks), and choline.
  • vitamins including, but not limited to, vitamin A, vitamin C, vitamin D (e.g., vitamin DI, D2, D3, D4, and/or D5), vitamin E
  • the pharmaceutical composition or combination comprises alcohol and a solvent.
  • the alcohol is ethanol.
  • the solvent is polyethylene glycol (PEG) or propylene glycol.
  • the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) an immunosuppressive medication.
  • the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) probiotic.
  • the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) steroid.
  • the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) antibiotic.
  • the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and an immunotherapy agent.
  • the present invention provides a pharmaceutical combination for treating a gastrointestinal-related disease or disorder, comprising: (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, anti-inflammatory agent and immunotherapy agent.
  • the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, and immunotherapy agent; to provide a combination therapy having an enhanced therapeutic effect compared to the effect of the psilocybin, psilocin, or analogs or derivatives thereof and the at least one active agent each administered alone.
  • gastrointestinal disease refers to any disease affecting the gastrointestinal tract or intestinal tract. This includes but not limited to diseases of the esophagus, stomach, first, second, and third part of the duodenum, jejunum, ileum, the ileo-cecal complex, large intestine (ascending, transverse, and descending colon), sigmoid colon, rectum, and anus.
  • gastrointestinal disease or disorder further refers to diseases of the accessory organs of digestion such as, but not limited to, of liver, gallbladder, and pancreas.
  • disorder refers to a disease or other pathological condition that associates with or that one of its symptoms includes gastrointestinal illness or discomfort.
  • an effective amount refers to the amount of the agent necessary to elicit the desired biological response.
  • the effective amount of an agent may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue or cell, and the like.
  • the term "effective amount” refers to an amount sufficient to produce the desired effect, e.g., to reduce or ameliorate the severity, duration, progression, or onset of a disease, disorder, or condition, or one or more symptoms thereof; prevent the advancement of a disease, disorder, or condition, cause the regression of a disease, disorder, or condition; prevent the recurrence, development, onset or progression of a symptom associated with a disease, disorder, or condition, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • a "therapeutically effective amount" of the psilocybin combinations described herein refers to an amount that is effective for preventing, ameliorating, or treating the specified disease or disorder.
  • treatment includes but is not limited to, alleviating a symptom of a disease or condition; and/or reducing, suppressing, inhibiting, lessening, or affecting the progression, severity, and/or scope of a disease or condition.
  • Amelioration or any grammatical variation thereof (e.g., ameliorate, ameliorating, and amelioration etc.), as used herein, includes, but is not limited to, delaying the onset, or reducing the severity of a disease or condition. Amelioration, as used herein, does not require the complete absence of symptoms.
  • the term “subject” designates a mammal, preferably a human, but may also designate an animal receiving veterinary treatment, particularly domestic animals or those used for recreational purposes (e.g., dogs, cats or horses).
  • the subject is a mammal. According to certain embodiments, the subject is a human subject.
  • gastrointestinal disease or disorder is selected from the group consisting of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastrointestinal motility disorders, constipation, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, functional heartburn, dyspepsia, visceral pain, gastroparesis, coeliac disease, lactose intolerance, traveler’s diarrhea, celiac disease, and chronic intestinal pseudoobstruction.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • GFD gastroesophageal reflux disease
  • duodenogastric reflux functional heartburn
  • dyspepsia visceral pain
  • gastroparesis coeliac disease
  • coeliac disease lactose intolerance
  • traveler’s diarrhea celiac disease
  • celiac disease chronic intestinal pseudoobstruction
  • the gastrointestinal disease is IBS.
  • IBS symptoms are usually related to pain or discomfort generally felt in the center of the abdomen around or above the navel. Some examples of discomfort include fullness, early satiety, which is a feeling of fullness soon after starting to eat, bloating and nausea. Some IBS patients experience failure of the relaxation of the upper stomach following an ingestion of food, a condition known as abnormal gastric accommodation reflex. About half of the patients with these symptoms also have a sensitive or irritable stomach which causes sensations of discomfort when the stomach contains even small volumes.
  • the pharmaceutical composition or combination improves gastrointestinal function. According to certain embodiments, the pharmaceutical composition or combination reduces abdominal pain. According to additional embodiments, the pharmaceutical composition or combination improves mucosal healing, restores small intestine function, and/or enhances fluid retention. According to further embodiments, the pharmaceutical composition or combination alleviates an array of associated disease symptoms selected from the group consisting of malabsorption, diarrhea, nausea, vomiting, electrolyte imbalance, and dehydration. Each possibility represents a separate embodiment of the invention. According to certain embodiments, the pharmaceutical composition or combination alleviates symptoms associated with undesirable gut microbiome.
  • the pharmaceutical composition or combination reduces intestinal insufficiency.
  • intestinal insufficiency is meant a pathological state of the intestine, in particular of the small intestine, in which the absorption of nutriments is reduced relative to normal, the reduction in the absorption of nutriments being linked to a reduction in the number and/or functionality of intestinal cells capable of carrying out this absorption, this reduction in the number and/or functionality of intestinal cells being itself due either to a physical elimination of these cells (in particular by surgery or by radiation), or to a pathological dysfunction of these cells.
  • Intestinal insufficiency is also linked to ageing. Protein-energy malnutrition is highly frequent in the elderly in which approximately 40% of those aged over 70 years are affected. In a malnutrition situation, ageing is characterized by morphological and functional modifications of the small intestine; these changes can lead to malabsorption and aggravate the pre-existing malnutrition. Moreover, this malnutrition aggravates changes in the digestive system linked to age. The degradation of the nutritional state furthers the risks of infections.
  • the pharmaceutical composition or combination is used for alleviation of short-bowel syndromes, short-bowel syndrome following an intestinal resection, in particular in the case of acute mesenteric ischemia, thrombosis of the superior mesenteric vein, volvulus of the small intestine and strangulated hernias, chronic intestinal pseudo-obstruction, radiation-damaged small intestine, Crohn's disease, abdominal traumatism; short-bowel syndrome results in particular from resections of the small intestine leaving a maximum of 1 meter of small intestine besides the duodenum; these resections lead in the immediate post-operative period to an intestinal insufficiency characterized by constant and major malabsorption, sometimes aggravated by gastric hypersecretion, which leads to the setting up of total parenteral nutrition, rapidly combined with continuous enteral nutrition, then to oral feeding; the adaptation of the remaining intestine is possible between 2 and 6 months after the procedure, but the improvement in the absorption capacities of the small intestine
  • the gastrointestinal disease is gastrointestinal inflammatory disease.
  • the gastrointestinal disease is inflammatory bowel disease (IBD).
  • IBD is a group of inflammatory conditions of the large intestine and small intestine. Symptoms of IBD are well known and include, without limitation, diarrhea, fever (e.g., low-grade fever), abdominal pain and cramping, blood in the stool (hematochezia), bleeding ulcers, bloating, bowel obstruction, unintended weight loss, and anemia.
  • forms of inflammatory bowel disease include Crohn's disease, ulcerates colitis, indeterminate colitis, and/or chemotherapy-induced colitis. Ulcerative colitis is an inflammatory disease of the large intestine.
  • ulcerative colitis the inner lining, or mucosa, of the intestine becomes inflamed (meaning the lining of the intestinal wall reddens and swells) and develops ulcers meaning an open, painful wound. Crohn's disease differs from ulcerative colitis in the areas of the bowel it involves, it most commonly affects the last part of the small intestine and parts of the large intestine. However, Crohn's disease isn't limited to these areas and can attack any part of the digestive tract.
  • corticosteroids and immunomodulator therapy e.g., azathioprine, and methotrexate
  • TNFa tumor necrosis factor alpha
  • infliximab a chimeric antibody
  • adalimumab a fully human antibody
  • most patients do not achieve sustained steroid-free remission and mucosal healing, clinical outcomes that correlate with true disease modification.
  • the treatment reduces inflammatory mediators such as TNF-alpha and IL-6.
  • the gastrointestinal disease is a celiac disease.
  • Celiac disease is a chronic enteropathy characterized by a food intolerance to gluten, and more particularly to proteins contained in certain cereals, such as gliadin, hordein or secalin; this disease occurs in genetically predisposed subjects; the intestinal mucosa of a patient suffering from celiac disease is the seat of an inflammatory process, partly of an immune nature, which causes in particular atrophy of the villi; the resultant intestinal insufficiency is characterized by intestinal malabsorption, which manifests itself in diarrhea with steatorrhea, emaciation and malnutrition; the biological consequences of malabsorption are in particular anemia associated with an iron, folate or vitamin B12 deficiency, a deficit of vitamin K-dependent coagulation factors, hypoproteinemia, hypoalbuminemia, hypocalcemia, hypomagnesemia and zinc deficiency.
  • the gastrointestinal disorder is constipation.
  • the constipation can be chronic constipation, idiopathic constipation, due to postoperative ileus, or caused by opiate use.
  • Clinically accepted criteria that define constipation include the frequency of bowel movements, the consistency of feces and the ease of bowel movement.
  • One common definition of constipation is less than three bowel movements per week.
  • Other definitions include abnormally hard stools or defecation that requires excessive straining.
  • Constipation may be idiopathic (functional constipation or slow transit constipation) or secondary to other causes including neurologic, metabolic or endocrine disorders.
  • Constipation may also be the result of surgery (postoperative ileus) or due to the use of drugs such as analgesics (like opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics.
  • analgesics like opioids
  • antihypertensives anticonvulsants
  • antidepressants antispasmodics
  • antipsychotics antipsychotics.
  • compositions or combination described herein are for use in treating primary sclerosing cholangitis (PSC).
  • PSC primary sclerosing cholangitis
  • PSC Primary sclerosing cholangitis
  • the pharmaceutical combination comprises (1) psilocybin or psilocin; and (2) an anti-scar medication.
  • the pharmaceutical combination comprises (1) psilocybin or psilocin; and (2) a paclitaxel (taxol) or rapamycin (sirolimus).
  • the present invention provides a pharmaceutical combination for treating primary sclerosing cholangitis (PSC), said pharmaceutical combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) an antibiotic.
  • the antibiotic is vancomycin.
  • the route of administration can be by any route and will be determined based on the physician and the patient. All other routes of administration of a therapeutically effective amount of an agent to treat the subject in need are contemplated herein and include, without limitation, enteral (e.g., orally or rectally), or parenteral (e.g., intravenous, intrathecal, subcutaneous), or other routes (e.g., intranasal, intradermal, intravitreal, subcutaneous, transdermal, topical, and intraperitoneal).
  • enteral e.g., orally or rectally
  • parenteral e.g., intravenous, intrathecal, subcutaneous
  • other routes e.g., intranasal, intradermal, intravitreal, subcutaneous, transdermal, topical, and intraperitoneal.
  • the pharmaceutical composition or combination is administered orally.
  • the pharmaceutical composition or combination is administered once a day, twice a week, once a week, once in two weeks, once in three weeks or once a month. According to yet further embodiments, the composition or combination is administered once in two months, once in three months, once in four months, once in five months or once in six months.
  • the pharmaceutical composition or combination is administered at least 30 minutes before ingestion of food. According to some embodiments, the pharmaceutical composition or combination is administered at least an hour, or two hours before ingestion of food.
  • the pharmaceutical composition or combination is administered for a period of greater than a week. According to some embodiments, the pharmaceutical composition is administered for a period of greater than four weeks. According to some embodiments, the pharmaceutical composition or combination is administered for a period of greater than two months. According to some embodiments, the pharmaceutical composition or combination is administered for a period of greater than 3, 4, 5, or 6 months.
  • the effective dose of the psilocybin component ranges from 0.01 to 500 mg/kg/day of body weight, from 1 to 250 mg/kg/day of body weight, from 2 to 100 mg/kg/day of body weight, or from 5 to 30 mg/kg/day, and may be in single dose or divided throughout the day.
  • Each possibility represents a separate embodiment of the invention.
  • the effective dose of the at least one active agent ranges from 0.01 to 500 mg/kg/day of body weight, from 1 to 250 mg/kg/day of body weight, from 2 to 100 mg/kg/day of body weight, or from 5 to 30 mg/kg/day, and may be in single dose or divided throughout the day.
  • Each possibility represents a separate embodiment of the invention.
  • the pharmaceutical composition or combination is administered at a unit dosage form of approximately 0.05 g/kg/day to approximately 0.5 g/kg/day.
  • the active agents of the present invention are effective over a wide dosage range.
  • the psilocybin and/or active agent component dosage is about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25, mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 1000 mg per day orally.
  • the unit dosage form is administered with food at any time of the day, without food at any time of the day, with food after an overnight fast (e.g., with breakfast).
  • the therapeutic methods according to the invention may involve combination therapies.
  • the oral compositions of the invention may be administered in combination with one or more additional compounds or therapies, the latter using enteral or parenteral and include, but are not limited to, oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and transdermal administration routes.
  • compositions disclosed herein may also be administered systemically or locally.
  • the pharmaceutical composition is formed into a dosage form suitable for oral, intranasal, intravenous, intraarterial, transmucosal, or subcutaneous administration.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the pharmaceutical compositions of the invention.
  • a therapeutically effective amount of the active components is an amount approved by the regulatory authority.
  • Kits containing the above compositions are also contemplated.
  • Compositions of the present invention can be packaged to contain, separately or in kit form together with a container, instructions or instruction brochure.
  • Cytokine secretion in response to different doses of psilocybin (0-500 ng), azathioprine and psilocybin-azathioprine combination are examined.
  • In-vitro assays are studied using macrophage murine J774A.1, human THP-1 cell lines, and EGC cells.
  • Colitis is induced in mice by addition of 3% Dextran Sodium Sulfate (DSS) to drinking water from day 0 to day 5, and test items are administered daily from day 7 for 14 days (500 ng psilocybin and 3 mg/kg azathioprine by interparental route). Animals are monitored for additional 14 days, for a total of 28 days.
  • DSS Dextran Sodium Sulfate
  • test items include combination of psilocybin with azathioprine, while the azathioprine and psilocybin alone are used as controls.
  • a prospective, double-blind, randomized, 8-week study of fixed doses is conducted in outpatients with active Crohn's Disease. Patients receive oral 0 ng (as placebo) to 500 ng psilocybin and 2-3 mg/kg azathioprine once daily for 60 days (azathioprine’s therapeutic response usually occurs after 6 to 8 weeks). Clinical status is assessed using the Crohn's Disease Activity Index (CDAI) and the Quality of Life Questionnaire (QOL). Independent t-test analyses are conducted for baseline and endpoint (LOCF) values. Analysis of Variance (ANOVA) are conducted on ratings scales in relationship to time. Side effects including loss of appetite, fatigue, nausea, and vomiting, are reported and analyzed. Additional side effects examined include blood in the urine or stool and development of mouth sores and ulcers.
  • a prospective, double-blind, randomized, 6-week study of fixed doses is conducted in outpatients with active ulcerative colitis.
  • Patients receive oral 0 ng (as placebo) to 500 ng psilocybin and 0.8- 1.2 g mesalamine (anti-inflammatory agent) once daily for 6 weeks.
  • Clinical status is assessed using the Ulcerative Colitis Disease Activity Index (UCDAI) and the Quality of Life Questionnaire (QOL).
  • UDAI Ulcerative Colitis Disease Activity Index
  • QOL Quality of Life Questionnaire
  • Independent t- test analyses are conducted for baseline and endpoint (LOCF) values.
  • Analysis of Variance (ANOVA) are conducted on ratings scales in relationship to time. Side effects including loss of appetite, fatigue, nausea, and vomiting, are reported and analyzed. Additional side effects examined include blood in the urine or stool and development of mouth sores and ulcers.
  • a prospective, double-blind, randomized, 12-week study of fixed doses is conducted in outpatients with primary sclerosing cholangitis (PSC).
  • PSC primary sclerosing cholangitis
  • Patients receive oral 0 ng (as placebo) to 500 ng psilocybin and oral vancomycin (antibiotic medication) at 500 mg, three times/day.
  • the primary outcome is a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline.
  • the biochemical response to treatment is expressed as the median percentage change in serum GGT, ALP, and ALT at months 1 and 3 from baseline values.
  • the paired Student’s t test is used to compare each liver biochemical parameters for each patient at months 1 and 3 to baseline values.
  • the Wilcoxon rank-sum test is used to compare the median liver chemistries’ values at the defined time intervals with the median liver chemistries at baseline.
  • Clinical status is also assessed using the Crohn's Disease Activity Index (CD Al) and the Quality of Life Questionnaire (QOL).
  • CD Al Crohn's Disease Activity Index
  • QOL Quality of Life Questionnaire
  • Independent t-test analyses are conducted for baseline and endpoint (LOCF) values. Analysis of Variance (ANOVA) are conducted on ratings scales in relationship to time. Side effects including loss of appetite, fatigue, nausea, and vomiting, are reported and analyzed. Additional side effects examined include blood in the urine or stool and development of mouth sores and ulcers.

Abstract

The present invention provides compositions and methods for treating gastrointestinal diseases or disorders. In particular, the present invention provides pharmaceutical compositions and formulations comprising psilocybin and an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.

Description

COMBINATIONS WITH PSILOCYBIN FOR TREATING
GASTROINTESTINAL DISEASES OR DISORDERS
FIELD OF THE INVENTION
The present invention relates to compositions and methods for treating gastrointestinal diseases or disorders. In particular, the present invention relates to pharmaceutical compositions and combinations comprising psilocybin and an additional therapeutic agent for use in treating bowel diseases, such as Crohn and colitis, and immune-related gastrointestinal diseases or disorders.
BACKGROUND OF THE INVENTION
Gastrointestinal, or stomach disorders, are very common and are responsible for a significant amount of suffering and morbidity in the population. Gastrointestinal disorders comprise a variety of ailments including, inter alia, constipation, irritable bowel syndrome, diverticular disease, colon polyps, and colitis. Gastrointestinal disorders can be triggered by various factors, including functional changes after surgery, inherited disorders, neurologic diseases, connective tissue disorders, metabolic abnormalities, and infections.
Psilocybin is a small compound, naturally occurring tryptamine known for its psychedelic properties. Over 100 species of mushrooms have been found to contain psilocybin, many falling within the genus Psilocybe. Psilocybin is a prodrug metabolized through in vivo dephosphorylation to psilocin, which is presumed to be the active agent in the central nervous system. Like other classic psychedelics, the behavioral effects of psilocybin appear to be mediated primarily by agonist activity at the 5 -hydroxy tryptamine (HT)2A receptor; however, 5-HT2A activity does not appear to account fully for its effects. Psilocybin is characterized by low physiological toxicity and low abuse liability (Johnson et al. Neurotherapeutics. 2017 Jul;14(3):734-740).
US Publication No. 2018/0221396 discloses compositions and methods comprising a psilocybin derivative. 2018/0221396 discloses the use of the compositions in a method of regulating a neurotransmitter receptor, e.g., a serotonin receptor.
US Publication No. 2019/0192498 discloses methods and compositions for enhancing neurogenesis, resolving neuropathy and improving neurological health and functioning using fungal extracts and their active ingredients, including species of mushrooms and mycelia containing psilocybin and psilocin, combined with erinacines and hericenones or fungal extracts containing those active ingredients, with the addition of nicotinic acid.
US Publication No. 2019/0350949 discloses cannabinoids and/or terpenes in combination with psilocybin and/or psilocin for use in the prevention or treatment of psychological or brain disorders.
US Publication No. 2021/0346346 discloses compositions and methods which comprise a therapeutically effective amount of a first purified psilocybin derivative and a therapeutically effective amount of a second compound selected from the group consisting of a second purified psilocybin derivative, a purified terpene, a serotonergic drug, an adrenergic drug, a dopaminergic drug, a purified erinacine, and a purified hericenone.
There is an unmet medical need for additional, well-tolerated, and effective therapies for patients with gastrointestinal-related diseases or disorders that relieve various associated symptoms such as pain and discomfort.
SUMMARY OF THE INVENTION
The present invention provides psilocybin, or a derivative thereof, in combination with at least one additional therapeutic agent for treating gastrointestinal-related disease or disorder. The present invention further provides in some embodiments methods of treating gastrointestinal disease or disorder, in particular irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), comprising administering psilocybin and an additional therapy selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, and immunotherapy agent.
It is now disclosed that psilocybin has a therapeutic beneficial effect on gastrointestinal disease, in particular IBD, and acts effectively with other therapies for treating gastrointestinal-related diseases or disorders. Without wishing to be bound by any particular theory or mechanism of action, the psilocybin has a beneficial effect on the gut microbiome and may potentiate drugs that treat gastrointestinal diseases. Advantageously, the combinations described herein enable the use of reduced amounts of the active agents, which reduces side effects while maintaining or even enhancing the drug's effectiveness against the disease. It is further disclosed that pharmaceutical compositions disclosed herein may have beneficial therapeutic effects on additional diseases or conditions that have been shown to be affected by gastrointestinal state such as neurodegenerative or psychiatric diseases.
The present invention further provides pharmaceutical compositions or combinations comprising psilocybin or psilocin for use in treating gastrointestinal disorder related to primary sclerosing cholangitis (PSC). According to one aspect, the present invention provides a pharmaceutical combination or composition for use in treating a gastrointestinal-related disease or disorder, said pharmaceutical combination or composition comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
According to some embodiments, the gastrointestinal disease is inflammatory bowel disease (IBD). According to certain exemplary embodiments, the inflammatory bowel disease is Crohn's disease. According to additional embodiments, the inflammatory bowel disease is ulcerative colitis (UC) or indeterminate colitis.
According to additional embodiments, the gastrointestinal disease or disorder is selected from the group consisting of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastrointestinal motility disorders, constipation, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, functional heartburn, dyspepsia, visceral pain, gastroparesis, and chronic intestinal pseudo-obstruction. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the gastrointestinal disorder is inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC).
According to some embodiments, the at least one psilocybin, psilocin, or analogs thereof; and the at least one active agent are present in a single pharmaceutical composition. According to additional embodiments, the at least one psilocybin, psilocin, or analogs thereof; and the at least one active agent are present in separate pharmaceutical compositions.
According to some embodiments, the active agents or active ingredients disclosed herein are the sole active agents or active ingredients within the pharmaceutical composition or combination.
According to some embodiments, the use comprises administering of the psilocybin, psilocin, or analogs or derivatives thereof; and the least one active agent, substantially simultaneously, concurrently, alternately, sequentially or successively. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the active agent is an immunosuppressive medication. According to some embodiments, the active agent is a probiotic. According to some embodiments, the active agent is steroid. According to some embodiments, the active agent is antibiotic. According to some embodiments, the active agent is an antiinflammatory agent. According to some embodiments, the active agent is an immunotherapy agent.
According to some embodiments, the immunosuppressive medication is selected from the group consisting of Azathioprine, calcineurin inhibitor, Methotrexate, and Mercaptopurine. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the immunosuppressive medication is Azathioprine (Imuran).
According to certain embodiments, the calcineurin inhibitor is cyclosporine.
According to some embodiments, the steroid is a corticosteroid. According to some embodiments, the steroid is a corticosteroid selected from the group consisting of Budesonide, Hydrocortisone, Methylprednisolone, and Prednisone. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the at least one active agent is quinuclidine or a derivative thereof.
According to some embodiments, the at least one active agent exhibits a therapy selected from the group consisting of anti-tumor necrosis factor-alpha therapy, anti- integrin therapy, and anti-interleukin- 12 and interleukin-23 therapy. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the at least one active agent is selected from the group consisting of adalimumab, certolizumab, infliximab, natalizumab, vedolizumab, ustekinumab and azulfidine. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the probiotic is Lactobacillus or
Bifidobacterium.
According to some embodiments, the anti-inflammatory agent is 5- aminosalicylate (5-ASA).
According to some embodiments, the at least one active agent is selected from the group consisting of Humira, Remicade, mesalamine, Stelara, Entyvio, sulfasalazine, azathioprine, Cimzia, budesonide, infliximab, adalimumab, vedolizumab, Entocort EC, Inflectra, ustekinumab, certolizumab, Renflexis, Avsola, hyoscyamine, Imuran, Risankizumab, Skyrizi, cholestyramine, rifaximin, and Azasan. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the use comprises orally administration of the at least one psilocybin, psilocin, or analogs thereof; and/or the at least one active agent.
According to some embodiments, the use comprises administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent in different administration routes.
According to some embodiments, the use comprises administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent once a day, once a week, once in two weeks, once in three weeks or once a month.
According to an additional aspect, the present invention provides a method of treating a gastrointestinal-related disease or disorder, comprising administering to a subject in need thereof a combination of: (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and anti-inflammatory agent.
The gastrointestinal-related disease or disorder and the at least one active agent is as described hereinabove.
According to some embodiments, the method comprising administering orally, or parenterally. According to specific embodiments, the method comprising administering orally.
According to certain embodiments, the at least one psilocybin, psilocin, or analogs thereof; and at least one active agent are administered in different routes of administration.
According to some embodiments, the method comprising administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent once a day, once a week, once in two weeks, once in three weeks or once a month.
According to some embodiments, the method is used in combination with additional therapeutic agents for treatment or prevention of gastrointestinal diseases or disorders.
According to some embodiments, the treatment decreases abdominal pain in said patient compared to said patient prior to treatment with the psilocybin combinations described herein.
According to additional embodiments, the gastrointestinal disease or disorder is immune-related disease.
A subject according to the present invention is typically a human subject. According to other embodiments, a subject according to the present invention is a nonhuman mammal.
According to an additional aspect, the present invention provides a pharmaceutical composition comprising: (1) a psilocybin, psilocin, or analogs thereof; and (2) an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent, and an antiinflammatory agent; and a pharmaceutical acceptable excipient, carrier or diluent.
According to some embodiments, the active agent is an immunosuppressive medication. According to some embodiments, the active agent is probiotic. According to some embodiments, the active agent is steroid. According to some embodiments, the active agent is antibiotic. According to some embodiments, the active agent is an immunotherapy agent. According to some embodiments, the active agent is an antiinflammatory agent.
According to some exemplary embodiments, the steroid is a corticosteroid selected from the group consisting of Budesonide, Hydrocortisone, Methylprednisolone, and Prednisone. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the immunosuppressive medication is selected from the group consisting of Azathioprine, calcineurin inhibitor, Methotrexate, and Mercaptopurine. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the immunosuppressive medication is Azathioprine (Imuran).
According to certain embodiments, the calcineurin inhibitor is cyclosporine.
According to some embodiments, the active agent exhibits a therapy selected from the group consisting of anti-tumor necrosis factor-alpha therapy, anti-integrin therapy, and anti-interleukin- 12 and interleukin-23 therapy. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the active agent is selected from the group consisting of adalimumab, certolizumab, infliximab, natalizumab, vedolizumab, and ustekinumab.
According to some embodiments, the probiotic is Lactobacillus or
Bifidobacterium.
According to some embodiments, the anti-inflammatory agent is 5- aminosalicylate (5-ASA).
According to some embodiments, the pharmaceutical composition comprises a psilocybin and immunosuppressive medication. According to some embodiments, the pharmaceutical composition comprises a psilocybin and probiotic. According to some embodiments, the pharmaceutical composition comprises a psilocybin and steroid. According to some embodiments, the pharmaceutical composition comprises a psilocybin and antibiotic. According to some embodiments, the pharmaceutical composition comprises a psilocybin and an immunotherapy agent. According to some embodiments, the pharmaceutical composition comprises a psilocybin and antiinflammatory agent.
According to another aspect, the present invention provides a pharmaceutical composition or combination comprising: at least one psilocybin, psilocin, or analogs thereof; and at least one compound or substance with therapeutic activity against a gastrointestinal disease or disorder, for use in treating a gastrointestinal disease or disorder.
According to some embodiments, the gastrointestinal disease is a Crohn disease.
According to some embodiments, the compound or substance with therapeutic activity is Indole. According to additional embodiments, the compound or substance with therapeutic activity is tryptophan.
According to certain exemplary embodiments, the compound or substance with therapeutic activity against a gastrointestinal disease or disorder is selected from the group consisting of immunosuppressive medication, probiotic, steroid, antibiotic and immunotherapy agent. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the pharmaceutical composition further comprises an excipient selected from the group consisting of emulsifiers, buffering agents, pH adjusting agents, preservatives, antioxidants, stabilizers, and combinations thereof. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the pharmaceutical composition further comprises electrolytes, vitamins, anti-oxidants, minerals, and/or flavoring agents.
According to some embodiments, the pharmaceutical composition is formulated in a form of a liquid or a gel.
According to some embodiments, the pharmaceutical composition further comprises triglycerides, fats, lipids, oils, fatty acids, solvents or mixtures thereof.
According to a yet additional aspect, the present invention provides a method of modulating 5TH receptors in the gastrointestinal tract (GI), comprising administering to a subject in need thereof: at least one agonist of psilocybin receptor; and at least one compound or substance with therapeutic activity against a gastrointestinal disease or disorder.
The psilocybin and the compound or substance with therapeutic activity against the gastrointestinal disease or disorder are as described hereinabove.
According to another aspect, the present invention provides a method of treating primary sclerosing cholangitis (PSC), comprising administering to a subject in need thereof a therapeutically effective amount of a psilocybin, psilocin, or analogs thereof. According to some embodiments, the method further comprises administering to the subject an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and an antiinflammatory agent.
The immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and an anti-inflammatory agent are as described hereinabove.
According to an additional aspect, the present invention a pharmaceutical combination or composition for use in treating a liver-related disease or disorder, said pharmaceutical combination or composition comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent suitable for use in treating liver-related disease or disorder.
According to some embodiments, the at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
According to some embodiments, the liver-related disease is primary sclerosing cholangitis (PSC).
According to some embodiments, the pharmaceutical combination or composition is for use in treating the bile duct.
According to some embodiments, the active agent is an anti-scar medication. According to some embodiments, the anti-scar medication is a corticosteroid. According to some embodiments, the active agent is paclitaxel (taxol) or rapamycin (sirolimus).
According to an additional aspect, the present invention provides a pharmaceutical composition comprising psilocybin, psilocin, or analogs or derivatives thereof, for use in treating primary sclerosing cholangitis (PSC).
According to some embodiments, the pharmaceutical composition further comprises an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and an antiinflammatory agent.
It is to be understood that any combination of each of the aspects and the embodiments disclosed herein is explicitly encompassed within the disclosure of the present invention.
Further embodiments and the full scope of applicability of the present invention will become apparent from and detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods of treating gastrointestinal diseases or disorders comprising administering to a subject in need thereof a therapeutic effective amount of psilocybin, psilocin, or analogs thereof in combination with at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, anti-inflammatory agent and immunotherapy agent.
The incidence of autoimmune diseases (AiD) has been steadily increasing in the last decades, as reported by The National Institute of Health (NIH) and other sources. There are currently over 100 defined autoimmune-related diseases affecting roughly 50 million Americans, or 20% of the population, according to the American Autoimmune Related Diseases Association (AARDA). The NIH also calculates that over $100 billion in health care costs is spent annually in the United States on treating those with autoimmune diseases, compared to cancer which has an estimated cost of $50 billion annually.
Autoimmunity is defined as the loss of tolerance to self-antigens in which the immune system attacks healthy tissues in an individual. While there are different characteristics of expression and tissues affected amongst the autoimmune disorder types, there are many shared mechanisms of action and potential origins. Many diseases that were initially considered to be unrelated to autoimmunity are now being reexplored as autoimmune-related, especially in the field of psychiatry. This includes major depressive disorder (MDD), schizophrenia, Parkinson’s disease, Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis. AiDs often encompass a variety of symptoms and features, but common characteristics observed among the various types of AiD include increased vascular and epithelial (e.g., intestinal) permeability, chronic inflammation, the presence of chronic infections, dysregulated Hypothalamic -pituitary- adrenal axis (HPA axis), mitochondrial dysfunction, and microbiome dysbiosis (Thompson, C. and A. Szabo, Immunology letters, 2020).
One AiD condition is inflammatory bowel disease (IBD), which mainly involves the gastrointestinal tract. The disease is classically divided into two subgroups, ulcerative colitis and Crohn’s disease. In ulcerative colitis, inflammation and sores are confined morphologically and microscopically to the mucosa, the innermost surface of the colon and the rectum. In Crohn’s disease, the infection is granulomatous and transmural, affecting the entire gastrointestinal tract from the mouth to the anus, with the skip area in-between. Crohn’s disease is a progressive disease that leads to bowel damage and disability that results from a complex interplay between genetic susceptibility, environmental factors, and altered gut microbiota, which leads to dysregulated innate and adaptive immune responses. Of note is that a large-scale study, which included 1,742 patients with IBD and 17,420 controls, found that incidence of dementia among patients with IBD was significantly elevated (5.5% vs 1.4% among controls), and that patients with IBD were diagnosed with dementia at earlier age (76.24 vs 83.45 among controls). Among dementia types, the risk of developing Alzheimer’s dementia demonstrated the greatest increase (Zhang, B., et al., Gut, 2021. 70(1): p. 85- 91).
Indeed, one of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the “second brain” and be responsible for neurodegenerative disorders like AD. In recent years the interest in the bi-directional communication between the gut and the brain has risen exponentially. This axis includes the enteric nervous system, consisting of neurons embedded in the lining of the gastrointestinal tract, the parasympathetic and sympathetic branches of the autonomous nervous system, and the neuroendocrine and neuro-immune system. A key concept is the gut microbiome, a collection of microorganisms in the gut that is regarded as a critical node in the brain-gut axis. It has been demonstrated that microbiota can influence CNS function and vice versa via effects on the gastrointestinal tract. For example, scientific evidence of this gut-brain axis interaction was provided by an animal study in which gut microbiota-free rats, transplanted with microbiota from depressed patients, developed depression-like features.
Brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain (Sochocka, M. et al., Molecular neurobiology, 2019. 56(3): p. 1841-1851). The idea that alterations in the brain immunomodulation are critical for AD pathogenesis provides the most integrative view on this cognitive disorder, considering that converging research lines have revealed the involvement of inflammatory processes in AD (Maccioni, R.B. et al., Academy of Sciences, 2009. 1153(1): p. 240-246). Indeed, AD neuropathology is strongly associated with the activation of inflammatory pathways, and long-term use of antiinflammatory drugs reduces the risk of developing the disease (Currais, A. et al., Journal of ethnopharmacology, 2014. 155(1): p. 830-840).
Pharmacological management of Crohn’s disease and ulcerative colitis typically involves a stepwise approach, and remission induction usually includes antiinflammatory drugs such as 5-aminosalicylate (5-ASA) for mild diseases, and corticosteroids for moderate and severe disease, or immune modifying agents such as thiopurine (azathioprine, 6-mercaptopurine), methotrexate, with addition of or switching to biologies for refractory cases. Biologies, antibodies with targeted action on inflammation proteins, that are used in the treatment of IBD usually include antitumor necrosis factor (anti-TNF) such as adalimumab and infliximab, and non anti- TNF such as vedolizumab and ustekinumab (Ho, C. and C. Argaez, Sequencing of Pharmacological Management of Crohn’s Disease and Ulcerative Colitis: A Review of Guidelines. 2019).
The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and lysergic acid diethylamide (LSD), coupled with anecdotal reports of cognitive benefits from micro-dosing, suggests that they may have a therapeutic role in a range of conditions due to their potential to stimulate neurogenesis, provoke neuroplastic changes and reduce inflammation. Preclinical work has highlighted psychedelics’ ability to induce neuroplasticity, synaptogenesis, and neural progenitor cell proliferation. It is now disclosed, unexpectedly, that psilocybin may act together with other therapies for gastrointestinal-related diseases, disorders or conditions. The enhanced benefit of combination therapy enables the use of reduced amount of the additional active agent and thus, may reduce undesired side effects.
The term “psilocybin”, “psilocin”, or analogs thereof as used herein includes any isoform, crystalline form, or salts thereof. In some embodiments, the psilocybin is in a crystalline form selected from the group consisting of Hydrate A, Polymorph A, Polymorph B, and any combination thereof. In some embodiments, the psilocybin described herein comprises more than one crystalline form.
The description below of several embodiments are made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the attached claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
According to one aspect, the present invention provides a pharmaceutical combination or composition for use in treating a gastrointestinal-related disease or disorder, said pharmaceutical combination or composition comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
Pharmaceutical compositions and combinations
According to an aspect, the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and an immunosuppressive medication.
According to a yet another aspect, the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and Azathioprine (Imuran).
According to a yet another aspect, the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and probiotic.
According to a yet another aspect, the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and steroid.
According to a yet another aspect, the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and antibiotic.
According to a yet another aspect, the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and an immunotherapy agent.
According to a yet another aspect, the present invention provides a pharmaceutical composition comprising a psilocybin, psilocin, or analogs thereof; and quinuclidine or a derivative thereof.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Humira.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Remicade.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) mesalamine.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Stelara.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) sulfasalazine.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Entyvio.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) azathioprine.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Cimzia.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) budesonide.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) infliximab.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) adalimumab.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) vedolizumab.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Entocort EC.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Inflectra.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) ustekinumab.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) certolizumab.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Renflexis.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Avsola.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) hyoscyamine.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Imuran. According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Risankizumab.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Skyrizi.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) cholestyramine.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) Azasan.
According to an aspect, the present invention provides a pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) rifaximin.
According to some embodiments, the pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent.
According to a yet another aspect, the present invention provides a pharmaceutical combination comprising: (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, an antiinflammatory agent, antibiotic, and immunotherapy agent.
The term “pharmaceutical combination” as used herein refers to either a pharmaceutical composition comprising one or more active pharmaceutical ingredient and one or more second therapeutic compounds or a pharmaceutical composition comprising an active therapeutic ingredient co-administered with a second therapeutic compound. According to some embodiments, the terms pharmaceutical combination and pharmaceutical composition are used herein interchangeably.
Ingredients of the compositions of the present invention may be artificially synthesized. Alternatively or additionally, ingredients which are found in natural sources, such as plant or fungi sources, may be extracted or purified from the natural sources. The present invention encompasses artificially synthesized compounds as well as compounds extracted and/or purified from natural sources.
Compositions according to the present invention may be in a form selected from the group consisting of a pill, a tablet, a caplet, a capsule, a softgel, a powder, and a lozenge. Additional suitable forms include sublingual and/or buccal administration compositions, sachets, bars, gummies, gummy caps, in yogurt and in functional foods and functional drinks. Compositions according to the present invention may be formulated for administration as a nasal spray. Compositions according to the present invention may also be formulated for administration via routs such as intravenous (IV), subcutaneous (SC), intramuscular (IM) and intraperitoneal (IP), or using inhalers and inhalation vaporizers. Each of the aforementioned possibilities represents a separate embodiment of the present invention. According to additional embodiments, the pharmaceutical composition is formulated for injectable administration.
According to certain embodiments the pharmaceutical composition or combination is formulated for an oral administration use.
According to some embodiments, the pharmaceutical composition or combination is formulated in a form of a liquid or a gel. According to other embodiments, the pharmaceutical composition or combination is a non-aqueous composition.
According to some embodiments, the pharmaceutical composition or combination is formulated as a capsule, a tablet, a liquid, or a syrup. In certain embodiments, the dosage form is granules or pellets delivered in a sachet or filled into capsule or compressed into a tablet.
According to some embodiments, the pharmaceutical composition or combination further comprises triglycerides, fats, lipids, oils, fatty acids, co-solvents or mixtures thereof. According to certain embodiments, the pharmaceutical composition or combination comprises an edible oil or fat. According to some embodiments, the pharmaceutical composition comprises an edible oil selected from the group consisting of copaiba oil, coconut oil, cottonseed oil, soybean oil, safflower oil, sesame oil, sunflower oil, castor oil, corn oil, olive oil, palm oil, peanut oil, and poppy seed oil.
According to some embodiments, the pharmaceutical composition further comprises electrolytes, vitamins, minerals, and/or flavoring agents.
According to some embodiments, the pharmaceutical composition is formulated for slow release of the active component. According to some embodiments, the pharmaceutical composition is formulated for slow release of psilocybin. In certain embodiments, the pharmaceutical composition further comprises a release retarding agent or a mixture of release retarding agents. According to some embodiments, the pharmaceutical composition is at least partly coated by an enteric-coating agent.
According to some embodiments, the composition is a gel, wherein the psilocybin component or the at least one active agent is entrapped in a gel matrix.
Solubilizing and emulsifiers may be used to improve the bioavailability of the active components. Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability for a given formulation provides an estimate of the relative fraction of the orally administered dose that is absorbed into the systemic circulation. Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs. Insufficient time for absorption in the gastrointestinal tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (e.g., if it is highly ionized and polar), time at the absorption site may be insufficient. Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver, both of which are common sites of first-pass metabolism (metabolism that occurs before a drug reaches systemic circulation).
According to some embodiments, within the compositions and methods of the present invention, the bioavailability enhancing agent is an edible oil or fat, a protective colloid, or both a protective colloid and an edible oil or fat. According to other embodiments, the bioavailability enhancing agent is also a lipophilic active agent taste masking agent. According to additional embodiments, the bioavailability of the lipophilic active agent in a subject is at least about 2 times, 5 times, or 10 times greater than the bioavailability of the lipophilic active agent in the subject in the absence of the bioavailability enhancing agent.
According to some embodiments, the pharmaceutical composition or combination comprises at least one micelle-forming compound selected from the group consisting of a polyoxyethylene ether, ester or alcohol; an alkali metal alkyl sulfate; a bile acid; lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening of primrose oil, trihydroxy oxo-cholanylglycine, glycerin, poly glycerin, lysine, polylysine, triolein, salts thereof, and mixtures thereof.
According to some embodiments, the pharmaceutical composition or combination comprises phospholipids. According to certain embodiments, the pharmaceutical composition comprises a phospholipid selected from the group consisting of naturally occurring phospholipids and synthetic phospholipids. According to certain embodiments, the synthetic phospholipid is selected from the group consisting of phosphocholines, phosphoethanolamines, phosphatidic acids, phosphoglycerols, phosphoserines, mixed chain phospholipids, lysophospholipids, pegylated phospholipids, and a combination thereof. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the phospholipid may form micelles, emulsions or liposomes. According to some embodiments, the phospholipid forms liposomes. According to some embodiments, the pharmaceutical composition further comprises cholesterol.
According to some embodiments, the pharmaceutical composition or combination comprises cyclodextrins. According to certain embodiments, the cyclodextrin is selected from the group consisting of hydroxypropyl P-cyclodextrin, sulfobutylether P-cyclodextrin, and methyl-P-cyclodextrin (MpCD) and combinations thereof.
According to some embodiments, the pharmaceutical composition or combination comprises a pharmaceutically acceptable solvent, i.e, a non-toxic solvent that is suitable for administration to a mammal with no unacceptable adverse effects. The solvent may be an aqueous or non-aqueous solvent.
The pharmaceutical composition or combination may optionally contain a stabilizer and/or a preservative.
According to some embodiments, the pharmaceutically carrier is an aqueous carrier.
The pharmaceutical composition or combination may also comprise one or more of the following additional additives: inorganic salts, antioxidants, colorants and flavoring agents. Non-limiting examples of inorganic salts include sodium, potassium, calcium and zinc salts, especially sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate. Examples of antioxidants include tocopherol, methyl paraben, ethyl paraben, ascorbic acid and mixtures thereof. Examples of flavoring agents include menthol, sorbitol and fruit flavors. Such additional additives may comprise between about 0.1 and 5 wt./wt. % of the composition.
Orally administered formulations such as tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
The term “sustained” as used herein refers to a composition which provides prolonged, long or extended release of the therapeutic agent. This term may further refer to a composition which provides prolonged, long or extended duration of action (pharmacokinetics) of the pharmaceutical composition of the present invention.
The pharmaceutical composition or combination may include additional ingredients including but not limited to the excipients described herein. In certain embodiments, one or more therapeutic agents of the dosage unit may exist in an extended or control release formulation and additional therapeutic agents may not exist in extended release formulation.
According to some embodiments, the pharmaceutical composition or combination further comprises at least one pharmaceutically acceptable excipient. According to additional embodiments, the excipient is selected from the group consisting of emulsifiers, buffering agents, pH adjusting agents, tonicity modifiers, preservatives, antioxidants, stabilizers, and a combination thereof.
According to some embodiments, the pharmaceutically acceptable carrier is an aqueous carrier. In some embodiments the aqueous carrier is a physiologically acceptable buffer having physiological or near-physiological pH. According to some embodiments, the pharmaceutical composition or combination further comprises one or more vitamins including, but not limited to, vitamin A, vitamin C, vitamin D (e.g., vitamin DI, D2, D3, D4, and/or D5), vitamin E, vitamin Bl (thiamine), vitamin B2 (e.g., riboflavin), vitamin B3 (e.g., niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (e.g., folate or folic acid), vitamin B12 (cobalamin), and vitamin K (e.g., vitamin KI, K2, K3, K4, and Ks), and choline.
According to some embodiments, the pharmaceutical composition or combination comprises alcohol and a solvent. According to some embodiments, the alcohol is ethanol. According to certain embodiments, the solvent is polyethylene glycol (PEG) or propylene glycol.
Methods of use
According to an aspect, the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) an immunosuppressive medication.
According to a yet another aspect, the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) probiotic.
According to a yet another aspect, the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) steroid.
According to a yet another aspect, the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) antibiotic.
According to a yet another aspect, the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and an immunotherapy agent.
According to a yet another aspect, the present invention provides a pharmaceutical combination for treating a gastrointestinal-related disease or disorder, comprising: (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, anti-inflammatory agent and immunotherapy agent.
According to a yet another aspect, the present invention provides a method for treating gastrointestinal disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of combination of (1) at least one psilocybin, psilocin, or analogs or derivatives thereof; and (2) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, and immunotherapy agent; to provide a combination therapy having an enhanced therapeutic effect compared to the effect of the psilocybin, psilocin, or analogs or derivatives thereof and the at least one active agent each administered alone.
As used herein, the term "gastrointestinal disease" refers to any disease affecting the gastrointestinal tract or intestinal tract. This includes but not limited to diseases of the esophagus, stomach, first, second, and third part of the duodenum, jejunum, ileum, the ileo-cecal complex, large intestine (ascending, transverse, and descending colon), sigmoid colon, rectum, and anus. The term “gastrointestinal disease or disorder” further refers to diseases of the accessory organs of digestion such as, but not limited to, of liver, gallbladder, and pancreas.
The term “disorder” as used herein refers to a disease or other pathological condition that associates with or that one of its symptoms includes gastrointestinal illness or discomfort.
The term "effective amount," as in "a therapeutically effective amount," of a therapeutic agent refers to the amount of the agent necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue or cell, and the like. More particularly, the term "effective amount" refers to an amount sufficient to produce the desired effect, e.g., to reduce or ameliorate the severity, duration, progression, or onset of a disease, disorder, or condition, or one or more symptoms thereof; prevent the advancement of a disease, disorder, or condition, cause the regression of a disease, disorder, or condition; prevent the recurrence, development, onset or progression of a symptom associated with a disease, disorder, or condition, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. For example, a "therapeutically effective amount" of the psilocybin combinations described herein refers to an amount that is effective for preventing, ameliorating, or treating the specified disease or disorder.
The term “treatment” or any grammatical variation thereof (e.g., treat, treating, and treatment etc.), as used herein, includes but is not limited to, alleviating a symptom of a disease or condition; and/or reducing, suppressing, inhibiting, lessening, or affecting the progression, severity, and/or scope of a disease or condition.
The term “amelioration” or any grammatical variation thereof (e.g., ameliorate, ameliorating, and amelioration etc.), as used herein, includes, but is not limited to, delaying the onset, or reducing the severity of a disease or condition. Amelioration, as used herein, does not require the complete absence of symptoms.
As used herein, the term “subject” designates a mammal, preferably a human, but may also designate an animal receiving veterinary treatment, particularly domestic animals or those used for recreational purposes (e.g., dogs, cats or horses).
According to some embodiments, the subject is a mammal. According to certain embodiments, the subject is a human subject.
According to some embodiments, gastrointestinal disease or disorder is selected from the group consisting of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastrointestinal motility disorders, constipation, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, functional heartburn, dyspepsia, visceral pain, gastroparesis, coeliac disease, lactose intolerance, traveler’s diarrhea, celiac disease, and chronic intestinal pseudoobstruction. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the gastrointestinal disease is IBS. IBS symptoms are usually related to pain or discomfort generally felt in the center of the abdomen around or above the navel. Some examples of discomfort include fullness, early satiety, which is a feeling of fullness soon after starting to eat, bloating and nausea. Some IBS patients experience failure of the relaxation of the upper stomach following an ingestion of food, a condition known as abnormal gastric accommodation reflex. About half of the patients with these symptoms also have a sensitive or irritable stomach which causes sensations of discomfort when the stomach contains even small volumes.
According to some embodiments, the pharmaceutical composition or combination improves gastrointestinal function. According to certain embodiments, the pharmaceutical composition or combination reduces abdominal pain. According to additional embodiments, the pharmaceutical composition or combination improves mucosal healing, restores small intestine function, and/or enhances fluid retention. According to further embodiments, the pharmaceutical composition or combination alleviates an array of associated disease symptoms selected from the group consisting of malabsorption, diarrhea, nausea, vomiting, electrolyte imbalance, and dehydration. Each possibility represents a separate embodiment of the invention. According to certain embodiments, the pharmaceutical composition or combination alleviates symptoms associated with undesirable gut microbiome.
According to some embodiments, the pharmaceutical composition or combination reduces intestinal insufficiency. By "intestinal insufficiency" is meant a pathological state of the intestine, in particular of the small intestine, in which the absorption of nutriments is reduced relative to normal, the reduction in the absorption of nutriments being linked to a reduction in the number and/or functionality of intestinal cells capable of carrying out this absorption, this reduction in the number and/or functionality of intestinal cells being itself due either to a physical elimination of these cells (in particular by surgery or by radiation), or to a pathological dysfunction of these cells.
Intestinal insufficiency is also linked to ageing. Protein-energy malnutrition is highly frequent in the elderly in which approximately 40% of those aged over 70 years are affected. In a malnutrition situation, ageing is characterized by morphological and functional modifications of the small intestine; these changes can lead to malabsorption and aggravate the pre-existing malnutrition. Moreover, this malnutrition aggravates changes in the digestive system linked to age. The degradation of the nutritional state furthers the risks of infections. According to some embodiments, the pharmaceutical composition or combination is used for alleviation of short-bowel syndromes, short-bowel syndrome following an intestinal resection, in particular in the case of acute mesenteric ischemia, thrombosis of the superior mesenteric vein, volvulus of the small intestine and strangulated hernias, chronic intestinal pseudo-obstruction, radiation-damaged small intestine, Crohn's disease, abdominal traumatism; short-bowel syndrome results in particular from resections of the small intestine leaving a maximum of 1 meter of small intestine besides the duodenum; these resections lead in the immediate post-operative period to an intestinal insufficiency characterized by constant and major malabsorption, sometimes aggravated by gastric hypersecretion, which leads to the setting up of total parenteral nutrition, rapidly combined with continuous enteral nutrition, then to oral feeding; the adaptation of the remaining intestine is possible between 2 and 6 months after the procedure, but the improvement in the absorption capacities of the small intestine most often remains insufficient.
According to some embodiments, the gastrointestinal disease is gastrointestinal inflammatory disease. According to certain embodiments, the gastrointestinal disease is inflammatory bowel disease (IBD). IBD is a group of inflammatory conditions of the large intestine and small intestine. Symptoms of IBD are well known and include, without limitation, diarrhea, fever (e.g., low-grade fever), abdominal pain and cramping, blood in the stool (hematochezia), bleeding ulcers, bloating, bowel obstruction, unintended weight loss, and anemia. According to some embodiments, forms of inflammatory bowel disease include Crohn's disease, ulcerates colitis, indeterminate colitis, and/or chemotherapy-induced colitis. Ulcerative colitis is an inflammatory disease of the large intestine. In ulcerative colitis, the inner lining, or mucosa, of the intestine becomes inflamed (meaning the lining of the intestinal wall reddens and swells) and develops ulcers meaning an open, painful wound. Crohn's disease differs from ulcerative colitis in the areas of the bowel it involves, it most commonly affects the last part of the small intestine and parts of the large intestine. However, Crohn's disease isn't limited to these areas and can attack any part of the digestive tract. The treatment of moderate to severe IBD poses significant challenges to treating physicians because conventional therapy with corticosteroids and immunomodulator therapy (e.g., azathioprine, and methotrexate) is associated with side effects and intolerance. Monoclonal antibodies targeting tumor necrosis factor alpha (TNFa), such as infliximab (a chimeric antibody) and adalimumab (a fully human antibody), are currently used in the management of Crohn's disease. Infliximab has also shown efficacy and has been approved for use in treating ulcerates colitis. However, approximately 10%-20% of patients with Crohn's disease are primary non-responders to anti TNF therapy. Other adverse events (AEs) associated with anti TNFs include elevated rates of bacterial infection, including tuberculosis, and, more rarely, lymphoma and demyelination. In addition, most patients do not achieve sustained steroid-free remission and mucosal healing, clinical outcomes that correlate with true disease modification.
According to some embodiments, the treatment reduces inflammatory mediators such as TNF-alpha and IL-6.
According to some embodiments, the gastrointestinal disease is a celiac disease. Celiac disease is a chronic enteropathy characterized by a food intolerance to gluten, and more particularly to proteins contained in certain cereals, such as gliadin, hordein or secalin; this disease occurs in genetically predisposed subjects; the intestinal mucosa of a patient suffering from celiac disease is the seat of an inflammatory process, partly of an immune nature, which causes in particular atrophy of the villi; the resultant intestinal insufficiency is characterized by intestinal malabsorption, which manifests itself in diarrhea with steatorrhea, emaciation and malnutrition; the biological consequences of malabsorption are in particular anemia associated with an iron, folate or vitamin B12 deficiency, a deficit of vitamin K-dependent coagulation factors, hypoproteinemia, hypoalbuminemia, hypocalcemia, hypomagnesemia and zinc deficiency.
According to some embodiments, the gastrointestinal disorder is constipation. The constipation can be chronic constipation, idiopathic constipation, due to postoperative ileus, or caused by opiate use. Clinically accepted criteria that define constipation include the frequency of bowel movements, the consistency of feces and the ease of bowel movement. One common definition of constipation is less than three bowel movements per week. Other definitions include abnormally hard stools or defecation that requires excessive straining. Constipation may be idiopathic (functional constipation or slow transit constipation) or secondary to other causes including neurologic, metabolic or endocrine disorders. Constipation may also be the result of surgery (postoperative ileus) or due to the use of drugs such as analgesics (like opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics.
According to some embodiments, the pharmaceutical compositions or combination described herein are for use in treating primary sclerosing cholangitis (PSC).
Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. The bile duct scarring that occurs in PSC narrows the ducts of the biliary tree and impedes the flow of bile to the intestines. Eventually, it can lead to cirrhosis of the liver and liver failure. PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer, and cholangiocarcinoma. It is now disclosed that certain pharmaceutical combinations that comprise psilocybin or psilocin as described herein, act synergistically with other therapeutic compounds and thus are highly effective in treating PSC and its symptoms.
According to some embodiments, the pharmaceutical combination comprises (1) psilocybin or psilocin; and (2) an anti-scar medication. According to certain exemplary embodiments, the pharmaceutical combination comprises (1) psilocybin or psilocin; and (2) a paclitaxel (taxol) or rapamycin (sirolimus).
According to an additional aspect, the present invention provides a pharmaceutical combination for treating primary sclerosing cholangitis (PSC), said pharmaceutical combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) an antibiotic. According to certain embodiment, the antibiotic is vancomycin.
The route of administration can be by any route and will be determined based on the physician and the patient. All other routes of administration of a therapeutically effective amount of an agent to treat the subject in need are contemplated herein and include, without limitation, enteral (e.g., orally or rectally), or parenteral (e.g., intravenous, intrathecal, subcutaneous), or other routes (e.g., intranasal, intradermal, intravitreal, subcutaneous, transdermal, topical, and intraperitoneal).
According to specific embodiments, the pharmaceutical composition or combination is administered orally.
According to some embodiments, the pharmaceutical composition or combination is administered once a day, twice a week, once a week, once in two weeks, once in three weeks or once a month. According to yet further embodiments, the composition or combination is administered once in two months, once in three months, once in four months, once in five months or once in six months.
According to some embodiments, the pharmaceutical composition or combination is administered at least 30 minutes before ingestion of food. According to some embodiments, the pharmaceutical composition or combination is administered at least an hour, or two hours before ingestion of food.
According to some embodiments, the pharmaceutical composition or combination is administered for a period of greater than a week. According to some embodiments, the pharmaceutical composition is administered for a period of greater than four weeks. According to some embodiments, the pharmaceutical composition or combination is administered for a period of greater than two months. According to some embodiments, the pharmaceutical composition or combination is administered for a period of greater than 3, 4, 5, or 6 months.
According to some embodiments, the effective dose of the psilocybin component ranges from 0.01 to 500 mg/kg/day of body weight, from 1 to 250 mg/kg/day of body weight, from 2 to 100 mg/kg/day of body weight, or from 5 to 30 mg/kg/day, and may be in single dose or divided throughout the day. Each possibility represents a separate embodiment of the invention.
According to some embodiments, the effective dose of the at least one active agent ranges from 0.01 to 500 mg/kg/day of body weight, from 1 to 250 mg/kg/day of body weight, from 2 to 100 mg/kg/day of body weight, or from 5 to 30 mg/kg/day, and may be in single dose or divided throughout the day. Each possibility represents a separate embodiment of the invention.
According other embodiments, the pharmaceutical composition or combination is administered at a unit dosage form of approximately 0.05 g/kg/day to approximately 0.5 g/kg/day.
The active agents of the present invention are effective over a wide dosage range. According to certain embodiments, the psilocybin and/or active agent component dosage is about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25, mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 1000 mg per day orally. According to some embodiments, the unit dosage form is administered with food at any time of the day, without food at any time of the day, with food after an overnight fast (e.g., with breakfast).
It is conceived that in some embodiments the therapeutic methods according to the invention may involve combination therapies. In other words, that the oral compositions of the invention may be administered in combination with one or more additional compounds or therapies, the latter using enteral or parenteral and include, but are not limited to, oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and transdermal administration routes.
The compositions disclosed herein may also be administered systemically or locally. According to some embodiments, the pharmaceutical composition is formed into a dosage form suitable for oral, intranasal, intravenous, intraarterial, transmucosal, or subcutaneous administration.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the pharmaceutical compositions of the invention.
It shall be understood that the amount of any active agent that is administered to a patient to treat that patient, will be administered in a therapeutically effective amount, as determined by ordinarily skilled physicians, pharmacologists, and toxicologists, that take into account the weight and age of the patient. In any event, a therapeutically effective amount of the active components is an amount approved by the regulatory authority.
A person skilled in the art can select the appropriate presentation form, and the method of preparing is on the basis of general knowledge, taking into account the nature of the constituents used and the intended use of the composition. Kits containing the above compositions are also contemplated. Compositions of the present invention can be packaged to contain, separately or in kit form together with a container, instructions or instruction brochure.
The following examples describe specific aspects of the invention to illustrate the invention and provide a description of the present methods for those skilled in the art. It should be noted that the term “and” or the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. As used herein, the term "about", when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
The Examples should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.
EXAMPLES
Example 1. Effect of psilocybin-azathioprine combination on cytokine secretion
Cytokine secretion in response to different doses of psilocybin (0-500 ng), azathioprine and psilocybin-azathioprine combination are examined. In-vitro assays are studied using macrophage murine J774A.1, human THP-1 cell lines, and EGC cells.
Example 2. Effect of psilocybin-azathioprine combination on colitis mouse models
Colitis is induced in mice by addition of 3% Dextran Sodium Sulfate (DSS) to drinking water from day 0 to day 5, and test items are administered daily from day 7 for 14 days (500 ng psilocybin and 3 mg/kg azathioprine by interparental route). Animals are monitored for additional 14 days, for a total of 28 days.
The test items include combination of psilocybin with azathioprine, while the azathioprine and psilocybin alone are used as controls.
Morbidity and mortality are monitored twice a day. Body weight is measured during acclimation, before DSS induction, three times a week thereafter and before termination. Detailed clinical observation are conducted daily. Macroscopic scores include rectal bleeding and stool consistency at baseline and every day. This score is combined with body weight loss into the Disease Activity Index (DAI). Mice reaching DAI = 7 or 20% body weight loss are euthanized according to ethics regulation.
Animals are sacrificed on Day 28. The Small intestine and colon are excised, measured and weighed for the determination of small intestine and Colon weight/length ratio. The gastrointestinal tract is fixed in the appropriate fixative, stained and evaluated. ELISA for anti/pro-inflammatory cytokines secreted from intestinal punches are assayed. Fluorescence-activated cell sorting (FACS) for immune cells phenotyping (colon) is conducted.
Example 3. Effect of psilocybin-azathioprine combination on Crohn's disease
A prospective, double-blind, randomized, 8-week study of fixed doses is conducted in outpatients with active Crohn's Disease. Patients receive oral 0 ng (as placebo) to 500 ng psilocybin and 2-3 mg/kg azathioprine once daily for 60 days (azathioprine’s therapeutic response usually occurs after 6 to 8 weeks). Clinical status is assessed using the Crohn's Disease Activity Index (CDAI) and the Quality of Life Questionnaire (QOL). Independent t-test analyses are conducted for baseline and endpoint (LOCF) values. Analysis of Variance (ANOVA) are conducted on ratings scales in relationship to time. Side effects including loss of appetite, fatigue, nausea, and vomiting, are reported and analyzed. Additional side effects examined include blood in the urine or stool and development of mouth sores and ulcers.
Example 4. Effect of psilocybin- mesalamine combination on ulcerative colitis
A prospective, double-blind, randomized, 6-week study of fixed doses is conducted in outpatients with active ulcerative colitis. Patients receive oral 0 ng (as placebo) to 500 ng psilocybin and 0.8- 1.2 g mesalamine (anti-inflammatory agent) once daily for 6 weeks. Clinical status is assessed using the Ulcerative Colitis Disease Activity Index (UCDAI) and the Quality of Life Questionnaire (QOL). Independent t- test analyses are conducted for baseline and endpoint (LOCF) values. Analysis of Variance (ANOVA) are conducted on ratings scales in relationship to time. Side effects including loss of appetite, fatigue, nausea, and vomiting, are reported and analyzed. Additional side effects examined include blood in the urine or stool and development of mouth sores and ulcers.
Example 5. Effect of psilocybin- vancomycin combination on primary sclerosing cholangitis (PSC)
A prospective, double-blind, randomized, 12-week study of fixed doses is conducted in outpatients with primary sclerosing cholangitis (PSC). Patients receive oral 0 ng (as placebo) to 500 ng psilocybin and oral vancomycin (antibiotic medication) at 500 mg, three times/day. The primary outcome is a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. The biochemical response to treatment is expressed as the median percentage change in serum GGT, ALP, and ALT at months 1 and 3 from baseline values. The paired Student’s t test is used to compare each liver biochemical parameters for each patient at months 1 and 3 to baseline values. The Wilcoxon rank-sum test is used to compare the median liver chemistries’ values at the defined time intervals with the median liver chemistries at baseline. Clinical status is also assessed using the Crohn's Disease Activity Index (CD Al) and the Quality of Life Questionnaire (QOL). Independent t-test analyses are conducted for baseline and endpoint (LOCF) values. Analysis of Variance (ANOVA) are conducted on ratings scales in relationship to time. Side effects including loss of appetite, fatigue, nausea, and vomiting, are reported and analyzed. Additional side effects examined include blood in the urine or stool and development of mouth sores and ulcers.
The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The means, materials, and steps for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention.

Claims

1. A pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
2. The pharmaceutical combination for use of claim 1, wherein the gastrointestinal disease or disorder is selected from the group consisting of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastrointestinal motility disorders, constipation, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, functional heartburn, dyspepsia, visceral pain, gastroparesis, and chronic intestinal pseudo-obstruction.
3. The pharmaceutical combination for use of claim 1, wherein the gastrointestinal disease is inflammatory bowel disease (IBD).
4. The pharmaceutical combination for use of claim 3, wherein the inflammatory bowel disease is ulcerative colitis (UC) or indeterminate colitis.
5. The pharmaceutical combination for use of claim 3, wherein the inflammatory bowel disease is Crohn's disease.
6. The pharmaceutical combination for use of claim 1, wherein the gastrointestinal disease or disorder is primary sclerosing cholangitis (PSC).
7. The pharmaceutical combination for use of any one of the preceding claims, wherein the at least one psilocybin, psilocin, or analogs thereof; and the at least one active agent are present in separate pharmaceutical compositions.
8. The pharmaceutical combination for use of any one of the preceding claims, said use comprising administering of the psilocybin, psilocin, or analogs or derivatives thereof; and the least one active agent, substantially simultaneously, concurrently, alternately, sequentially or successively.
9. The pharmaceutical combination for use of any one of claims 1 to 6, wherein the at least one psilocybin, psilocin, or analogs thereof; and the at least one active agent are present in a single pharmaceutical composition.
10. The pharmaceutical combination for use of any one of the preceding claims, wherein the at least one active agent exhibits a therapy selected from the group consisting of anti-tumor necrosis factor-alpha therapy, anti-integrin therapy, anti- interleukin- 12 and interleukin-23 therapy.
11. The pharmaceutical combination for use of any one of the preceding claims, wherein the immunosuppressive medication is selected from the group consisting of Azathioprine, calcineurin inhibitor, Methotrexate, and Mercaptopurine.
12. The pharmaceutical combination for use of claim 11, wherein the calcineurin inhibitor is cyclosporine.
13. The pharmaceutical combination for use of any one of claims 1 to 9, wherein the steroid is a corticosteroid selected from the group consisting of Budesonide, Hydrocortisone, Methylprednisolone, and Prednisone.
14. The pharmaceutical combination for use of any one of claims 1 to 9, wherein the at least one active agent is selected from the group consisting of adalimumab, Azulfidine, certolizumab, infliximab, natalizumab, vedolizumab, and ustekinumab.
15. The pharmaceutical combination for use of any one of claims 1 to 9, wherein the probiotic is Lactobacillus or Bifidobacterium.
16. The pharmaceutical combination for use of any one of the preceding claims, wherein the use comprises orally administration of the at least one psilocybin, psilocin, or analogs thereof; and/or the at least one active agent.
17. The pharmaceutical composition for use of any one of the preceding claims, wherein the use comprises administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent once a day, once a week, once in two weeks, once in three weeks or once a month.
18. A method of treating a gastrointestinal-related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an anti-inflammatory agent, and immunotherapy agent.
19. The method of claim 18, wherein the administering of the psilocybin, psilocin, or analogs or derivatives thereof; and the least one active agent is carried out substantially simultaneously, concurrently, alternately, sequentially or successively.
20. The method of any one of claims 18 and 19, wherein the at least one psilocybin, psilocin, or analogs thereof; and/or the at least one active agent are administered orally.
21. The method of any one of claims 18 and 19, wherein the at least one psilocybin, psilocin, or analogs thereof; and the at least one active agent are administered in different routes of administration.
22. The method of any one of claims 18 to 21, comprising administering the at least one psilocybin, psilocin, or analogs or derivatives thereof; and the at least one active agent once a day, once a week, once in two weeks, once in three weeks or once a month.
23. The method of any one of claims 18 to 22, said method is used in combination with additional therapeutic agents for treatment or prevention of gastrointestinal diseases or disorders.
24. The method of any one of claims 18 to 23, wherein the subject is human.
25. A pharmaceutical composition comprising: (1) a psilocybin, psilocin, or analogs thereof; and (2) an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, an antiinflammatory agent, and immunotherapy agent; and a pharmaceutical acceptable excipient, carrier or diluent.
26. The pharmaceutical composition of claim 25, wherein the active agents within the pharmaceutical composition consist of: (1) a psilocybin, psilocin, or analogs thereof; and (2) an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent, and an anti-inflammatory agent.
27. The pharmaceutical composition of any one of claims 25 or 26, comprising psilocybin.
28. The pharmaceutical composition of any one of claims 25 to 27, wherein the active agent is a steroid selected from the group consisting of Budesonide, Hydrocortisone, Methylprednisolone, and Prednisone.
29. The pharmaceutical composition of any one of claims 25 to 27, wherein the active agent is an immunosuppressive medication selected from the group consisting of Azathioprine, calcineurin inhibitor, Methotrexate, and Mercaptopurine.
30. The pharmaceutical composition of any one of claims 25 to 27, wherein the immunosuppressive medication is Azathioprine (Imuran).
31. The pharmaceutical composition of any one of claims 25 to 27, wherein the active agent is an immunotherapy selected from the group consisting of adalimumab, certolizumab, infliximab, natalizumab, vedolizumab, and ustekinumab.
32. The pharmaceutical composition of any one of claims 25 to 27, wherein the active agent is probiotic selected from the group consisting of Lactobacillus or Bifidobacterium.
33. The pharmaceutical composition of claim 25 to 27, wherein the active agent exhibits a therapy selected from the group consisting of anti-tumor necrosis factoralpha therapy, anti-integrin therapy, and anti-interleukin- 12 and interleukin-23 therapy
34. The pharmaceutical composition of any one of claims 25 to 33, wherein the pharmaceutical composition further comprising an excipient selected from the group consisting of emulsifiers, buffering agents, pH adjusting agents, preservatives, antioxidants, stabilizers, and combinations thereof.
35. The pharmaceutical composition of any one of claims 25 to 34, wherein the pharmaceutical composition further comprising electrolytes, vitamins, antioxidants, minerals, and/or flavoring agents.
36. The pharmaceutical composition of any one of claims 25 to 35, wherein the pharmaceutical composition further comprising triglycerides, fats, lipids, oils, fatty acids, solvents or mixtures thereof.
37. A pharmaceutical composition comprising: at least one psilocybin, psilocin, or analogs thereof; and at least one compound or substance with therapeutic activity against a gastrointestinal disease or disorder, for use in treating a gastrointestinal disease or disorder.
38. A method of treating primary sclerosing cholangitis (PSC), comprising administering to a subject in need thereof a therapeutically effective amount of a psilocybin, psilocin, or analogs thereof.
39. The method of claim 38, further comprises administering to the subject an active agent selected from the group consisting of an immunosuppressive medication, probiotic, steroid, antibiotic, immunotherapy agent and an anti-inflammatory agent.
40. A pharmaceutical combination for use in treating a gastrointestinal-related disease or disorder, said combination comprising a therapeutically effective amount of (i) psilocybin, psilocin, or analogs or derivatives thereof; and (ii) at least one active agent selected from the group consisting of Humira, Remicade, mesalamine, Stelara, Entyvio, sulfasalazine, azathioprine, Cimzia, budesonide, infliximab, adalimumab, vedolizumab, Entocort EC, Inflectra, ustekinumab, certolizumab, Renflexis, Avsola, hyoscyamine, Imuran, Risankizumab, Skyrizi, cholestyramine, rifaximin, and Azasan.
PCT/IL2023/050030 2022-01-11 2023-01-10 Combinations with psilocybin for treating gastrointestinal diseases or disorders WO2023135595A1 (en)

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