WO2024079648A1 - Delivery system for the controlled release of psychedelic compound, pharmaceutical composition and uses thereof - Google Patents
Delivery system for the controlled release of psychedelic compound, pharmaceutical composition and uses thereof Download PDFInfo
- Publication number
- WO2024079648A1 WO2024079648A1 PCT/IB2023/060211 IB2023060211W WO2024079648A1 WO 2024079648 A1 WO2024079648 A1 WO 2024079648A1 IB 2023060211 W IB2023060211 W IB 2023060211W WO 2024079648 A1 WO2024079648 A1 WO 2024079648A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- delivery system
- controlled release
- psychedelic
- release delivery
- psilocybe
- Prior art date
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Definitions
- the present invention relates to a delivery system for the controlled release of psychedelic compounds, preferably derived from psychedelic mushrooms belonging to the Psilocybe genus.
- Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a substituted indolealkylamine and belongs to the group of hallucinogenic tryptamines.
- psilocybin is a prodrug: in fact, when it is orally administered, while passing through the liver it undergoes dephosphorlyation to psilocin active drug, which can cross the blood-brain barrier and produce its psychoactive effects. In this step, a not quantifiable amount of psilocin is destroyed, thus it is not possible to guarantee a drug precise dosage.
- psychedelic drugs and entheogens that are derived from and extracted from mushrooms, fungi, plants, botanicals, animals, flora, or synthesized in the laboratory are highly unstable. They can degrade over time after manufacturing and during storage before their use. Degradation appears more problematic for drugs made from natural product drug extraction techniques.
- psychedelics are characterized by a rapid metabolism and clearance in the body through the action of both monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH); thus, only a small amount of said psychedelics is able to act on a serotonin receptor.
- Monoamine oxidases are metabolic enzymes attached to cytosolic side of the outer membrane of mitochondria of neuronal, glial and several cell types. Specifically, they catalyze the oxidative deamination of neuroactive and vasoactive biogenic compounds (including serotonin and tryptamines) and xenobiotic amines into the corresponding aldehyde and ammonia, both in the central nervous system and peripheral tissues.
- MAOIs monoamine oxidase inhibitors
- MAOIs monoamine oxidase inhibitors
- Monoamine oxidase A is predominantly responsible for the metabolism of psilocin (Reniers et al., “Synthesis and evaluation of [3-carboline derivatives as potential monoamine oxidase inhibitors”, Bioorg. Med. Chem. (2011 ) v. 19(1 ), p. 134-44).
- MAOIs monoamine oxidases inhibitors
- transdermal patches useful for the sustained and controlled dose deliver (macro and microdose) of psilocybin directly into the bloodstream, bypassing the liver, and transmucosal lozenge for the sustained and controlled dose deliver (macro and microdose) of psilocybin slowly over time (Mycrodose Therapeutics Inc.).
- US20220054402 discloses a delivery system for psychedelic drugs based on nano-dimensional structures able to deliver fast psychedelic drugs through the skin, through the gastrointestinal tract, and to the brain through the olfactory and trigeminal nerves in the nasal cavity.
- psychedelic drugs or “psychedelic compounds” or “psychedelics” are synonymous, and they mean classes including tryptamines, phenethylamines, and lysergamides.
- Some of the psychedelic drugs being researched for therapy include psilocybin, psilocin LSD (lysergic acid diethylamide), DMT (diemethyltryptamine), Ibogaine, mescaline, and MDMA (3,4-methylenedioxymethamphetamine).
- the “psychedelic compounds” are preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
- the psychedelic psilocybin mushrooms include a polyphyletic, informal group of fungi that contain psilocybin, psilocin, or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject
- Preferred psychedelic compounds used in the invention comprise psilocybin and/or psilocin and/or their derivatives, such as baeocystin, norpsilocin, norbaeocystin and/or aeruginascin, and combination thereof. Also comprised in the definition of said psychoactive compounds are the extracts of psychedelic psilocybin mushrooms, preferably belonging to the Psilocybe genus.
- Psilocybe genus may refer to the following non-limiting examples of suitable mushrooms containing psilocybin-like psychedelic compounds: Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe wasaroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe y 11.
- pharmaceutically acceptable salts or derivatives refers to those salts or derivatives which possess the biological effectiveness and properties of the salified or derivatized compound and which and which do not produce adverse reactions when administered to a mammal, preferably a human.
- the pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include but are not limited to: carbonate, hydrochloride, hydrobromide, sulphate, hydrogen sulphate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulphonate, and para-toluenesulphonate. Further information on pharmaceutically acceptable salts can be found in Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH, 127-133, (2008), herein incorporated by reference.
- the pharmaceutically acceptable derivatives include the esters, the ethers and the N-oxides.
- Psilocybin is the common name of 4-phosphoryloxy-N,N- dimethyltryptamine.
- Psilocin is the common name of 4-hydroxy-N,N-dimethyltryptamine.
- Boeocystin is the common name of 4-phosphoryloxy-N- methyltryptamine.
- Nepsilocin is the common name of 4-hydroxy-N-methyltryptamine.
- Nebaeocystin is the common name of 4-Hydroxytryptamine 4- phosphate.
- “Aeruginascin” is the common name of N,N,N-trimethyl-4- phosphoryloxytryptamine.
- controlled release can be considered synonymous, and they refer to delivers of a drug, namely psychoactive compounds with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage).
- MAOIs means monoamine oxidases inhibitors. Preferred MAOIs belong to the [3-carboline class of inhibitors.
- micrometric indicate objects having dimensions of the order of micrometres.
- micrometric indicate objects having dimensions less than micrometres, namely of the order of hundreds of nanometers.
- the present invention relates to a delivery system for the controlled release of psychedelic compounds, preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
- the invention also relates to a pharmaceutical composition comprising the controlled release delivery system of the invention.
- a further object of the invention is the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury- induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a-induced inflammatory disease.
- the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a- induced inflammatory disease.
- the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
- the present invention relates to a delivery system for the controlled release of psychedelic compounds, preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
- the controlled release delivery system of the invention comprises a) polymeric spheres, namely micro- and nano- spheres, comprising at least one psychedelic compound, and b) a polymeric fibrous membrane.
- the at least one psychedelic compound is encapsulated into the polymeric spheres.
- the fibrous membrane is made up of micrometric polymeric fibers, or it is made up of submicrometric polymeric fibers.
- the micrometric or submicrometric polymeric fibers are intertwined and/or aligned to make up the fibrous membrane.
- the micrometric fibers commonly lead to the development of bigger voids between the fibers, whereas the submicrometric ones to a tighter structure.
- the fibrous membrane is made up of micrometric polymeric fibers, wherein the micrometric polymeric fibers comprise the polymeric spheres comprising the at least one psychedelic compound.
- the fibrous membrane is made up of submicrometric polymeric fibers, wherein the polymeric spheres comprising the at least one psychedelic compound are embedded into the voids between the submicrometric polymeric fibers which form the fibrous membrane.
- the polymeric spheres comprising at least one psychedelic compound are embedded into the voids by filtration under vacuum conditions.
- the at least one psychedelic compound can be a compound of the class of tryptamines, phenethylamines and/or lysergamides, such as psilocybin, psilocin, LSD (lysergic acid diethylamide), DMT (diemethyltryptamine), ibogaine, mescaline, MDMA (3,4-methylenedioxymethamphetamine) and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
- tryptamines phenethylamines and/or lysergamides
- psilocybin psilocin
- LSD lysergic acid diethylamide
- DMT diemethyltryptamine
- ibogaine mescaline
- MDMA 3,4-methylenedioxymethamphetamine
- the at least one psychedelic compound can be derived from psychedelic psilocybin mushrooms, wherein said psychedelic psilocybin mushrooms preferably belong to the Psilocybe genus.
- the at least one psychedelic compound can be psilocybin, psilocin, baeocystin, norpsilocin, norbaeocystin, aeruginascin and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
- the at least one psychoactive compound can be an extract of psychedelic psilocybin mushrooms, preferably belonging to the Psilocybe genus.
- the psychedelic psilocybin mushrooms include a polyphyletic, informal group of fungi that contain psilocybin, psilocin or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject.
- Non limiting examples of suitable psilocybin-containing mushrooms that are in the genus Psilocybe include Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe wasaroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yieuxsis, Psilocybe liniformans, Psilocybe xalapensis
- the polymeric spheres may also comprise an antioxidant together with the at least one psychedelic compound.
- Preferred antioxidants are selected from ascorbic acid, tannic acid, carotenoids, melatonin, curcumin, retinol, silver derivatives, zinc derivatives and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
- the polymeric spheres are produced with hydrophilic polymers.
- Preferred hydrophilic polymers are poly(vinyl alcohol), zein, polyvinylpyrrolidone, chitosan, agarose and/or alginate.
- the polymeric spheres can be produced for example by emulsion method or mini spray dryer.
- the encapsulation of the at least one psychedelic compound within polymeric spheres stabilizes the at least one psychedelic compound better than the direct embedding of the at least one psychedelic compound within the micrometric polymeric fibers.
- the fibrous membrane is made up of polyester polymers, preferably selected from polylactic acid, polycaprolactone, and/or polyhydroxyalkanoates.
- the polymer used to produce the micrometric and the submicrometric polymeric fibers of the fibrous membranes is a polyester, such as polylactic acid, polycaprolactone, polyglycolide, poly(lactic-co- glycolic acid) and/or polyhydroxyalkanoates.
- Polyesters in fact, allow to obtain micrometric polymeric fibers and submicrometric polymeric fibers showing higher mechanical properties with respect to those prepared using natural and hydrophilic polymers.
- micrometric and submicrometric polymeric fibers are produced by electrospinning technique.
- micrometric polymeric fibers or submicrometric polymeric fibers are obtained.
- chloroform and dichloromethane commonly allow to obtain micrometric fibers
- tetrahydrofuran, formic acid/acetic acid chloroform/N,N-dimethylformamide submicrometric fibers.
- micrometric polymeric fibers comprising the spheres comprising at least one psychedelic compound
- a polymer solution of the selected polymer and of the polymeric spheres is firstly prepared. Then the electrospinning procedure is carried out. In this way, the micrometric polymeric fibers comprising the spheres encapsulating the at least one psychedelic compound are obtained.
- the micrometric fibers have an average diameter comprised between 0,5 pm and 15 pm, preferably between 1 pm and 3 pm.
- the submicrometric fibers have an average diameter comprised between 400 nm and 600 nm, preferably between 450 nm and 550 nm and more preferably the average diameter is 500 nm.
- At least one MAOI may be immobilized on the micrometric or submicrometric polymeric fibers, preferably by physi- or chemi-sorption, in order to further stabilize the at least one psychedelic compound during the controlled release.
- Preferred MAOIs belong to the [3-carboline class of inhibitors that comprise: harman, harmine, norharmane, harmol, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DH[3C), tetrahydro- [3-carboline (TH[3C), tetrahydroharmine, methyl-tetrahydro-[3-carboline MTH[3C, pinoline, 1 -trichloromethyl-1 ,2,3,4tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3-carboline-3-carboxylate ([3CCE
- Objects of the invention is also a pharmaceutical composition comprising the controlled release delivery system of the invention.
- the pharmaceutical composition comprising the controlled release delivery system of the invention is a transdermal pharmaceutical composition.
- a further object of the invention relates to the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a-induced inflammatory disease.
- the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
- the invention relates to a pharmaceutical composition comprising the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a- induced inflammatory disease.
- the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
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Abstract
A controlled release delivery system comprising: a) polymeric spheres comprising at least one psychedelic compound of the class of tryptamines, phenethylamines and/or lysergamides, preferably psilocybin, psilocin, LSD, DMT, ibogaine, mescaline, MDMA and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof, and b) a polymeric fibrous membrane. Said controlled release delivery system for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a-induced inflammatory disease.
Description
DESCRIPTION TITLE
Delivery system for the controlled release of psychedelic compound, pharmaceutical composition and uses thereof
FIELD OF INVENTION
The present invention relates to a delivery system for the controlled release of psychedelic compounds, preferably derived from psychedelic mushrooms belonging to the Psilocybe genus.
BACKGROUND OF THE INVENTION
In recent years, the scientific interest towards the potential use of psilocybin and other psychedelics for medical applications, such as the psychiatric disorders treatment, including mood disorders, depression, anxiety and alcoholism and nicotine addiction is increasing (Rucker, J.J.H et al., “Psychiatry & psychedelic drugs. Past, present & future”, Neuropharmacology (2018), v.142, p. 200-218).
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a substituted indolealkylamine and belongs to the group of hallucinogenic tryptamines.
As well known, psilocybin is a prodrug: in fact, when it is orally administered, while passing through the liver it undergoes dephosphorlyation to psilocin active drug, which can cross the blood-brain barrier and produce its psychoactive effects. In this step, a not quantifiable amount of psilocin is destroyed, thus it is not possible to guarantee a drug precise dosage.
Many psychedelic drugs and entheogens that are derived from and extracted from mushrooms, fungi, plants, botanicals, animals, flora, or synthesized in the laboratory are highly unstable. They can degrade over time after manufacturing and during storage before their use. Degradation appears more problematic for drugs made from natural product drug extraction techniques.
Moreover, psychedelics are characterized by a rapid metabolism and clearance in the body through the action of both monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH); thus, only a small amount of said psychedelics is able to act on a serotonin receptor.
Monoamine oxidases (MAOs) are metabolic enzymes attached to cytosolic side of the outer membrane of mitochondria of neuronal, glial and several cell types. Specifically, they catalyze the oxidative deamination of neuroactive and vasoactive biogenic compounds (including serotonin and tryptamines) and xenobiotic amines into the corresponding aldehyde and ammonia, both in the central nervous system and peripheral tissues. Several monoamine oxidase inhibitors (MAOIs) have been extensive employed as antidepressants and neuroprotective agents in Parkinson’s disease, as well as in the treatment of anxiety. There are two main isoforms, MAO-A and MAO-B. Monoamine oxidase A is predominantly responsible for the metabolism of psilocin (Reniers et al., “Synthesis and evaluation of [3-carboline derivatives as potential monoamine oxidase inhibitors”, Bioorg. Med. Chem. (2011 ) v. 19(1 ), p. 134-44).
Thus, the use of monoamine oxidases inhibitors (MAOIs) could allow to inhibit the metabolic breakdown and clearance of psychedelic compounds (Ostadkarampour, M. et al., “Monoamine oxidase inhibitors: a review of their anti-inflammatory therapeutic potential and mechanisms of action”, Frontiers in Pharmacology, (2021 ), v. 12, p. 676239).
Additionally, several psychedelic drugs, entheogens, and medicinal mushroom extract compounds show poor bioavailability, as well as difficulty in passing the Blood to Brain Barrier (BBB).
For these reasons, the development of an appropriate drug delivery system could allow to overcome the above cited disadvantages and to guarantee a controlled psychedelics release over time with the consequent reduction of the number of administrations.
In this respect, some solutions have been proposed: psilocybin formulations such as natural or synthetic derived capsules, sublingual sprays, gel caps, effervescent tablets, and oral strips are known (Revive Therapeutics Ltd.).
Already known are also transdermal patches useful for the sustained and controlled dose deliver (macro and microdose) of psilocybin directly into the bloodstream, bypassing the liver, and transmucosal lozenge for the sustained and controlled dose deliver (macro and microdose) of psilocybin slowly over time (Mycrodose Therapeutics Inc.).
The US patent application US20220054402 (Nanoalchemie) discloses a delivery system for psychedelic drugs based on nano-dimensional structures able to deliver fast psychedelic drugs through the skin, through the gastrointestinal tract, and to the brain through the olfactory and trigeminal nerves in the nasal cavity.
Despite the above solutions, it remains the need for delivery systems for psychedelics, which are safe, precise in the dosage and operating in sustained and controlled dose manner.
DEFINITIONS
Unless otherwise defined, all the terms of the art, notations and other scientific terms used herein are intended to have the meanings commonly understood by those who are experts in the technique to which this description belongs. In some cases, terms with commonly understood meanings are defined here for clarity and I or for ready reference; the inclusion of these definitions in this description should therefore not be interpreted as representing a substantial difference with respect to what is generally understood in the art.
The terms "comprise", "have", "include", "contain", "comprising", "having", "including" and "containing" are to be understood as open terms (i.e. the meaning "comprising, but not limited to") and are to be considered as a
support also for terms such as "essentially consist of”, “consisting essentially of”, “consist of” or “consisting of”.
For all the ranges indicated in the text and in the claims of the present patent application, it is understood that the extremes of these ranges are included.
The terms “psychedelic drugs” or “psychedelic compounds” or “psychedelics” are synonymous, and they mean classes including tryptamines, phenethylamines, and lysergamides. Some of the psychedelic drugs being researched for therapy include psilocybin, psilocin LSD (lysergic acid diethylamide), DMT (diemethyltryptamine), Ibogaine, mescaline, and MDMA (3,4-methylenedioxymethamphetamine).
The “psychedelic compounds” are preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
The psychedelic psilocybin mushrooms include a polyphyletic, informal group of fungi that contain psilocybin, psilocin, or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject
Preferred psychedelic compounds used in the invention comprise psilocybin and/or psilocin and/or their derivatives, such as baeocystin, norpsilocin, norbaeocystin and/or aeruginascin, and combination thereof. Also comprised in the definition of said psychoactive compounds are the extracts of psychedelic psilocybin mushrooms, preferably belonging to the Psilocybe genus.
The pharmaceutically acceptable salts, derivatives, hydrate, or solvate of the above cited psychedelic compounds are comprised in the definition too.
The term “Psilocybe genus” may refer to the following non-limiting examples of suitable mushrooms containing psilocybin-like psychedelic compounds: Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe
cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and combinations thereof.
The term “pharmaceutically acceptable salts or derivatives” herein refers to those salts or derivatives which possess the biological effectiveness and properties of the salified or derivatized compound and which and which do not produce adverse reactions when administered to a mammal, preferably a human. The pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include but are not limited to: carbonate, hydrochloride, hydrobromide, sulphate, hydrogen sulphate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulphonate, and para-toluenesulphonate. Further information on pharmaceutically acceptable salts can be found in Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH, 127-133, (2008), herein incorporated by reference. The pharmaceutically acceptable derivatives include the esters, the ethers and the N-oxides.
“Psilocybin” is the common name of 4-phosphoryloxy-N,N- dimethyltryptamine.
“Psilocin” is the common name of 4-hydroxy-N,N-dimethyltryptamine.
“Baeocystin” is the common name of 4-phosphoryloxy-N- methyltryptamine.
“Norpsilocin” is the common name of 4-hydroxy-N-methyltryptamine.
“Norbaeocystin” is the common name of 4-Hydroxytryptamine 4- phosphate.
“Aeruginascin” is the common name of N,N,N-trimethyl-4- phosphoryloxytryptamine.
The terms “controlled release”, “controlled delivery”, “modified release” and “modified delivery” can be considered synonymous, and they refer to delivers of a drug, namely psychoactive compounds with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage).
The term “MAOIs” means monoamine oxidases inhibitors. Preferred MAOIs belong to the [3-carboline class of inhibitors.
The term “micrometric” indicate objects having dimensions of the order of micrometres.
The term “submicrometric” indicate objects having dimensions less than micrometres, namely of the order of hundreds of nanometers.
SUMMARY OF INVENTION
The present invention relates to a delivery system for the controlled release of psychedelic compounds, preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
The invention also relates to a pharmaceutical composition comprising the controlled release delivery system of the invention.
A further object of the invention is the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury- induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a-induced inflammatory disease.
According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic
arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
Lastly, the invention relates to a pharmaceutical composition comprising the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a- induced inflammatory disease.
According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
DETAILED DESCRIPTION
The present invention relates to a delivery system for the controlled release of psychedelic compounds, preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
The controlled release delivery system of the invention comprises a) polymeric spheres, namely micro- and nano- spheres, comprising at least one psychedelic compound, and b) a polymeric fibrous membrane.
According to a preferred embodiment, the at least one psychedelic compound is encapsulated into the polymeric spheres.
The fibrous membrane is made up of micrometric polymeric fibers, or it is made up of submicrometric polymeric fibers. The micrometric or submicrometric polymeric fibers are intertwined and/or aligned to make up the fibrous membrane. The micrometric fibers commonly lead to the development of bigger voids between the fibers, whereas the submicrometric ones to a tighter structure.
According to a preferred embodiment, the fibrous membrane is made up of micrometric polymeric fibers, wherein the micrometric polymeric fibers
comprise the polymeric spheres comprising the at least one psychedelic compound.
According to another preferred embodiment, the fibrous membrane is made up of submicrometric polymeric fibers, wherein the polymeric spheres comprising the at least one psychedelic compound are embedded into the voids between the submicrometric polymeric fibers which form the fibrous membrane.
According to a preferred embodiment, the polymeric spheres comprising at least one psychedelic compound are embedded into the voids by filtration under vacuum conditions.
The at least one psychedelic compound can be a compound of the class of tryptamines, phenethylamines and/or lysergamides, such as psilocybin, psilocin, LSD (lysergic acid diethylamide), DMT (diemethyltryptamine), ibogaine, mescaline, MDMA (3,4-methylenedioxymethamphetamine) and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
According to a preferred embodiment, the at least one psychedelic compound can be derived from psychedelic psilocybin mushrooms, wherein said psychedelic psilocybin mushrooms preferably belong to the Psilocybe genus.
More preferably, the at least one psychedelic compound can be psilocybin, psilocin, baeocystin, norpsilocin, norbaeocystin, aeruginascin and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
The at least one psychoactive compound can be an extract of psychedelic psilocybin mushrooms, preferably belonging to the Psilocybe genus.
According to a preferred aspect, the psychedelic psilocybin mushrooms include a polyphyletic, informal group of fungi that contain psilocybin, psilocin or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject.
Non limiting examples of suitable psilocybin-containing mushrooms that are in the genus Psilocybe include Psilocybe atlantis, Psilocybe
azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and combinations thereof.
Optionally, the polymeric spheres may also comprise an antioxidant together with the at least one psychedelic compound. Preferred antioxidants are selected from ascorbic acid, tannic acid, carotenoids, melatonin, curcumin, retinol, silver derivatives, zinc derivatives and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
According to a preferred embodiment, the polymeric spheres are produced with hydrophilic polymers. Preferred hydrophilic polymers are poly(vinyl alcohol), zein, polyvinylpyrrolidone, chitosan, agarose and/or alginate.
The polymeric spheres can be produced for example by emulsion method or mini spray dryer.
Preferably, the encapsulation of the at least one psychedelic compound within polymeric spheres stabilizes the at least one psychedelic compound better than the direct embedding of the at least one psychedelic compound within the micrometric polymeric fibers.
The fibrous membrane is made up of polyester polymers, preferably selected from polylactic acid, polycaprolactone, and/or polyhydroxyalkanoates.
Preferably, the polymer used to produce the micrometric and the submicrometric polymeric fibers of the fibrous membranes is a polyester,
such as polylactic acid, polycaprolactone, polyglycolide, poly(lactic-co- glycolic acid) and/or polyhydroxyalkanoates.
Polyesters, in fact, allow to obtain micrometric polymeric fibers and submicrometric polymeric fibers showing higher mechanical properties with respect to those prepared using natural and hydrophilic polymers.
The micrometric and submicrometric polymeric fibers are produced by electrospinning technique.
Depending on the solvent which is used for the electrospinning process, as well as the polymer concentration and the applied process conditions, micrometric polymeric fibers or submicrometric polymeric fibers are obtained. For example, chloroform and dichloromethane commonly allow to obtain micrometric fibers, whereas tetrahydrofuran, formic acid/acetic acid, chloroform/N,N-dimethylformamide submicrometric fibers.
To obtain the micrometric polymeric fibers comprising the spheres comprising at least one psychedelic compound, a polymer solution of the selected polymer and of the polymeric spheres is firstly prepared. Then the electrospinning procedure is carried out. In this way, the micrometric polymeric fibers comprising the spheres encapsulating the at least one psychedelic compound are obtained.
In a preferred embodiment, the micrometric fibers have an average diameter comprised between 0,5 pm and 15 pm, preferably between 1 pm and 3 pm.
In another preferred embodiment, the submicrometric fibers have an average diameter comprised between 400 nm and 600 nm, preferably between 450 nm and 550 nm and more preferably the average diameter is 500 nm.
Optionally, at least one MAOI may be immobilized on the micrometric or submicrometric polymeric fibers, preferably by physi- or chemi-sorption, in order to further stabilize the at least one psychedelic compound during the controlled release.
Preferred MAOIs belong to the [3-carboline class of inhibitors that comprise: harman, harmine, norharmane, harmol, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DH[3C), tetrahydro- [3-carboline (TH[3C), tetrahydroharmine, methyl-tetrahydro-[3-carboline MTH[3C, pinoline, 1 -trichloromethyl-1 ,2,3,4tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3-carboline-3-carboxylate ([3CCE), [3- carboline-3-carboxylate ([3CCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8- methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, plakortamines D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
Objects of the invention is also a pharmaceutical composition comprising the controlled release delivery system of the invention.
According to a preferred aspect, the pharmaceutical composition comprising the controlled release delivery system of the invention is a transdermal pharmaceutical composition.
A further object of the invention relates to the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a-induced inflammatory disease.
According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis. Lastly, the invention relates to a pharmaceutical composition comprising the controlled release delivery system of the invention for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic
pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a- induced inflammatory disease.
According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
Claims
1. A controlled release delivery system comprising: a) polymeric spheres comprising at least one psychedelic compound of the class of tryptamines, phenethylamines and/or lysergamides, preferably psilocybin, psilocin, LSD, DMT, ibogaine, mescaline, MDMA and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof, and b) a polymeric fibrous membrane.
2. The controlled release delivery system according to claim 1 , wherein the at least one psychedelic compound is derived from psychedelic psilocybin mushrooms, preferably from psychedelic psilocybin mushrooms belonging to the Psilocybe genus, and more preferably the at least one psychedelic compound is psilocybin, psilocin, baeocystin, norpsilocin, norbaeocystin, aeruginascin and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
3. The controlled release delivery system according to claim 1 , wherein the at least one psychoactive compound is an extract of psychedelic psilocybin mushrooms, preferably an extract of psychedelic psilocybin mushrooms belonging to the Psilocybe genus.
4. The controlled release delivery system according to any one of claim 1 to 3, wherein the at least one psychedelic compound is encapsulated into the polymeric spheres.
5. The controlled release delivery system according to any one of claim 1 to 4, wherein the polymeric spheres further comprise an antioxidant, preferably selected from ascorbic acid, tannic acid, carotenoids, melatonin, curcumin, retinol, silver derivatives, zinc derivatives and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
6. The controlled release delivery system according to any one of claim 1 to 5, wherein the polymeric spheres are made of hydrophilic polymers, preferably selected from: poly(vinyl alcohol), zein, polyvinylpyrrolidone, chitosan, agarose and alginate.
7. The controlled release delivery system according to any one of claim 1 to 6, wherein the fibrous membrane is made up of micrometric polymeric fibers, or it is made up of submicrometric polymeric fibers.
8. The controlled release delivery system according to claim 7, wherein the fibrous membrane is made up of micrometric polymeric fibers and wherein the micrometric polymeric fibers comprise the polymeric spheres comprising the at least one psychedelic compound.
9. The controlled release delivery system according to claim 7, wherein the fibrous membrane is made up of submicrometric polymeric fibers and wherein the polymeric spheres comprising the at least one psychedelic compound are embedded into the voids between the submicrometric polymeric fibers which form the fibrous membrane.
10. The controlled release delivery system according to any one of claim 1 to 9, wherein the fibrous membrane, the micrometric polymeric fibers and the submicrometric polymeric fibers are made up of polyester polymers, preferably selected from polylactic acid, polycaprolactone, polyglycolide, poly(lactic-co-glycolic acid) and/or polyhydroxyalkanoates.
11 . The controlled release delivery system according to any one of claim 1 to 10, further comprising at least one MAOIs, preferably selected from [3- carbolines, more preferably selected between harman, harmine, norharmane, harmol, 6-methoxyharmalan, harmalan, harmaline, harmalol,
dihydro-[3-carbolines (DH[3C), tetrahydro-p-carboline (THpC), tetrahydroharmine, methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 - trichloromethyl-1 ,2,3,4tetrahydro-b-carboline (TaClo), 6- methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p- carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8- methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, plakortamines D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combination thereof.
12. A pharmaceutical composition comprising the controlled release delivery system according to any one of the claims 1 to 11 .
13. The pharmaceutical composition according to claim 12, characterized in that it is a transdermal pharmaceutical composition.
14. A ccontrolled release delivery system according to any one of claims 1 to 11 or a pharmaceutical composition according to any one of claim 12 to 13, for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a-induced inflammatory disease.
15. A controlled release delivery system according to claim 14, wherein the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
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