Solid lipid nanoparticles as robust drug delivery systems

Abstract

Disclosed is a process for the assembly solid lipid nanoparticles (SLNs) by a process that comprises: (a) combining (i) a therapeutic amount of one or psychedelics, (ii) a solid lipid at room temperature (25 °C) that can be composed of mono-, di, and tri-glycerides, (iii) a primary surfactant, (iv) a co-surfactant(s) (b) high-shear mixing said ingredients in a container to form a coarse-emulsion product, and (c) subjecting the coarse-emulsion through a microfluidic device to produce a solid lipid nanoparticle nanoemulsion containing a psychedelic(s).

Description

Solid Lipid Nanoparticles as Robust Drug Delivery Systems407-P016PCTREFERENCE TO RELATED APPLICATIONS

[0001] This application is related to U.S. Provisional patent application Ser. No. 63 / 734,866 that was filed on December 17, 2024, the disclosure of which is hereby incorporated by reference.FIELD OF THE INVENTION

[0002] The invention relates to formulations of psychedelic compounds (including their prodrugs), including tryptamine-scaffold and / or phenethylamine-scaffold psychedelic agents that exhibit therapeutic benefits.BACKGROUND OF THE INVENTION

[0003] Many people worldwide are afflicted with psychological or mood disorders, such as depression, anxiety, and post-traumatic stress disorders. Many of these conditions are believed to involve a person's serotonin system, including interactions between (A) the neurotransmitter serotonin (often abbreviated 5-HT) and (B) several different subtypes of serotonin neurotransmitter receptors found in the human body.

[0004] A variety of compositions are known to modulate activity at the serotonin receptors. A number of pharmaceuticals (antidepressants, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, etc.) have become available.Almost all these pharmaceuticals target neurotransmitter receptors, e.g., serotonergic receptors, adrenergic receptors, dopaminergic receptors, etc., and in different ways. All ten of the leading pharmaceutical products for treating mood disorders (such as depression, obsessive compulsive disorder, and / or anxiety disorders) target serotonin pathways.

[0005] In a review of many mushroom species with potential neurogenerative properties, the psilocybin or psilocyban species (i.e., "psilocybin-containing") are not mentioned, either alone or in combinations with the edible and medicinal mushroom species (Phan, David et al. 2017); however, this is likely an oversight deliberate or otherwise as these molecules specifically act as neurogeneratives. A good summary of the role of psilocybin in humans can be found in Passie (Passie, Seifert et al. 2002). That psilocybin has neurogenerative properties was elucidated by Catlow (Catlow, Song et al. 2013). See also US Publication Number 2022 / 0313367 (Trant,Hosie et al. 2025). The disclosures of these publications are hereby incorporated by reference.

[0006] Both the medical establishment and conventional wisdom define psychedelic substances, (including those in the tryptamine and phenethylamine family, and including substances classified as 5-HT2A agonists and antagonists), by their ability to determine certain alterations in consciousness, emotion, and cognition, including positive and negative psychotomimetic symptoms (e.g., psychedelic effects, psychedelic experience, psychotomimetic effects). These effects are known to laymen and doctors for their potential recreational misuse and to researchers in the psychiatric field for their potential therapeutic uses in psychiatry and research applications for the study of brain function.

[0007] Psychedelic or entheogenic substances are presently under investigation for the treatment of several psychiatric and neurological diseases, disorders and symptoms, including but not limited to depression, PTSD, OCD, addiction, and end- stage-cancer-associated anxiety. The psychedelic experience, which includes positive and negative psychotomimetic effects induced by a psychedelic GPCR agonist or antagonist, is an integral part of the intended treatment. For therapeutic purposes, GPCR agonist or antagonistic psychedelic drugs are generally administered in a controlled setting and preceded and followed by counseling and or Opsychotherapy and the whole session is supervised and closely monitored. The administration of the GPCR agonist or antagonist is administered at a dose that produces psychedelic and or psychotomimetic symptoms should be paired with ancillary therapies, which include a particular physical setting, in addition to pre, during, and post drug administration counseling and / or psychotherapy (talk therapy) to achieve therapeutic efficacy for certain psychiatric disorders. The psychedelic experience (which can include alterations in consciousness, emotion, and cognition, and positive and negative psychotomimetic symptoms) is thus viewed by researchers and scientists as integral part of the potential therapeutic efficacy of psychedelic drugs. See US Publication No. 2022 / 0143051 (Manfredi, Inturrisi et al. 2020) which is hereby incorporated by reference.

[0008] Controlled, reliable administration of psychedelic agents within botanical or fungal material is challenging without isolation of the active pharmaceutical ingredients (APIs). Even when "magic mushrooms", for example, are properly identified, those mushrooms vary greatly in terms of the concentration of psilocybin,psilocin, and other (often overlooked) active ingredients. Accordingly, administering a specific composition or a particular dose using mushrooms is not reliable because of the variability in the chemical composition of mushrooms even in the same species or even in the different parts of mushrooms’ anatomy. This is consistent with many botanical and fungal species possessing relevant APIs.

[0009] Some of the major challenges to be overcome to create stable, robust, reproducible, and biologically active products include: (a.) lipophilicity or hydrophilicity of the API that in term limit (b.) the limited bioaccessibility of the API partially due to the (c) extensive degradation of the API during formulation, storage, or in vivo owing to metabolic pathways, and (d) the inability of the API to cross the blood-brain barrier if psychoactivity is to be demonstrated.

[0010] It would be desirable to have a composition and method for administering psychedelics that would provide a consistent, therapeutically useful dose.

[0011] Psychedelic active pharmaceutical ingredients (APIs), such as psilocybin, mescaline, psilocin, ibogaine, LSD, and bufotenin, are being studied for their use in the treatment of major depressive disorder (MDD), substance use disorder (SUD), and neurodegenerative disorders, neurological disorders, and inflammatory disorders. Formulation and delivery challenges associated with even the serumsoluble psychedelic APIs and their prodrugs-such as stress-induced degradation, limited bioavailability, and significant first-pass metabolism-have combined to make it difficult to identify functional formulations.

[0012] 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is a naturally occurring tryptamine derivative and analogue of psilocin found in a range of fungal, plant, and animal species such as seeds of the Anadenanthera genus, mushrooms of the Amanita genus, and in the venom and eggs of toads in the Incilius and Alvarius genus. They have been used for millennia for their hallucinogenic effects.

[0013] Seeds of Anadenanthera colubrina and Anadenanthera peregrina were smoked by indigenous peoples of the northern regions of Argentina up to 4000 years ago. These seeds (containing up to 0.04 wt% of 5-MeO-DMT) were dried, roasted and ground to produce a powdered preparation known as a snuff ("hataj", "cohoba", "yopo") for insufflation and smoking in pipes. Modern literature tells us that intranasal, intravenous, and smoking (inhalation) are the common forms of administration due to rapid metabolization of 5-MeO-DMT during oral administration. Inhalation of 5-MeO-DMT (1-5 mg) produces effects within 4-5 mins that last for upto one hour. 5-MeO-DMT is not under international control and has experienced a recent resurgence in interest, along with other psychedelic APIs, for the therapeutic treatment of MDD, SUD, and various neurodegenerative disorders.

[0014] Currently, it is statistically significant that people who are prescribed antidepressants are subjected to difficult and sometimes debilitating side effects that affect their daily lives. Depression is one of the largest epidemics in the world, which suggests that other classes of therapeutics must be investigated to provide effective therapies for its treatment. This has led to renewed interest in cannabis and entheogen research.

[0015] The fundamental idea behind the current work is a "Trojan Horse" delivery system that uses some type of encapsulating technology to overcome the variable solubility profiles, bio-accessibility, and susceptibility to enzymatic and oxidative degradation of psychedelics. Such encapsulating delivery systems can carry the API payload across biological barriers that are otherwise effectively impermeable to the unformulated APIs.

[0016] There are very few examples of formulations of psychedelics in the literature (Shen, Lv et al. 2022, Witowski, Hess et al. 2024, Fandiho, Hutton et al. 2025). To be useful, these formulations must be able to be readily consumed in a clinical setting or as a prescription medication without the need for special storage or in situ formulation by a trained chemist

[0017] .It would be desirable to have an effective formulation for the delivery of psychedelics (such as but not limited to psilocybin, psilocin, ibogaine, LSD, mescaline and bufotenin) that would be bioavailable and bioeffective in therapeutically effective doses.

[0018] Recent clinical trials using forms of psychedelics have been on-going. A vaporizable form of 5-MeO-DMT (GH Research PLC, Dublin, Ireland) was published that detailed the efficacy of 5-MeO-DMT for treatment-resistant depression and required three daily doses of in situ produced 5-MeO-DMT aerosols for successful biological uptake several adverse drug reactions were reported in the study which are more associated with the dosing form rather than the drug itself (Reckweg, van Leeuwen et al. 2023). Another 5-MeO-DMT intranasal spray has entered phase Ila clinical trials (Beckley Psytech Ltd., Oxford, UK) (Rucker, Roberts et al. 2024); this involves a single inhalable dose of 5-MeO-DMT, is well-tolerated, and produces a sustained antidepressant outcome for 3 months. While no serious adverse eventswere observed, mild nasal discomforts were reported, possibly linked to the use of NaOH in the nasal composition. Nevertheless, we note that the stated composition may also lead to API degradation in situ because of the alkalinity. In any case, neither composition encapsulated the API to facilitate transmucosal uptake in the nose (bypassing the blood-brain-barrier), and instead both seek a simple introduction of the unmodified polar API into the bloodstream.

[0019] Most formulation approaches to improve bioavailability of water insoluble, highly lipophilic drugs are based on either particle size reduction technologies (e.g. micronization or nano-particle generation) to increase drug dissolution rate and / or achieve transient solubilization, or technologies to achieve a sustained solubilization of the drug, such as complexation, or use of lipid-based delivery systems. The particle size reduction technologies often fail to overcome bioavailability limitations. See U.S. Pat. No. 11 ,617,758 (Dhingra and Bernstein 2020).

[0020] A widely used approach to achieve sustained solubilization and overcome poor fasted-state bioavailability of lipophilic drugs is to use solutions in lipid vehicles containing surfactants that constitute:

[0021] Solid lipid nanoparticles (SLNs) typically produce opaque emulsions with lipid droplet sizes of <500 nm.

[0022] These emulsions are isotropic mixtures of (a) at least one drug, (b) a solid lipid organic vehicle, (c) a primary surfactant and, optionally (d) one (or more) cosu rfactant(s). These formulations rapidly form relatively stable oil-in-water (o / w) emulsions after being subjected to microfluidic processing where the drug is contained in nanometer-size droplets.

[0023] SLNs can also be formed through self-emulsification methods.

[0024] SLNs show high drug solubilizing capacity and enhancement in both rate and extent of absorption by lymphatic uptake. Moreover, it is possible to form blends that are composed of several excipients, such as pure triglycerides or mixtures of mono-, di- and triglycerides.

[0025] Orally administrated SLNs widen the accessibility of lipidic excipients to offer flexibility of function with respect to improving bioavailability of drugs by manipulating their release profiles and protecting them from enzymatic and / or chemical degradation while facilitating their passage in the gastrointestinal tract until their intestinal absorption, and ultimately passage through the blood brain barrier(BBB) once present in the bloodstream. SLNs may also demonstrate cell-penetrating properties.

[0026] It would be desirable to have an effective process to make stable, effective, SLN compositions that could be used with psychedelics.

[0027] It would also be desirable to have a process for creating SLNs to make a composition comprising psychedelics in therapeutically effective concentrations to produce a therapeutically effective composition for the treatment of a human or mammal patient.SUMMARY OF THE INVENTION

[0028] It is an object of the invention to provide a composition and method for its administration to a patient having a therapeutic need that would provide a consistent, therapeutically useful dose of a psychedelic agent.

[0029] It is also an objective of the invention to provide a composition and method of administration that would deliver a therapeutically effective amount of a psychedelic agent to a patient in need that would provide a bioavailable, bio-effective dose in therapeutically effective dosages.

[0030] It is further an objective of the invention to provide an effective process to make a stable, effective, SLN delivery composition that could be used with psychedelic agents.

[0031] Additionally, it is an object of the invention to provide a process for producing SLNs in a composition incorporating psychedelic agents in therapeutically effective concentrations to produce a therapeutically effective composition for the treatment of a human or other mammal patient.

[0032] In accordance with these and other objects of the invention that will become apparent from the description herein, compositions according to the invention are in the form of an solid oil-in-water nanoemulsion that comprises: (a) a therapeutic amount of one or more psychedelic agents, (b) a lipid that is solid at room temperature (25 °C) and which comprises a mixture of mono-, di, and triglycerides, (c) a primary surfactant, and (d) optionally, one or more co-surfactant(s).

[0033] The invention also contemplates a process for the manufacture of the SLNs of the present invention by a process that comprises: (a) combining ingredients that include: (i) a lipid that includes mono-, di, and tri- glycerides in liquid form, (ii) a therapeutic amount of one or more psychedelic agents, (iii) a primarysurfactant, (iv) optionally, one or more co-surfactant(s), (b) mixing said ingredients with high-shear conditions to form a coarse-emulsion product, and (c) subjecting the coarse-emulsion product to high shear mixing conditions in a a microfluidic production device that will produce a SLN nanoemulsion product that contains said one or more psychedelics.

[0034] The nanoemulsion form of the present invention provides a stable formulation that is well-suited for delivery of one or more psychedelics via ingestion, thereby providing a familiar and comfortable form of dosing to a patient. The small average droplet size of the nanoemulsion and ability of the active ingredient to cross the blood-brain barrier present unique opportunities for compositions that can deliver therapeutic benefits without the limitations encountered by prior efforts.DETAILED DESCRIPTION OF THE INVENTION

[0035] Disclosed herein is a design of a stable, solid lipid nanoparticle, drug delivery system exhibiting nanometer sized droplets containing (a) a therapeutic amount of one or more psychedelic agents in the emulsified droplets. Each of these is a hydrophilic or lipophilic drug that is variably soluble in serum and well suited for SLNs delivery.

[0036] Preferred psychedelic agents comprise psilocybin, 5-MeO-DMT, N,N- DMT, psilocin, mescaline, ibogaine, and / or bufotenine or their prodrugs or pharmaceutically acceptable salts in an amount within the range of 1 - 80 wt%, preferably 15-30 wt% based on total weight of the SLNs. When used in a liquid form, a suitable amount of the psychedelic agent(s) is an amount within the range from about 0.1 - 1000 mg / mL, preferably an amount within the range of 0.5 - 500 mg / mL, and more preferably an amount within the range of 1 - 100 mg / mL.

[0037] The composition of the present invention also includes (b) an organic vehicle, (c) a primary surfactant, and (d) (optionally) one or more co-surfactants.

[0038] Suitable organic vehicles include medium-chain and long-chain mono-, di, and tri- glyceride oils that are present in solid state at room temperature (25 °C). The triglyceride oil is generally used in an amount within the range from about 1 - 50 wt%, preferably an amount within the range of 10 - 40 wt %, and even more preferably an amount within the range of 20 - 35 wt %, and most optimally within the range of 1 - 10 wt% based on total SLNs weight.

[0039] Suitable primary surfactants generally include a lipophilic surfactant that is selected from apricot kernel oil PEG-6 esters, arachidyl glucoside, beheneth-5, beheneth-10, beheneth-20, beheneth-25, beheneth-30, butylene glycol, C9-11 pareth-3, C14-22 alcohol & C12-20 alkyl glucoside, calcium stearoyl lactylate, caprylyl / capryl glucoside, caprylyl / decyl glucoside, ceteareth-6, ceteareth-6 (&) stearyl alcohol, ceteareth-10, ceteareth-12, ceteareth-15, ceteareth-20, ceteareth-23, ceteareth-25, ceteareth-30, ceteareth-33, ceteareth-80, ceteareth-100, cetearyl alcohol (&) ceteareth20, cetearyl alcohol (&) ceteareth30, cetearyl alcohol (&) cetearyl glucoside, cetearyl alcohol (&) PEG40 castor oil (&) sodium cetearyl sulfate, cetearyl alcohol (&) polysorbate 60, cetearyl alcohol, cetearyl alcohol (&) sodium cetearyl sulfate, cetearyl alcohol & sodium lauryl sulfate, cetearyl alcohol (&) sodium cetearyl sulfate (&) sodium lauryl sulfate, cetearyl glucoside, cetearyl alcohol (&) cetearyl glucoside, cetearyl olivate, cetearyl olivate (&) sorbitan olivate, cetearyl wheat straw glycosides, ceteth-2, ceteth-5, ceteareth-7, ceteth-10, ceteth-20, sphingomyelin, phosphatidylcholine, cholesterol, cetrimonium chloride, cetyl palmitate, cetyl PEG / PPG-10 / 1 dimethicone, cocamide DEA, cocamide MEA, coco glucoside, corn oil PEG-6 esters, D-a-tocopheryl polyethylene glycol 1000 succinate, decaglyceryl tetraoleate, deceth-3, decyl glucoside, diacetyl tartaric acid esters of mono and diglycerides (DATEM), diethylene glycol monoethyl ether, diethylene glycol monooleate, diglyceryl dioleate, diglyceryl monooleate, diisostearoyl polyglyceryl-3 dimer dilinoleate, dimethyl isosorbide, distearyldimonium chloride, erythorbyl laurate, ethoxylated monodiglycerides, ethoxylated monodiglycerides, ethylene glycol, ethylhexyl stearate, glycerol mono and distearate, polyoxyethylene stearate, glyceryl behenate, glyceryl caprylate, glyceryl caprylate / caprate, glyceryl laurate, glyceryl monooleate, glyceryl myristate, glyceryl oleate, glyceryl oleate citrate, glyceryl stearate, glyceryl stearate, glyceryl stearate citrate, glyceryl stearate SE, glyceryl stearate SE, sucrose stearate, glycol distearate, glycol stearate, hexaglyceryl monolaurate, Kolliphor HS15, laureth-3, laureth-4, laureth-5, laureth-7, laureth-9, laureth-10, Iaureth23, lauroyl polyoxyl-32 glycerides, lauryl glucoside, lecithin, linoleamide DEA, linoleoyl polyoxyl glycerides, lysolecithin, macrogol 6 glycerol caprylocaprate, methyl glucose sesquistearate, methyl laurate, methylpropanediol, monolaurin, myristyl glucoside, nonylphenol ethoxylate, nonylphenol ethoxylate, nonylphenol polyoxyethylene ether, octoxynol-40, octyldodeceth-20, octyldodecyl xyloside, octylphenol polyoxyethylene ether, oleicacid, oleth-2, oleth-3, oleth-5, oleth-10, oleth-20, oleth-30, olive oil PEG-7 esters, palmitamidopropyltrimonium chloride, PEG-4 dilaurate, PEG-4 rapeseedamide, PEG-5 glyceryl stearate, PEG-7 glyceryl cocoate, PEG-7 olivate, PEG-8 beeswax, PEG8 C12-C20 alkyl ester, PEG-8 caprylic / capric glycerides, PEG-8 dioleate, PEG-8 laurate, PEG-8 oleate, PEG-12 dimethicone, PEG-12 laurate, PEG-20 almond glycerides, PEG-20 glyceryl stearate, PEG-20 methyl glucose sesquistearate, PEG- 25 hydrogenated castor oil, PEG-30 dipolyhydroxystearate, PEG-30 glyceryl cocoate, PEG-30 glyceryl stearate, PEG-32 hydrogenated palm glycerides, PEG-40 hydrogenated castor oil, PEG-40 sorbitan peroleate, PEG-60 almond glycerides, PEG-60 glyceryl isostearate, PEG-75 lanolin, PEG-75 shea butter glycerides, PEG- 80 sorbitan laurate, PEG-100 stearate, pentylene glycol, polyethylene glycol octyl ether, polyglyceryl oleate, polyglyceryl-2 dipolyhydroxystearate, polyglyceryl-2 oleate, polyglyceryl-2 sesquioleate, polyglyceryl-2 stearate, polyglyceryl-3 beeswax, polyglyceryl-3 caprate, polyglyceryl-3 caprylate, polyglyceryl-3 dicitrate / stearate, polyglyceryl-3 distearate, polyglyceryl-3 distearate, glyceryl stearate citrate, polyglyceryl-3 methylglucose distearate, polyglyceryl-3 oleate, polyglyceryl-3 polyricinoleate, polyglyceryl-6 polyhydroxystearate, polyglyceryl-6 polyricinoleate, polyglyceryl-6 stearate, polyglyceryl-6 behenate, polyglyceryl-6 stearate, polyglyceryl-6 behenate, C18-22 hydroxyalkyl hydroxypropyl guar, polyglyceryl-10 caprylate, polyglyceryl-10 caprylate / caprate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 oleate, polyglyceryl-10 pentahydroxystearate, polyglyceryl- 10 tristearate, polyoxyl 20 cetostearyl ether, polyoxyl castor oil, propylene glycol isostearate, polysorbate 20, polysorbate 22, polysorbate 23, polysorbate 24, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan oleate, sorbitan olivate, sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate, sorbitan stearate (and) sucrose cocoate, sorbitan trioleate, sorbitan tristearate, stearamide MEA, steareth-2, steareth-20, steareth-21 , steareth-100, sucrose cocoate, sucrose distearate, sucrose esters, sucrose laurate, sucrose monolaurate, sucrose palmitate, sucrose stearate, tetraglyceryl monooleate, tetraglyceryl monostearate, trideceth-3, trideceth-5, trideceth-6, trideceth-7, trideceth-8, trideceth-9, trideceth-9 (&) PEG-40 hydrogenated castor oil, trideceth-10, trideceth-12, trideceth-12, tridecyl stearate, triglyceryl monooleate, trilaureth-4 phosphate, and the like. An especially preferred lipophilic surfactant is lecithin.

[0040] A suitable second surfactant for the invention can include a hydrophilic surfactant that is selected from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween 60, polysorbate 80 (polyoxyethylene 80 sorbitan monooleate), PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl- 10 oleate, polyglyceryl- 10 myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, cholic acid, PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, propylene glycol isostearate, oleth-10, polysorbate 60 NF, isosteareth-20, isoceteth-20, PEG-100 stearate, decanoyl-N- methylglucamide, n-decyl-D-glucopyranoside, n-decyl-D-maltopyranoside, n- dodecyl-D-glucopyranoside, n-dodecyl-D-maltoside, heptanoyl-N- methylglucamide, n-heptyl-D-glucopyranoside, n-heptyl-D-thioglucoside, n-hexyl-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-D-glucopyranoside, octanoyl-1 -N- methylglucamide, n-octy1 -D-glucopyranoside, octyl-D-thioglucopyranoside; cysteine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoic anhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5- phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K, vitamin B6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, benzalkonium chloride, benzethonium chloride, docecyl trimethyl ammonium bromide, sodium docecyl sulfates, dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodium sulfonsuccinic acid, L-ascorbic acid and its salts, D-glucoascorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone, mannoic lactone,ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)- cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), polyethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol, and penta(propylene glycol), polypropylene glycol) oligomers, a block copolymer of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof. An especially preferred hydrophilic surfactant is polyoxyethylene 80 sorbitan monooleate.

[0041] The total amounts of primary surfactant and co-surfactant(s), combined, are generally within a range from about 1 - 50 wt%, preferably an amount within the range of 10 - 40 wt%, and more preferably an amount within the range from about 15 - 35 wt%, and optimally within the range of 1 - 10 wt% of the total SLNs weight.

[0042] The general method of treatment comprises administering to a human or mammal subject a therapeutically effective amount of an acceptable psychedelic or psychedelic analogue in one or more pharmaceutically acceptable carriers or excipients.

[0043] The administered composition is formulated for oral, sublingual, intranasal, pulmonary administration, buccal, rectal, transdermal, transmucosal, epidural, intrathecal, intraocular topical, creams, lotions, gels and eye drops using one or more excipients that are traditionally used in such formulations. A preferred form of delivery is by way of a measured aliquot of a volume of suspended SLNs into a patient's mouth.

[0044] In another aspect, the invention comprises a method of treating a mental disorder (such as a mood disorder, psychiatric disorder, and / or neurological disorder) by a process that comprises the step of administering an effective amount of a ligand described herein. In some embodiments, the mental disorder is a depressive condition, including unipolar and bipolar depressive conditions, such as but not limited to depression, depression from generalized anxiety, major depression, treatment resistant depression and postpartum depression.

[0045] The invention provides for the treatment and / or prevention of psychiatric disorders, neurological disorders, degenerative disorders, and / or inflammatory disorders. In another aspect, the invention relates to the use of a composition described herein to treat a mental disorder, or in the manufacture of a medicament for treating a mental disorder, such as depression. All such treatments include a step that comprises administering to an afflicted patient a therapeutically effective amount of a composition according to the invention.

[0046] As used herein, the term "neurological disorders" refers to any structural, biochemical and / or electrical abnormalities in the brain, spinal cord or other nerves and includes neurodevelopment and neurodegenerative diseases that may benefit from neural plasticity modulation. In a preferred embodiment, the term "neurological disorder" refers to one or more disorders selected from the following acquired brain injury, ataxia brain tumor, dementia, dystonia epilepsy, temporal lobe epilepsy, pain associated with neurological disorders, headache disorders, functional and dissociative neurological symptoms, neuroinfections, meningitis, disorders associated with malnutrition, motor neuron disease, multi-system atrophy, multiple sclerosis, amyotrophic lateral sclerosis, mesial temporal lobe hippocampal sclerosis, muscular dystrophy, myalgic encephalomyelitis, Parkinson's disease, progressive supranuclear palsy, cerebral palsy, Huntington's disease, Alzheimer's disease, frontal lobe dementia, vascular dementia, dementia with Lewy bodies, mild cognitive impairment (MCI) associated with aging and chronic disease and its treatment, including chemotherapy, immunotherapy and radiotherapy, mild corticobasal degeneration, disorders associated with accumulation of beta amyloid, and / or with the accumulation or disruption of tau protein and its metabolites, Lyme encephalopathy, toxic encephalopathy, cognitive decline associated with aging, spina bifida, hydrocephalus, spinal injury, stroke, Tourette syndrome, and transverse myelitis, corticobasal degeneration, supranuclear palsy, epilepsy; nervous system trauma, nervous system infections, nervous system inflammation, including inflammation from autoimmune disorders, including NMDAR encephalitis, and cytopathology from toxins (including microbial toxins, heavy metals, and pesticides etc.), stroke, multiple sclerosis, Huntington's disease, mitochondrial disorders, Fragile X syndrome, Angelman syndrome, hereditary ataxias, neuro-otological and eye movement disorders, amyotrophic lateral sclerosis, tardive dyskinesias (TD), hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficitdisorders; restless leg syndrome, autism spectrum disorders, tuberous sclerosis, Rett syndrome, cerebral palsy, disorders of the reward system including eating disorders [including anorexia nervosa (AN) and bulimia nervosa (BN), and binge eating disorder (BED), trichotillomania, dermotillomania, nail biting, migraine, fibromyalgia, and peripheral neuropathy of any etiology. Symptoms or manifestations of nervous system disorders that may be treated or prevented by neuroplastogen substances and drugs include a decline, impairment, or abnormality in cognitive abilities including executive function, attention, cognitive speed, memory, language functions (speech, comprehension, reading and writing) orientation in space and time, praxis, ability to perform actions, ability to recognize faces or objects, concentration, and alertness; abnormal movements including akathisia, bradykinesia, tics, myoclonus, dyskinesias, including dyskinesias relate to Huntington's disease, levodopa induced dyskinesias and neuroleptic induced dyskinesias, dystonias, tremors, including essential tremor, and restless leg syndrome; parasonmias, insonmia, disturbed sleep pattern; psychosis; delirium; agitation; headache; motor weakness, spasticity, impaired physical endurance; sensory impairment, including impairment of vision and visual field defects, smell, taste, hearing and balance, and dysesthesias; dysautonomia; and ataxia, impairment of balance or coordination, tinnitus, neuro-otological and eye movement impairments, neurological symptoms of alcohol withdrawal, including delirium, headache, tremors, hallucinations, hypertension.

[0047] The broad term "degenerative disorders" generally refers to one or more disorders selected from the following degenerative disorders, neurodegenerative diseases of the retina like glaucoma, diabetic retinopathy and age-related macular degeneration, retinitis pigmentosa, Usher disease and Bardet-Biedl syndrome, motor neuron disease, prion disease, spinocerebelluar ataxia and apathy syndrome.

[0048] The term "inflammatory disorders" generally refers to one or more disorders selected from the following inflammatory disorders, of atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome, Crohn's disease, septicemia, depression, schizophrenia, multiple sclerosis, conjunctivitis, Alzheimer's disease, chronic obstructive pulmonary disease, neuroinflammation, metabolic syndrome, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD), complications of NAFLD, non-alcoholic steatohepatitis (NASH), and conjunctivitis.

[0049] The general method of treatment comprises administering to a human or mammal subject in need thereof a therapeutically effective amount of an acceptable psychedelic or psychedelic analogue composition according to the invention in one or more pharmaceutically acceptable carriers or excipients.

[0050] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e. , prophylactic, and palliative treatment, i.e. , relieve, alleviate, or slow the progression of the patient's disease, disorder, or condition.

[0051] As used herein, "psychedelic state" is an altered state of consciousness experienced by a person, which may include intensified sensory perception, perceptual distortion or hallucinations, and / or feelings of euphoria or despair. Psychedelic states have been described as resulting from psychedelic drugs such as DMT (dimethyltryptamine), 5-MeO-DMT, LSD, mescaline or psilocin. Other known psychedelic drugs include the but are not limited to, 4-hydroxy analogs of N-Methyl- N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine (DiPT).

[0052] The term "psychiatric disorders" refers to one or more disorders selected from the following psychiatric disease as defined as defined by DSM-5 and ICD-11 that may benefit from modulation of neural plasticity, including Schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, COVID depressive disorder, generalized anxiety disorders, obsessive- compulsive and related disorders, trauma- and stressor-related disorders, dissociative disorders, somatic symptom and related disorders, feeding and eating disorders, elimination disorders, sleep-wake disorders, sexual disruptive, impulsecontrol, and conduct disorders, substance related and addictive disorders, panic disorder, agoraphobia, social anxiety disorder, phobias, posttraumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, anorexia nervosa, binge eating disorder, bulimia nervosa, psychosis, schizophrenia, substance addiction, personality disorders, neurocog nitive disorders, personality disorders, paraphilic disorders and for the reduction of suicidal ideation in a patient suffering from a life-threatening disease.FORMULATIONS AND COMPOSITIONS

[0053] The invention also provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the compositions described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally, oneor more additional therapeutic agents. While it is possible for a composition described herein to be administered alone, it is preferable to administer the composition as a pharmaceutical composition.

[0054] The term "pharmaceutical composition" means a composition according to the invention combined with at least one additional, pharmaceutically-acceptable carrier.

[0055] A "pharmaceutically-acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including but not limited to adjuvants, excipients or vehicles, such as diluents, osmotic complement, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, polymers, solubilizing agents, stabilizers, antioxidants and dispensing agents, depending on the nature of the mode of administration and dosage forms. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0056] As used herein, "oral" administration includes swallowing for ingestion in the stomach or gut, and further includes lingual, sublingual, buccal and oropharyngeal administration. The compositions of this invention can be administered for any of the uses or methods described herein by any suitable means, for example, orally, such as tablets, capsules (each of which may include sustained release or timed release formulations), pills, powders, granules, elixirs, suspensions (including nano suspensions, micro suspensions, spray-dried dispersions), syrups, and emulsions; sublingually (e.g. as thin films, effervescent tablets or tablets that dissolve spontaneously under the tongue); parenterally, such as by subcutaneous, intravenous, intramuscular injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; or rectally such as in the form of suppositories.

[0057] The dosage regimen for the compositions described herein will, of course, vary depending upon known factors, such as the pharmacokinetic and pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of therecipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient; and, the effect desired. The selected dosage level may also depend on the additional factors including the activity of the particular compositions and pharmaceutical compositions described herein, whether an ester, salt or amide substituent is of the composition is used, the time of administration, the rate of excretion or metabolism of the particular composition being employed, the rate and extent of absorption, the duration of the treatment, other drugs that may be administered to the patient, compositions and / or materials used in combination with the particular composition employed and like factors well known in the medical arts.

[0058] Generally, the dosage of the drug or prodrug for a therapy session, when used for the indicated effects, will range between about 0.001 to about 500 mg per dose, preferably between about 0.01 to about 200 mg per dose, and most preferably between about 0.1 to about 50 mg per dose, such as 10, 20, 30, 40, 50, 100 or 200 mg. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0059] Compositions of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in multiple divided doses, such as two, three, or four times daily. Alternatively, the doses may be provided on a weekly, biweekly, or monthly basis. In a preferred embodiment, only one or two doses are required for an antidepressant effect that may extend for 1 , 2, 3 or 6 months, or more.

[0060] For tablet dosage forms, depending on the dose, the composition of the present invention may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.

[0061] In addition to the present composition, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

[0062] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars,polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0063] Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.

[0064] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

[0065] Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

[0066] Exemplary tablets contain up to about 80 wt% of the present composition, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

[0067] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet, dry, or melt granulated, melt congealed, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

[0068] A typical capsule for oral administration contains at least one of the formulations of the present invention (e.g. 25 mg), lactose (e.g. 75 mg), and magnesium stearate (e.g. 15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0069] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0070] Liquid formulations may also be administered in the form of a nasal spray that provides direct contact with mucosal membranes in relatively close proximity to the BBB. A preferred mechanism for delivery is a nasal spray that delivers a metered amount with each pump, so the volume of sprayed nanoemulsion is substantially consistent from dose to dose.

[0071] Compositions of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol containing polymers, in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0072] Drug cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and noninclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. The materials most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148, the disclosures of which are incorporated herein by reference in their entireties (Stella and Rajewski 1990, Stella and Rajewski 1993, Petrus and Vandecruys 1999).

[0073] Regardless of the route of administration selected, the compositions of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0074] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compositions of the invention employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0075] In general, a suitable daily dose of a composition of the invention will be an amount of the composition which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0076] As used herein, a "therapeutically effective amount" refers to that amount of a composition being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of depression, a therapeutically effective amount refers to that amount which has the effect of reducing the severity of depression. Depression severity may be assessed using well-known structured assessment tools such as Structured Clinical Interview for DSM-5 (SCID-5) and the GRID-Hamilton Depression Rating Scale (GRIDHAMD). A therapeutically effective amount may be less than that required for a psychedelic state.

[0077] An effective dosage can be administered in one or more administrations. For the purposes of this invention, an effective dosage of drug, composition, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, composition or pharmaceutical composition may or may not be achieved in conjunction with another therapy, drug, composition, or pharmaceutical composition.THERAPEUTIC METHODS AND USES

[0078] Treatment with the novel compositions of the present invention may substantially alleviate clinical or subclinical depression and may avoid relapse, particularly if used in combination with psychotherapy for the treatment of depression. It is known that administration of an effective dose of psilocybin produced rapid and large reductions in depressive symptoms, and many subjects achieve remission through a four-week follow up (Davis, Barrett et al. 2021 ). Without restriction to a theory, it is believed that the psychedelic state is associated with the beneficial effects, however, some compositions which are 5HT2AR agonists or antagonists may provide the desired therapeutic effect without the psychedelic state. One aspect of the invention comprises prodrugs of those 5HT2AR agonists which do provide a beneficial therapeutic state.

[0079] In general, the present invention includes the use of a composition of the present invention herein, to treat any disease or disorder which may be alleviated by a psychedelic and / or a 5HT2AR agonist, or the use of a composition of the present invention herein to manufacture a medication to treat any disease or disorder which may be alleviated by a psychedelic and / or 5HT2AR agonist, or a method of treating any disease or disorder which may be alleviated by a psychedelic and / or 5HT2AR agonist (Jain, Gumpper et al. 2025). The present invention is also suitable for treating diseases or disorders that are related to 5HT2AR agonists.

[0080] In some embodiments, the invention may comprise the use of the compositions of the present invention to treat mental disorders. In some embodiments, the invention may comprise the use of the compositions of the present invention to treat depression, and particularly drug resistant depression. Other conditions that may be treated include but are not limited to: anxiety disorders, including anxiety in advanced stage illness e.g. cancer as well as generalized anxiety disorder, depression including major depressive disorder, postpartum depression, cluster headaches, obsessive compulsive disorder, personality disorders including conduct disorder, drug and substance use disorders including: alcohol dependence, nicotine dependence, opioid dependence, cocaine dependence and other addictions including gambling disorder, eating disorder and body dysmorphic disorder, chronic pain, or chronic fatigue.

[0081] In some embodiments, the invention may comprise a method of treating mental disorders comprising administering to a subject a therapeutically effective amount of a composition of the present invention. In one embodiment, there is provided a method of treating depression by administering to a subject a therapeutically effective amount of a composition of the present invention. The depression effects may be drug-resistant depression or major depressive disorder.

[0082] For example, a patient diagnosed with depression may be screened prior to treatment and then prepared for a dosing session by a trained psychotherapist. Within a dosing session, a composition of the present invention may be administered by injection of a sterile solution at a rate of 0.01-0.3 mg / kg to the patient or any of the other methods for delivery described herein. The patient is preferably seated for the duration of the session while being blindfolded. For safety, a trained health care professional may monitor the patient throughout the dosing session, which may last up to 12 hours. In some cases, music may be played for the patient. When the healthcare professional can determine that the drug substance has cleared, the psychotherapist may assist the patient with any questions relating to the psychedelic experience, and then the patient may be discharged.

[0083] To further alleviate any anxiety that may occur relative to therapy, the physician may prefer to divide the therapeutic dose and thereby reduce the initial onset of psychoactivity before applying the full complement of the dosage to achieve the full effect.

[0084] In some embodiments, treatment with a composition of the present invention may be combined with concomitant treatment with another anti-depressant drugs, either concurrently or consecutively. In preferred embodiments, treatment with a composition of the present invention is combined with psychotherapy, which may be applied prior to or after treatment. If prior to, the session may focus the patient on the intent of treatment. If after, psychotherapy is preferably performed within 48 hours of the dosing session to help the patient integrate any feelings, emotions, visions or thoughts that may have occurred during the session, as well as to allow the psychotherapist to offer advice on how best to change thinking or behavior patterns so as to improve anti-depression outcomes, as appropriate. Psychotherapy may continue as needed after the dosing session, for example, up to an additional 3 months, to help the patient integrate any experiences or learnings that occurred to the patient during the dosing session.EXAMPLES

[0085] Our testing was done with O-octanoyl bufotenin (OBf (Homon, Prasad et al. 2025)), a lipidic prodrug of bufotenin that is not regulated as a controlled substance, but which behaves in formulation in ways that are similar to controlled psychedelics.

[0086] Described herein are studies that were performed to develop an encapsulating nanoemulsion composition and its method of manufacture for psychedelics. The experimental design provided multiple compositions of different ratios of oil, primary, and co-surfactant(s). These compositions were initially prepared by creating a molten lipid melt of the solid lipid and adding the psychedelic agent, and any lipophilic surfactants to create a homogenous melt. The thus created nanoemulsions are prepared by high-shear mixing of the molten lipid melt with a preheated aqueous phase (5 - 10 °C above melting point of solid lipid) containing anyhydrophilic co-surfactant(s) to produce a coarse emulsion. The nanoemulsions are then created by high-pressure homogenization of the coarse emulsion post high- shear mixing. This is known as the SLN. The SLN showed enhanced colloidal stability under physical and chemical stressors, as well as upon storage. Formulated OBf showed higher chemical stability when compared to a solution of pure OBf dissolved in ethanol in the presence of stressors.

[0087] Flow cytometry established that the SLN containing OBf enters cells.

[0088] The emulsions produced in our examples show enhanced stability under physical and chemical duress, as well as upon storage where no OBf degradation was detected over 4 weeks storage at 4 °C in formulation.

[0089] Cytotoxicity assays on three cell lines reveal negligible toxicity of formulated OBf at therapeutic concentrations.

[0090] As can be expected, selection of excipients and titration of their respective ratios are important to the final composition. For our preferred system, we used Compritol 888 as the lipid, lecithin as the lipophilic surfactant, and polysorbate 80 as the hydrophilic co-surfactant.

[0091] For our primary emulsifier, the following properties were desired: (i) low histamine release to prevent allergic reactions; (ii) thermal stability, suitable for sterilization and other heating events during creation of the formulation; (iii) lower hemolytic activity; and (iv) inherent biocompatibility.

[0092] The resulting SLN was characterized by dynamic light scattering (DLS) to determine the average diameter of micellar droplets as well as to measure changes in polydispersity index and surface charge (^-potential). Emulsion droplets were imaged using a scanning electron microscope after appropriate sample preparation.

[0093] The nanoemulsions were stress tested under different chemical and physical environments mimicking commercial production and storage conditions to evaluate its long-term stability. The average droplet sizes, polydispersity index, and ^-potentials for our nanoemulsions were promising under this stress testing.

[0094] Biological assays were used to evaluate the effect of our nanoemulsions on cells. Cytotoxicity was evaluated using healthy and cancer cells. Cellular uptake studies confirmed that the SLN exhibited greater uptake by human cells without attendant toxicity.

[0095] Quantitative (flow cytometry) cellular uptake was tested by coencapsulating a fluorescent dye (Coumarin-6, SLN is diluted to a dye concentrationof 1 pg / mL with cell growth media) to detect cellular uptake. The result of the experiment shows augmented cellular uptake in comparison with the unformulated Coumarin-6 solution (1 pg / mL dissolved in dimethylsulfoxide). These results confirm that SLNs should be excellent delivery vehicle compositions for psychedelics.

[0096] Cell uptake studies using flow cytometry of glioma (brain) U251 cells exposed to formulated vs. unformulated dye confirm about 100% uptake of the coencapsulated dye with OBf by the cells after 5 minutes versus the unencapsulated dye (1 pg / mL dissolved in dimethylsulfoxide) only reaching 5.7 % cell uptake after 5 minutes.

[0097] The SLN oil-in-water (O / W) nanoemulsions of OBf were prepared by a method previously described by the inventors (Banerjee, Binder et al. 2021), the disclosure of which is hereby incorporated by reference. Initially, Compritol 888 (3%), soy lecithin (2%) and OBf (1%) were melted in a round-bottom flask at 80 °C in a bead bath with low magnetic stirring which began the oil phase preparation. Simultaneously in a beaker, polysorbate 80 (2%) was dissolved in boiling water (92%). Once the oil melt was completely homogenous, the hot aqueous phase was added to the flask containing the molten lipid melt. This blend was then subjected to the high sheer mixer (IKA T18 digital) at 12000 rpm for intervals of 1 minute on and 1 minute off for 3 cycles. The coarse emulsion was then subjected to high-pressure homogenization once pre-heated with boiling water. The output of the homogenizer (Nano DeBee, BEE International, USA) was directly inputted into a container submerged in an ice bath to enforce nanoprecipitation during the 8 cycles of homogenization (20,000 - 30,000 psi) using the Z8 nozzle with an aperture size of 0.20 mm. Directly following, the formulation was placed into the fridge (4 °C) for long term storage. For the preparation of Coumarin-6-doped nanoemulsions, 100 pg-g-1 of Coumarin-6, with respect to the final concoction, was added into the oil phase at the same time as the OBf. The rest of the process was conducted as described above.

[0098] To determine lipid particle size distributions in the SLN, DLS, also known as photon correlation spectroscopy, was applied. This technique generated Z- average diameters of the dispersed lipid phase droplets (dz), the polydispersity index (PDI), as well as zeta potential (electrical potential of the particles’ slipping plane). Diluted samples (100-fold dilutions) were used to avoid multiple scattering. The measurements were conducted with the Zetasizer (Nano Z S, Malvern InstrumentsLtd., UK). The Z-average diameters of the dispersed phase droplets were calculated from the autocorrelation function of the intensity of light scattered from the particles. Phase-separated nanoemulsions were re-mixed by shaking prior to dilution for DLS measurements.

[0099] The ability for the SLN to encapsulate OBf was tested by encapsulation efficiency. 5 g of formulation was added to an Amicon® Ultra Centrifugal Filter, 3 kDa MWCO. They were centrifuged for 25 minutes at 20 °C at 4500 rpm. The pellet and supernatant were massed and aliquoted for HPLC. The encapsulation efficiency was calculated according to the following formula:

[0100] Given the known oxidative instability of the indole scaffold present in OBf (Liu, Zhao et al. 2020), encapsulation into the solid lipid core of the lipid nanoparticle can serve as a bulwark to reactive species. We found that the solid lipid core appeared to improve the encapsulated API’s chemical stability of the resulting nanoemulsion after exposure to a variety of chemical stressors.

[0101] As Table 1 shows, the SLN forms emulsions with average droplet sizes of ca. 100 nm, a narrow range of nanoparticle sizes, and exceptional encapsulation efficiency. We expect that this basic formulation will produce nanoemulsions having an average droplet size within the range from about 10 nm to less than 300 nm, preferably within the range of about 20 - 250 nm, and even more preferably within the range of about 30 - 200 nm.SLN 99 ± 2 0.26 99.6 ± 4Stress Tests

[0102] The SLN of the present invention that were produced upon high-energy processing of the two pre-constituted phases (an aqueous phase containing polysorbate 80, and an oil phase containing Compritol 888, lecithin, and OBf) werestress-tested to examine the effect of storage times, heat, freeze / thaw cycles, and chemical additives on emulsion stability and OBf potency. The results show that the present nanoemulsion composition offered enhanced protection to OBf under conditions of simulated stress in comparison with unformulated OBf dissolved in ethanol. None of the stressors examined could induce phase separation in the thus created SLN.

[0103] Cellular uptake studies showed quantitative penetration of glioma cells by the formulation. Cytotoxicity studies for these systems showed dilution dependent cytotoxicity to different cell lines, tapering to negligible toxicity values at therapeutic API doses.

[0104] Testing of the SLNs containing OBf proved that the emulsions are extremely stable even in the presence of highly alkaline and acidic stressors, and no colloidal destabilization phenomena is observed visually. See Table 2:

[0105] Biological studies on OBf: glioblastoma U251 untreated cells were run first to set the negative control as indicated by the absence of fluorescence. The cells treated with SLN containing OBf showed about 100 % cellular uptake after 5 minutes of exposure to the cells, compared to 5.7 % cell uptake with unformulated drug (1 pg / mL dissolved in dimethylsulfoxide). The fluorescent peak completely shifted to the zone of positive fluorescence. SLNs containing OBf were taken up by cells. These results further demonstrate that the nanoemulsions of the present invention can increase the permeability and liquidity of the membrane, promote the transmembrane transfer of the API, and increase the amount of cell intake of the API.

[0106] Cytotoxicity evaluation: our tests show a dilution dependent cytotoxicity of SLN containing OBf. The SLNs (no drug) were tested on their own for toxicity fromthe excipients. The results determined that the excipients were non-toxic at therapeutic concentrations. Experimental Details - Materials

[0107] All materials were purchased from Sigma Aldrich (St. Louis, MO, USA) unless otherwise stated and used as received. Compritol 888 pellets were purchased from Gattefosse (Saint-Preist, France). Lecithin and medium chain triglycerides (MCT oil) was purchased from Charles Tenant and Company Ltd. (North York, ON, Canada). -Polysorbate 80 was purchased from Aaron Chemicals (San Diego, CA, USA). HPLC-grade water (EMD Millipore, Burlington MA, USA) was used in all experiments. 4',6-diamidino-2-phenylindole (DAPI) and (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) (MTT) was purchased from Aaron Chemicals (San Diego, CA, USA). Octanoyl bufotenin (OBf) was synthesized in the Trant synthetic lab and was used as received. Measurements of pH were conducted using a freshly calibrated, according to the manufacturer’s instructions, pH meter (Milwaukee MW102 PRO+).

[0108] Three different cell lines were used for the cytotoxic evaluation of the tested formulation:

[0109] L2: Rat lung cell line (ATCC)

[0110] GBM 251 : Glioblastoma cancer cells (Cytion)

[0111] HepG2: Liver cancer cells (ATCC)Preparation of the OBf Nanoemulsions

[0112] The SLN oil-in-water (O / W) nanoemulsions of OBf were prepared by a method previously described (Banerjee, Binder et al. 2021), the disclosure of which is hereby incorporated by reference. Initially, Compritol 888 (3 %), soy lecithin (2 %) and OBf (1 %) were melted in a round-bottom flask at 80 °C in a bead bath with low magnetic stir which began the oil phase preparation. Simultaneously in a beaker, polysorbate 80 (2 %) was dissolved in boiling water (92 %). Once the oil melt was completely homogenous, the hot aqueous phase was added to the flask containing the molten lipid melt. This blend was then subjected to the high sheer mixer (IKA T18 digital) at 12000 rpm for intervals of 1 minute on and 1 minute off for 3 cycles. The coarse emulsion was then subjected to high-pressure homogenization once preheated with boiling water. The output of the homogenizer (Nano DeBee, BEE International, USA) was directly inputted into a container submerged in an ice bath toenforce nanoprecipitation during the 8 cycles of homogenization (20,000 - 30,000 psi) using the Z8 nozzle with an aperture size of 0.20 mm. Directly following, the formulation was placed into the fridge (4°C) for long term storage. For the preparation of Coumarin-6 doped nanoemulsions, 100 pg-g-1 of Coumarin-6, with respect to the final concoction, was added into the oil phase at the same time as the OBf. The rest of the process was conducted as described above.

[0113] Long-term storage: To examine the effect of long-term storage on the colloidal and chemical stability of the nanoemulsion and encapsulated API, we stored them in tightly capped amber glass vials in a refrigerator at 4 °C. Two aliquots were periodically removed from the vials, one aliquot is diluted in preparation for DLS, and the other is handed off as-is to the Trant analytical lab. Measurements were performed immediately after high pressure homogenization, and after that, once every seven days for up to six weeks.

[0114] Flash heating: 1 g of the SLN was placed in a preheated water bath, and the internal temperature of the nanoemulsion was maintained at 80 °C for 1 minute. This protocol is a more extreme version of the high-temperature short-time (HTST) pasteurization process (typically, 71.5 °C for 15 s) that fruit juices and milk beverages are subjected to in the industry. The nanoemulsion was then allowed to cool to room temperature, and a part of it was diluted for DLS study. The rest was retained for HPLC analysis.

[0115] Freeze-thaw cycle: 1 g of the SLN was placed in a freezer at a temperature of -20 °C. for 1 hour. The nanoemulsion was then removed from the freezer and allowed to revert to room temperature. A part of the thawed nanoemulsion was diluted for DLS study, and the rest was retained for HPLC analysis.

[0116] Additives: in a representative experiment, varying masses of CaC12-2H2O, sucrose, and potassium sorbate were added individually to 1 g portions of the nanoemulsions at certain pre-determined concentrations. To ensure complete dissolution of the additive, the aliquots were vortexed for 1 min each. After an incubation period of 12-18 h, the aliquots were vortexed again for 1 min prior to dilution for DLS studies. It is to be noted that HPLC analysis studies were not carried out in the context of salt, sugar and preservative addition to the nanoemulsions, given that they are not expected to degrade OBf in any meaningful way. Any drop inOBf for these experiments may be attributed to colloidal events leading to instability rather than to chemical transformations.

[0117] Extraction procedure: 100 - 150 mg of emulsion samples were weighed individually into 15 mL falcon tubes and 5 mL methanol (HPLC grade) were added to the samples. Samples were vortexed for 10 seconds and placed in an ultrasonic bath for 15 min at room temperature. After the sonication, sample was spun at 4000 rpm for 5 min in a centrifuge (Avantor). Aliquots of resultant clear supernatant were used for HPLC analysis.

[0118] Sample acquisition and data analysis: Chromatographic analysis of supernatants from sample extraction was performed using an Agilent 1260 Liquid Chromatography system fitted with a photodiode array detector and using an Agilent Zorbax Eclipse plus C18 column (4.6 x 150 mm, 3.5 pm). For data acquisition, the following gradient run was applied using a mobile phase combination of methanol / 0.01% phosphoric acid and water: 50% CH3OH for 0 - 3 mins, 95% CH3OH for 4 - 10 mins, 100% CH3OH for 11 - 12.30 mins and 50% CH3OH for 13 - 15 mins. The flow rate of mobile phase was set at 0.5 mL-min-1 , with an injection volume of 5 pL for the sample. OBf was detected at a wavelength of 282 nm, with column compartment set to 35 °C. Mobile phase solvents were of HPLC grade and filtered with 0.20 pm filters before analysis. Standard dilutions of OBf ranging from 1.0165 mL-min-1 to 0.001065 mL min-1 were run alongside sample extracts and standard peak areas with their corresponding concentration used to plot a calibration curve for calculating the concentration of OBf in the samples.

[0119] Cell culture: The rat lung cell line L2 was purchased from American Type Culture Collection (ATCC, Rockville, MD, USA) and was cultured in Dulbecco’s Modified Eagle’s Medium / Nutrient Mixture F-12 Ham (DMEM-F12, Sigma-Aldrich, St. Louis, MO, USA), 10% fetal bovine serum (FBS, Sigma-Aldrich), and 1% penicillin / streptomycin (Sigma-Aldrich) at 37 °C under 5% CO2 in a humidified atmosphere. The human liver cancer cell line HepG2 was obtained from ATTC and were grown in Dulbecco’s modified Eagle's medium (DMEM, Sigma-Aldrich), 10% FBS (Sigma-Aldrich), and 1% penicillin / streptomycin (Sigma-Aldrich) at 37 °C in a 5% CO2 atmosphere with 95% humidity. The human glioblastoma cell U251 was purchased from Cytion and cultured in Minimal Essential Medium+ Earl’s Balanced Salts (MEM / EBSS, Hyclone, Logan, UT, USA), 10% FBS (Sigma-Aldrich), 1% penicillin / streptomycin (Sigma-Aldrich), and 1% Non-Essential Amino Acids (NEAA,Sigma-Aldrich) at 37 °C at 5% C02 and 95% humidity. All the cell lines were subcultured when they got to 70% confluency.

[0120] Cellular uptake of the Coumarin-6-loaded solid lipid nanoparticles (SLNs) was evaluated by flow cytometry in human glioblastoma U251 cells and L2 rat lung cells. Cells were seeded in 6-well plates at a density of 1 x 106cells per well (1 mL total medium per well) and incubated at 37 °C with 5% CO2and 95% humidity until they reached approximately 60-70% confluency. The Coumarin-6-loaded SLNs were diluted in the appropriate growth medium to obtain a final Coumarin-6 concentration equivalent to 1 pg-mL“1of Coumarin-6. After removing the medium, cells were incubated with the fresh SLN-containing medium for 5, 15, and 30 minutes (37 °C, 5% CO2, 95% humidity). Following incubation, the medium was aspirated, and cells were gently washed twice with DPBS to remove non-internalized SLNs. Cells were then harvested and resuspended in 0.5 mL DPBS containing 2 mM EDTA to generate a single-cell suspension. Assay was analyzed using the BD LSR Fortessa™ X-20 flow cytometer (Becton Dickinson).

[0121] The cytotoxicity of the SLN was measured by the MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on three different cell lines: L2 rat lung, HepG2 human liver cancer cells, and human glioblastoma U251 cells according to standard methods (Vistica, Skehan et al. 1991). Briefly, the cells were seeded at 3x103 cells / well for L2 cell, 2x103 cells / well for HepG2, and 3x103 cells / well for U251 cells in a 96-well micro titer plates (100 pL inclusive of media, per well). After 24 h incubation in the wells at 37eC in 5% CO2 with 95% humidity, cells were treated with 150 pL of the samples at four different concentrations (100, 1000, 10000, and 100000 dilution factor). After incubation for 48 h, the media was discarded and 100 pL of 0.5 mg-mL-1 MTT stock solution was added to each well and the plates were incubated for an additional 4 h at 37 °C under 5% CO2 and 95% humidity. After discarding the MTT solution from wells, the obtained formazan crystals were solubilized with 100 pL / well of DMSO (dimethyl sulfoxide), and the absorbance was measured at 570 nm using a microplate reader (SpectraMax M5e, Molecular Devices, USA). Cell viability (%) was calculated as a ratio of absorbance in treated cells to absorbance in control cells (intact cells without treatment).

[0122] Unless otherwise indicated, all experiments were performed in triplicate, data is represented as means ± standard deviation and the data was analyzed using either MS Excel or Origin Pro 8.5 graphing software (MA, USA). For the stress tests, three replicate studies were performed, and either the average of the measured values used, or both values plotted on the relevant graph.

Claims

CLAIMS1 . An oil-in-water nanoemulsion composition comprising: (a) a therapeutic amount of one or more psychedelic agents, (b) a lipophilic surfactant, and (c) a lipid composition that is solid at room temperature (25 °C) as an organic vehicle.

2. A nanoemulsion composition as in claim 1 wherein said lipophilic surfactant comprises mono-, di-, and tri- esters of behenic acid.

3. A nanoemulsion composition as in claim 2 wherein said mono-, di-, and triesters of behenic acid comprises glyceryl behenate.

4. A nanoemulsion composition as in claim 3 wherein said glyceryl behenate comprises glyceryl dibehenate.

5. A nanoemulsion composition according to claim 1 further comprising a primary surfactant.

6. A nanoemulsion composition according to claim 5 wherein said primary surfactant comprises lecithin.

7. A nanoemulsion composition according to claim 1 further comprising a cosurfactant.

8. A nanoemulsion composition according to claim 7 wherein said co-surfactant comprises Tween 80.

9. A nanoemulsion composition according to claim 1 wherein said psychedelics comprise 5-MeO-DMT, 4-MeO-DMT, 4-AcO-DMT (4-acetoxy-dimethyltrypamine, LSD, psilocybin, psilocin, mescaline, ibogaine, octanoyl bufotenin, and / or bufotenin.

10. A nanoemulsion composition according to claim 9 wherein said psychedelics comprises ibogaine, octanoyl bufotenin, or 5-MeO-DMT.

11. A nanoemulsion composition according to claim 10 wherein said psychedelic is octanoyl bufotenin.

12. A nanoemulsion composition according to claim 1 having an average droplet size in said emulsion that is within the range from about 10 nm to less than 300 nm.

13. A nanoemulsion composition according to claim 12 wherein the average droplet size is within the range from about 50-250 nm.

14. A nanoemulsion composition according to claim 13 wherein the average droplet size is within the range from about 30-200 nm.

15. A nanoemulsion composition according to claim 1 in liquid form and having a concentration of psychedelic agents comprise an amount within the range from about 0.1 -1000 mg / ml.

16. A nanoemulsion composition according to claim 15 comprising a concentration of psychedelic agents in an amount within the range of 1 -100 mg / ml.

17. A process for the manufacture of the solid lipid nanoparticles by a process that comprises: combining: (i) a therapeutic amount of one or more psychedelics, (ii) an oil that is solid at room temperature (25 °C) and that comprises one or more mono-, di, and tri- glycerides, (iii) a primary surfactant, mixing said ingredients under high shear conditions to form a coarse emulsion product, and subjecting said coarse emulsion to nanoemulsification in a microfluidic device that produces a solid lipid nanoparticle nanoemulsion composition containing a therapeutic amount of one or more psychedelic agents.

18. A nanoemulsion according to claim 17 wherein said primary surfactant comprises lecithin.

19. A nanoemulsion according to claim 18 further comprising a co-surfactant comprising Tween 80.

20. A coarse micro-sized oil-in-water (O / W), pre-nanoemulsion composition comprising a therapeutic amount of one or more psychedelics and one or more surfactants.

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