Neuroactive delivery by niosome nanoformulation for improved blood-brain-barrier penetration

Abstract

Disclosed is a process for the assembly niosome vesicles by a process that comprises: (a) dissolving: (i) a therapeutic amount of one or more psychedelics, (ii) a primary non-ionic surfactant, (iii) optionally, one or more ionic or non-ionic co- surfactant(s), and (iv) an inhibitor of a metabolic enzyme pertaining to psychedelics in an organic solvent; (b) removing the organic solvent to form a thin-film; (c) hydrating the thin film with an aqueous medium to form coarse sized particles; and (d) processing the coarse sized particles with high-shear conditions and microfluidic processing using a microfluidic production device that will produce a niosome product that contains said one or more psychedelic agents.

Description

Neuroactive Delivery by Niosome Nanoformulation for Improved Blood- Brain-Barrier Penetration407-P019PCTREFERENCE TO RELATED APPLICATIONS

[0001] This application is related to U.S. Provisional patent applications Ser. No.63 / 760,846 that was filed on February 20, 2025, and Ser. No. 63 / 826,138 that was filed on June 18, 2025, the disclosures of which are 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 improved penetration of the blood-brain-barrier for enhanced 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 serotonergic, dopaminergic, or adrenergic pathways.

[0005] In a review of many mushroom species with potential neurogenerative properties, the psilocybin or psilocybin 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 orotherwise 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) and further reviewed by Adeyinka (Adeyinka, Forsyth 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-HT2AR 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 G-protein coupled receptor (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 psychotherapy 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:

[0010] a. Lipophilicity or hydrophilicity of the API,

[0011] b. The limited bioaccessibility of the API,

[0012] c. Extensive degradation of the API during storage, or in vivo owing to metabolic pathways, and

[0013] d. The inability of the API to cross the blood-brain barrier (BBB) if psychoactivity is to be demonstrated.

[0014] It would be desirable to have a composition and method for administering psychedelics that would provide a consistent, therapeutically useful dose.

[0015] 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.

[0016] 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.

[0017] Seeds of Anadenanthera colubrina and Anadenanthera peregrina were smoked by indigenous peoples of the northern regions of Argentina up to 4000 yearsago. 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 up to 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.

[0018] 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.

[0019] 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.

[0020] 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, Trant, Banerjee et al. 2024). 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

[0021] 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.

[0022] 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 successfulbiological 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 events were 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 BBB), and instead both seek a simple introduction of the unmodified polar API into the bloodstream.

[0023] 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).

[0024] Niosomes are microscopic (sizes <500 nm), bilayered, non-ionic surfactant vesicles that can act as stable, cost-effective, and biodegradable nanocarriers for delivering both hydrophilic and hydrophobic drugs. Niosomes 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] Niosomes are sealed, spherical vesicles ranging from the nano- to micrometre scale, formed by the self-assembly of non-ionic surfactants with an optional addition of charged amphiphiles and cholesterol in aqueous media. In addition to their biocompatibility, biodegradability, osmotic stability, suitability for freeze-drying, ease of storage, and cost-effectiveness, niosomes offer a lamellar structure composed of lipophilic surfactant bilayers surrounding an aqueous core allowing for the encapsulation of both hydrophilic and hydrophobic APIs without compromising particle stability. Their high cellular uptake and permeability makeniosomes a favorable system for delivering various therapeutic agents (Roohinejad, Greiner et al. 2018).

[0026] Orally administrated niosomes widen the ability 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 BBB once present in the bloodstream. Niosomes may also demonstrate cell-penetrating properties.

[0027] It would be desirable to have an effective process to make stable, effective, niosome compositions that could be used with psychedelics.

[0028] It would also be desirable to have a process for creating niosomes 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

[0029] 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.

[0030] 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.

[0031] It is further an objective of the invention to provide an effective process to make a stable, effective, niosome delivery composition that could be used with psychedelic agents.

[0032] Additionally, it is an object of the invention to provide a process for producing niosomes 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.

[0033] 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 niosomes that comprises (a) at least one drug, (b) a primary non-ionic surfactant, optionally (c) one (or more) ionic or non-ionic co-surfactant(s), and, optionally, (d) an inhibitor of a metabolic enzyme pertaining to psychedelics. These formulations rapidly form relatively stable niosomes after sufficient preparation and optional microfluidic processing for further reductions in particle size where the drug is contained in nanometer-sized particles.

[0034] The invention also contemplates a process for the manufacture of the niosomes of the present invention by a process that comprises: (a) dissolving (i) a therapeutic amount of one or more psychedelic agents, (ii) a primary non-ionic surfactant, and (iii) an inhibitor of a metabolic enzyme pertaining to psychedelics in an organic solvent to form a first composition; (b) removing the organic solvent from said first composition to form a thin-film; (c) hydrating the thin film with an aqueous medium to form coarse sized particles, (d) processing the coarse sized particles under high-shear conditions and microfluidic processing using a microfluidic production device to produce a niosome product that contains said one or more psychedelic agents.

[0035] The niosome 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 particle size of the niosomes and ability of the active ingredient to cross the bloodbrain-barrier and presents opportunities for compositions that can deliver therapeutic benefits without the limitations encountered by prior efforts.DETAILED DESCRIPTION OF THE INVENTION

[0036] Disclosed herein is a design of a stable, niosome drug delivery system exhibiting nanometer sized particles containing a therapeutic amount of one or more psychedelic agents in the particles. Each of these is a hydrophilic and / or lipophilic drug that is variably soluble in serum and well suited for niosome delivery.

[0037] Preferred psychedelic agents comprise psilocybin, 5-MeO-DMT, N,N-DMT, psilocin, mescaline, ibogaine, and / or bufotenin 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 niosomes. 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.

[0038] The composition of the present invention also includes a primary nonionic surfactant, optionally one or more ionic or nonionic co-surfactants, and, optionally, an inhibitor of a metabolic enzyme(s) pertaining to psychedelics.

[0039] Suitable nonionic co-surfactants generally include a surfactant that is selected from triethanolamine phosphate, rhamnose monohydrate, 4-ethoxybenzaldehyde, N-acetyl-alpha-D-glucosamine, butyl thioglycolate, benzenemethanol, nicotinyl alcohol, quinuclidine, stearyl erucamide, N,N-dibenzylethanolamine, triclocarban, oxobenzoxazinyl naphthalene sulfoanilide, glyceryl triacetyl ricinoleate, cyclohexyl methacrylate, diphenyl ether, 2-pentylcinnamic alcohol, D,L-alpha-tocopherol, N-benzyl-N-methylethanolamine, dibromocyanoacetamide, isopropyl laurate, naringin, ethyl caffeate, tetrahydroxypropyl ethylenediamine, n-butyldiethanolamine, N,N-dibutyl-1 ,3-propanediamine, trilaurylamine, alpha, alpha-dimethylbenzenepropanol, 2-ethylhexyl acetate, bakuchiol, diisostearyl dimer dilinoleate, adipic acid, bis(2-ethylhexyl) ester, ethyl cinnamate, ethyl linalool, benzyl cinnamate, 2-phenylethyl acetate, stearyl gallate, bornane dione, cetyl ricinoleate, fluorescent brightener 135, cinoxate, chlorphenesin, anethole, cinnamyl alcohol, cinnamal, caffeic acid phenethyl ester, gamma-nonalactone, gamma-undecalactone, c.i. pigment violet 19, (L)-alpha-terpineol, 4-methylbenzaldehyde, 1 ,4-cyclohexanedimethanol, anise alcohol, taed, propylene glycol dioleate, dibutyl fumarate, isopropyl cyanoacrylate, geranyl acetate, ethylene brassylate, ditridecyl thiodipropionate, dicapryl adipate, dibutyl adipate, diethylene glycol dinonanoate, pentadecalactone, stearic acid, 2-(2-hydroxyethoxy)ethyl ester, glycol ricinoleate, dipropyl adipate, diethylhexylamine, dihydrocitronellol, citronellol, ethyl laurate, block polyethylene-polypropylene glycol, tridecyl neopentanoate, pyridoxine dicaprylate, dimethyl succinate, 1 ,2,6-hexanetriol, diethyl acetyl aspartate, tris(decyl)amine, adipic acid dihydrazide, Ginkgolide J, trideceth carboxamide MEA, 7-hydroxycitronellal, N-ethyl-O-toluenesulfonamide, 1 ,3-butanediol, myrtenyl acetate, dehydrozingerone, bis(1 -methylheptyl) adipate, melamine, PEG-4 dimethacrylate, oleamidopropyl dimethylamine, 1,16-hexadecalactone, 2-butoxyethyl stearate, dibutyl sebacate, methyl hesperidin, isopropyl myristate, ethylene distearamide, santalol, ethylene dioleamide, dihexyl adipate, isobutyl palmitate, butyl myristate, ethyl caprate, caprylyl butyrate, diethyl sebacate, methyl caprate, cetyl-PG hydroxyethyl palmitamide, d-glucopyranose, oligomeric, C10-16-alkyl glycosides, ethyl ethanolamine, nonylphenoxypolyethanol-iodine complex, 1 ,1'-oxydi-2-propanol, glyceryl stearates, dipropylene glycol dimethyl ether, 2-methyl-oxirane, polymer with oxirane, ether with (1,2-ethanediyldinitrilo)tetrakis(propanol) (4:1), methyl caprylate, methyl 2-octynoate, 1,5-pentanediol, trimethylolpropane tricaprylate / tricaprate, stearamide MEA, oleamide MEA, glycol stearate, ethyl stearate, ethyl oleate, tri-n-octylamine, n-butylethanolamine, 1 ,2-octanediol, methyl 10-undecenate, methyl laurate, 1 -octanol, (12E)-oxacyclohexadec-12-en-2-one, diethylene glycol monoethyl ether, dimethyl glutarate, 1 ,2-decanediol, lauryl glycol, lauramide, di-n-octylamine, isopropyl stearate, isopropyl oleate, ethoxydiglycol acetate, 1 -decanol, triethylene glycol monomethyl ether, diethylene glycol diethyl ether, diisostearyl maleate, methyl palmitate, undecyl alcohol, 10-undecen-1-ol, 10-undecenal, 1 ,10-decanediol, triethylene glycol monoethyl ether, 1 -dodecanol, lauraldehyde, methyl stearate, methyl oleate, methyl linoleate, dodecylguanidine, dimethyl palmitamine, 1-tridecanol, myristyl alcohol, dimethyl myristamine, erucamide, stearyl alcohol, triisostearyl citrate, ethylhexylbicycloheptene dicarboximide, 4-hydroxybenzophenone, estratetraenol, bromophenol blue, phenylethyl caffeate, 2-amino-2-methylpropane-1 ,3-diol, pentaerythritol tetrastearate, 2-butyl-2-ethyl-1 ,3-propanediol, angoroside c, linalyl acetate, mdm hydantoin, retinal, quercetin, 2-hydroxybenzophenone, guanosine, cholesteryl nonanoate, tazarotene, dichlorantin, phenyl salicylate, homosalate, benzyl salicylate, salicylic acid, 2-ethylhexyl ester, maltol, neomycin b, cetyl stearate, delta-tocopherol, ethyl linolenate, methyl salicylate, triceteareth phosphate, methylene di-t-butylcresol, hydroxyethyl isobutyl piperidine carboxylate, benzophenone, 2-tetradecyl-1-eicosanol, dihydrocoumarin, 1 ,2-decanediol, lauramide dea, benzoic acid, p-hydroxy-, ethyl ester, isobutyl benzoate, diethylene glycol dibenzoate, triethylene glycol dibenzoate, low erucic acid rapeseed oil, 3-t-butyl-4-hydroxyanisole, N,N-diisopropyl-1 ,2-ethanediamine, ethyl vanillin, vanillin, p-methyl acetophenone, pigment yellow 97, c.i. vat yellow 33, triolein, c.i. pigment orange 36, amyl cinnamal, decanedioic acid, bis(2-ethylhexyl) ester, solvent red 1, 3-phenyl-1 -propanol, p-anisaldehyde, diethyl succinate, dilauryl thiodipropionate, ethyl pelargonate, 3-(2-propenyloxy)-1 ,2-propanediol, methyl dehydroabietate, allyl caproate, Z-oxacycloheptadec-8-en-2-one, hypocrellin B, butyl stearate, ethyl myristate, spermidine, lauramine, stearamide, dimethyl stearamine, stearamine, caproyl sphingosine, isobornyl acetate, benzotriazolyl dodecyl p-cresol, usnic acid, tridecyl isononanoate, methoxypropylgluconamide, tris-hydroxymethylnitromethane, trioctyldodecyl citrate, sucrose acetate isobutyrate, sucrose octaacetate, dibutylene tetrafurfural, neopentyl glycol, 2,4,7,9-tetramethyl-5-decyne-4,7-diol, ethanolamine thioglycolate, xanthophyll, hydroxyanasatil retinoate, retinyl acetate, cholesteryl isostearyl carbonate, alpha-isomethyl ionone, hexadecanoic acid, isohexadecyl ester, 2,6-di-tert-butyl-p-cresol, beta-cyclodextrin, methyl ethers, nopyl acetate, Z,Z-9,12-octadecadienoic acid dimer, octyldodecyl diester, ascorbyl glucoside, macadamia ternifolia seed oil, trinonyl phosphate, 9-decen-1-ol, 3-hydroxybenzophenone, n-acetyl dihydrosphingosine, glucosylrutin, pentaerythrityl distearate, quinine, dimethyl phthalate, benzophenone-8, benzophenone-6, benzophenone-2, benzophenone-1 , benzophenone-3, alcloxa, c.i. solvent red 27, santalyl acetate, myristyl lactate, batyl stearate, glyceryl monoricinoleate, propylene glycol monostearate, glyceryl hydroxystearate, dinonyl phenol, vat orange 1 , neohesperidin, vat violet 9, vat blue 14, c.i. vat orange 2, vat blue 18, vat violet 1, 2,6-dimethyl-2-heptanol, n-octadecylstearamide, rifampin, disperse orange 37, propylene glycol monooleate, flutamide, 4-amino-1 -butanol, beta,beta-dimethyl-benzenepropanol, glyceryl abietate, sorbitan laurate, sorbitan stearate, sorbitan oleate, tetrahydroabietyl alcohol, benzophenone-11 , 1-(2-methoxypropoxy)-2-propanol, pargeverine, propylene glycol myristyl ether acetate, dimethylsilanol hyaluronate, triundecanoin, thianthol, dimethyldibenzylidene sorbitol, capramide dea, di-n-propyl 2,5-pyridinedicarboxylate, butyl benzoate, 4-hexylresorcinol, 2-heptylcyclopentanone, ascorbyl palmitate, 2,4-dinonylphenol, butyl lactate, cis-4-(1-methylethyl)-cyclohexanemethanol, stearyl glycyrrhetinate, betaterpineol, 2,3-dihydro-1h-indole-5,6-diol hydrobromide, trihydroxystearin, lauryl laurate, dimethyl diacetyl cystinate, chitin, methyl acetyl ricinoleate, butyl acetyl ricinoleate, tetrahydroxyethyl ethylenediamine, benzyl acetate, tannic acid, benzyl laurate, vitamin d, tocopherols, dimethylol urea, fumaric acid, bis(2-ethylhexyl) ester, bis(2-methylpropyl) hexanedioate, 2,3-dihydroxypropyl ricinoleate, stearamidoethyl ethanolamine, methyl 12-hydroxystearate, methyl ricinoleate, diethyl adipate, chloroaluminum phthalocyanine, aloin, 2,6-diaminopyridine, hexetidine, maleic acid, bis(2-ethylhexyl) ester, 1 ,4-bis(glycidyloxymethyl)cyclohexane, 2-hydroxypropyl laurate, myristamide mea, 2-hydroxypropyl stearate, butyl oleate, lauramide mea, isopropyl palmitate, c.i. pigment green 36, nonyl acetate, palmitamine, oleyl alcohol, stearamide mea-stearate, cinnamal, phenol red, syringaldazine, acetyl triethylhexyl citrate, 2,2,4-trimethyl-1,3-pentanediol, dimethyl capramide, trilinolenin,dehydroabietylamine, picolinamide, benzylhemiformal, thiodiglycolamide, alphalactose, pigment blue 15, dimethyl brassylate, levamisole, pentyl dimethyl paba, dl-beta-tocopherol, 1-0-hexyl-2,3,5-trimethylhydroquinone, oxyquinoline, diethylhexyl carbonate, beta-ionone, citronellyl acetate, phytol, solvent red 43, 3-benzylidene camphor, tropicamide, n-butylphthalimide, boric acid, cyclic nitrilotriethylene ester, ginkgolide a, ginkgolide c, ginkgolide b, rutin, acetyl hexamethyl indan, disperse red 354, n-lauryl diethanolamine, bromochlorophene, diethylhexyl butamido triazone, retinyl retinoate, dimethylol ethylene thiourea, 1 -hydroxyethyl 4,5-diamino pyrazole sulfate, pizotifen, 3-dodecyloxypropane-1 ,2-diol, 3-decanol, pyrantel, 1-propoxypropan-2-ol, 6-methyl-5-hepten-2-ol, dipropylene glycol, ethyl ether, 2-butoxy-1 -propanol, polysi licone- 13, 1 ,3,5-tris(3-(dimethylamino)propyl)-s-hexahydrotriazine, erythrosine acid, isostearyl glycolate, ethyl ximenynate, isostearyl acetyl glutaminate, pigment red 122, 5-oxa-2-octyne-1 ,7-diol, agribrom, 1,6-hexanediol diglycidyl ether, triallyl phosphate, oleyl palmitamide, fenchol, zeatin, 2-ethylhexyl pivalate, isobutenyl methyltetrahydropyran, DL-menthyl acetate, benzophenone-10, diethyl l-glutamate, dl-panthenol, 3-butoxy-1 -propylamine, dimyristyl thiodipropionate, 4-(1,1-dimethylpropyl)cyclohexanone, gamma-L-galactonolactone, beta-tocopherol, 3-propoxy-1 -propylamine, 10-hydroxydecanoic acid, dicaprylyl carbonate, pantethine, asiaticoside, stearamidoethyl diethylamine, ditridecyl adipate, laudanosine, doxycycline monohydrate, benzene, 1 ,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-, cholesteryl oleyl carbonate, ethylpentyl methoxychromone, dihexyldecyl lauroyl glutamate, methyl pelargonate, tricyclodecenyl propionate, stearoxypropyl dimethylamine, diglycol guanidine succinate, nictoflorin, myristyl stearate, behenyl behenate, octyldecyl oleate, oleyl stearate, oleyl erucate, oleyl linoleate, neoruscogenin, phenylparaben, 2,4-dichlorobenzenemethanol, 5-phenyl-1 h-tetrazole, trioctyl phosphate, ethyl arachidonate, xylyl dibutylbenzofuranone, 2-sec-butylthiazole, stearyl caprylate, clindamycin, L-ascorbic acid, tetrakis(2-hexyldecanoate), tributylcresylbutane, benzophenone-12, 2,3-dihydroxypropyl (9Z, 12Z, 15Z)-9,12,15-octadecatrienoate, dibutyloctyl sebacate, 2,6-dimethyloct-7-en-2-ol, cetyl dimethylbutyl ether, tri(2-ethylhexyl)amine, 2-isobutylthiazole, tribehenin, pentaerythrityl tetramyristate, bisethylhexyloxyphenol methoxyphenyl triazine, pyricarbate, streptozocin, 4-butyl-resorcinol, hydroxypalmitoyl sphinganine, silanetriol glutamate, 2-butenoic acid, hexyl ester, (R)-(-)-mevalonolactone, dihexyl fumarate, prazosin, propylene glycoldibenzoate, ethyl p-methoxycinnamate, pentaerythrityl tetraoleate, isopentyl lactate, tbhq, acetyl dipeptide- 1 cetyl ester, tridecyl salicylate, diacetylcurcumin, neopentyl glycol dimethacrylate, niacinamide ascorbate, ethylhexyl hydroxystearate benzoate, diiodomethyl p-tolyl sulfone, ethanolamine HCI, phosphonic acid, (3-((hydroxymethyl)amino)-3-oxopropyl)-, dimethyl ester, Z-3-octen-1-ol, 1-decanamine, 3-thiomorpholinone, tripalmitolein , dodecanoic acid, 2-ethylhexyl ester, lactamide, amyl benzoate, amyl salicylate, solvent orange 1, undecylenamide mea, tetrahydromagnolol, ergosterol endoperoxide, triisononanoin, neohesperidin dihydrochalcone, hydroxyethyl urea, octadecyl di-t-butyl-4-hydroxyhydrocinnamate, daunorubicin, cetyl laurate, methylheptyl isostearate, perillaldehyde, acetyl hexamethyl tetralin, 2-ethylhexyl 4-(dimethylamino)benzoate, hema acetoacetate, pentanedioic acid, bis(2-ethylhexyl) ester, methyl 2,5-dihydroxybenzoate, methyl 2,4-dihydroxybenzoate, dimethyl behenamine, 4-cyclohexene-1 ,2-dicarboxylic acid, bis(oxiranylmethyl) ester, 2-methyl-1 ,3-propanediol, isoquercitrin, phytosphingosine acetamide, diacetyl benzoyl lathyrol, 1-nonen-3-ol, 1-decanamine, n-methyl-n-octyl-, octadecanoic acid, 2-ethylhexyl ester, propyl methacrylate, 2-nonen-1-ol, l-menthol, cholesteryl lanolate, 1-methyl-3-phenylpropylamine, cetyl oleate, oleyl myristate, myristyl laurate, (1 R,2R,3S,5R)-(-)-2,3-pinanediol, 5-methyl-3-heptanone oxime, demethoxycurcumin, 2-octyldodecyl stearate, propylene glycol dilaurate, lauryl pea, octyldodecyl oleate, miconazole nitrate, isopropyl linoleate, miconazole, isopropyl lauroyl sarcosinate, (-)-6-methyl-2-(4-methyl-3-cyclohexen-1-yl)-5-hepten-2-ol, propyl benzoate, peoniflorin, adriamycin, ditrimethylolpropane, tetrahydropiperine, decursinol, thiophanate, hexyl nicotinate, methyl mercaptoacetate, ethoxyethyl methacrylate, laurylamine dipropylenediamine, 4-hydroxyindole, viridiol, tolnaftate, threitol, 2-hexyldecan-1-ol, pigment red 3, stearyl behenate, hesperidin methyl chaicone, ethyl 2-acetylheptanoate, l-fucose, drometrizole, hydroxymethoxybenzyl pelargonamide, methylthioadenosine, cetearyl glucoside, methyl 9-octadecenoate, phenyldimethoxyacetophenone, 2-isobutyl-3-methoxypyrazine, dihydroergocristine mesylate, tripropylene glycol, acetyl trihexyl citrate, ethoxylated tridecyl alcohol, 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3, 5-dione, polyethylene glycol dimethyl ether, tert-butyl-4-methoxyphenol, isooctyl thioglycolate, triisooctyl phosphate, clobetasol, clobetasol propionate, clobetasone butyrate, pentaerythrityl dioleate, cis-3-hexenyl benzoate, trixylyl phosphate, sucrose monostearate, 3-methoxybutanol, polytetramethylene glycol, ppg stearate, stearyl alcohol, propoxylated,polyoxymethylene diacetate, isobutyl myristate, dipropylene glycol, trimethyl hydroxypentyl isobutyrate, 4-(1 ,1 ,3,3-tetramethylbutyl)-phenol, polymer with formaldehyde and oxirane, 2,2'-(octadec-9-enylimino)bisethanol, polyethylene glycol, polyethylene glycol (mw 4,000,000), polyethylene glycol (mw 3,000,000), polyethylene oxide (mw 2,000,000), polypropylene glycol, stearic acid, isohexadecyl ester, mannide monooleate, sucrose monolaurate, diacetin, L-ascorbic acid, monooctadecanoate, pentyl isovalerate, isoamyl crotonate, triisodecyl phosphate, phytonadione epoxide, glyceryl monooleate, tripropylene glycol monomethyl ether, triisooctylamine, ethyl phenethyl acetal, polyglycerol, glyceryl dioleate, 3-methyl-1 ,3-butanediol, 2-ethyl-2-hydroxymethyl-1 ,3-propanediol, propoxylated, glycols, polypropylene, 1 ,2,3-propanetriyl ether, stearyl palmitate, cetyl myristate, hydroxybenzomorpholine, 4-nonylphenol polyethylene glycol ether, trimethylolpropane triethylhexanoate, 1 ,2,3-propanetriol, dimer, propoxylated, 2-methyl-4-isothiazolin-3-one hydrochloride (1:1), 5-chloro-2-methyl-4-isothiazolin-3-one, decyl alcohol, ethoxylated, l-menthyl acetate, tridecanol, sorbitan palmitate, sorbitan trioleate, dihydroabietyl alcohol, erucylamine, Z-9-octadecenoic acid, 2-ethylhexyl ester, decanoic acid, monoester with 1 ,2,3-propanetriol, octanoic acid, monoester with 1 ,2,3-propanetriol, propylene glycol ricinoleate, 1 ,2,3-propanetriol, monoacetate, sucrose monopalmitate, solvent orange 2, polyethylene glycol mono(2-ethylhexyl) ether, tris(nonylphenyl)phosphite, methyl 4-tert-butylbenzoate, glyceryl monolinoleate, polypropylene glycol dioleate, polytrimethylene terephthalate resins, 4-hydroxy-benzoic acid, dodecyl ester, glyceryl dipalmitate, glyceryl monopalmitate, sorbitan tristearate, medrysone, 2-methyl-4-isothiazolin-3-one, dedm hydantoin, ethyl pyrrolidone, triisostearin, isooctanol, diethoxyethyl succinate, 4,5-dihydro-2-(heptadecenyl)-1H-imidazole-1 -ethanol, dipropylene glycol dibenzoate, diisodecyl adipate, propylene glycol monolaurate, sucrose distearate, dihydromyricetin, tetradecanoic acid, monoester with 1 ,2,3-propanetriol, glyceryl monolaurate, sucrose monomyristate, glyceryl triacetyl hydroxystearate, octyl alcohol, ethoxylated, myristyl nicotinate, isotridecyl alcohol, isostearyl alcohol, trierucin, azulene, hydroxymethyl-5, 5-dimethylhydantoin, glyceryl dilaurate, cysteamine bitartrate, stearyl stearate, hydroxypropyl methacrylate, gamma-d-galactonolactone, neopentyl glycol dicaprate, N,N-dimethyl-2-ethylhexylamine, N,N-dimethyl-octadecen-1 -amine, erucic acid, monoester with 1 ,2,3-propanetriol, ethyl trimethylcyclopentene butenol, L-ascorbic acid, dihexadecanoate, neopentyl glycoldiethylhexanoate, oxacycloheptadec-10-en-2-one, trimethyl pentaphenyl trisiloxane, methyl benzodioxepinone, trihexadecylamine, glucosamine sulfate, 3-isopropoxy-1-propylamine, procyanidin b2, sorbitan dioleate, dicaprylyl maleate, butanedioic acid, bis(2-ethylhexyl) ester, ethylhexyl hydroxystearate, 1 ,2-propanediol, monobutyl ether, isolongifolene ketone exo, 5,6-indolinediol, farnesyl acetate, kanamycin b sulfate, cetyl caprylate, cetyl caprate, hexadecanoic acid, 2-ethylhexyl ester, tetradecanoic acid, 2-ethylhexyl ester, methoxy peg / ppg aminopropyl dimethicone, octyl beta-D-glucopyranoside, 1-(1-methyl-2-propoxyethoxy)-2-propanol, dipropylene glycol monobutyl ether, di(3-aminopropoxy)ethane, sec-butyl methacrylate, 5-bromo-5-nitro-1 ,3-dioxane, propanol, 1(or 2)-propoxy-, xanthorrhizol, docosanoic acid, monoester with 1 ,2,3-propanetriol, DL-fructose, ethyl (2E,4Z)-2,4-decadienoate, diethylamino hydroxybenzoyl hexyl benzoate, ethyl d-glucoside, cholesteryl oleate, cysteamine tosylate, ubidecarenone, glyceryl dilinoleate, docosanamide, 4-(2-(1 ,1 -dimethylethyl)-5-methylphenoxy)phenol, N-isobutyldiethanolamine, 1,1 ,4,7,10,10-hexamethyltriethylenetetramine, isobutyl pelargonate, tris-biphenyl triazine, hygromycin b, ppg oleate, octrizole, methyl glucoside, tridecyl stearate, propylene glycol caprylate, octadecanoic acid, isotridecyl ester, octadecanoic acid, isodecyl ester, octadecanoic acid, monoester with 1,2,3-propanetriol, dimethiconol, glycerol, ethoxylated, lauramidopropyl dimethylamine, 4-(4-hydroxy-4-methylpentyl)-3-cyclohexene-1-carboxaldehyde, N-acetyllactosamine, O-cymen-5-ol, myristyl myristate, glucuronolactone, solvent red 41 , 4-nitroguaiacol, 2-tetradecyloctadecan-1 -ol, dibenzylidene sorbitol, N-methyl-4-methoxynaphthalimide, cholesteryl dichlorobenzoate, trimethylolpropane trimethacrylate, 3-isobutoxy-1 -propylamine, tobramycin, trioleyl phosphate, bis-demethoxycurcumin, triethylhexyl trimellitate, fluorescein-5-isothiocyanate, pyrantel tartrate, bilobalide, diisononyl adipate, dihydro pentamethylindanone, 5-chloro-2-(4-chlorophenoxy)-phenol, ethylene glycol monohydroxystearate, 1 ,7-dioxacycloheptadecan-8-one, diethyl palmitoyl aspartate, 2',3'-dideoxythymidine, glucosamine, methyl L-tyrosinate HCI, hexyl laurate, 2-hexyldecyl laurate, polyethylene glycol monoundecyl ether, 3,5,5-trimethylhexan-1-ol, madecassoside, D-mannose, dipropylene glycol monomethyl ether, dithiothreitol, polyethylene glycol, bis(3-aminopropyl)ether, stearyl lactate, cetyl lactate, honokiol, (all-Z)-5,8, 11 ,14-eicosatetraenoic acid, 2,3-dihydroxypropyl ester, cholesteryl stearate, bromothalonil, calcium didocosanoate, dimethylol glycol, tetrabutyl ethylidenebisphenol, tetrahydrodiferuloylmethane, lauryl oleate, tocopheryl linoleate,rhamnose, stearamide amp, isohexadecanol, natural red 26, sorbitan distearate, dimethylhydroxy furanone, triisodecyl trimellitate, cetyl alcohol, 4-methylbenzylidene camphor, oleyl oleate, decyl oleate, methyl dihydrojasmonate, poly(oxy-1 ,2-ethanediyl), alpha-(isononylphenyl)-omega-hydroxy-, polypropylene glycol methyl ether, sucrose stearate, dodecanoic acid, ester with 1 ,2-propanediol, 2-octyldodecyl 5-oxo-l-prolinate, hexamidine, minoxidil, 4-pentylphenyl 4-methoxybenzoate, 2-(2H-benzotriazol-2-yl)-4,6-bis(1 ,1-dimethylethyl)-phenol, N,N,N'-trimethyl-N'-[3-(dimethylamino)propyl]-1 ,3-propanediamine, glucose pentaacetate, raspberryketone glucoside, 2-butyl-1 -octanol, imidazolidinyl urea, 1 ,9-nonanediol, ethyl menthane carboxamide, icosane-1,2-diol, linoleamide, erythrulose, cholesteryl hydroxystearate, ethyl ferulate, dideoxyadenosine, dicetyl ether, 7,7,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1 ,16-diyl bismethacrylate, ethyl serinate, stearic hydrazide, propylene glycol dipelargonate, bis(1,2,2,6,6-pentamethyl-4-piperidyl) sebacate, 1 ,3,5-triazine-2,4,6-triamine phosphate, beta-D-galactopyranose, pentaacetate, isooctadecanoic acid, isooctadecyl ester, trans-anethole, isopropylparaben, decyl myristate, pentaerythritol tetrabenzoate, tridecyl phosphate, 4-(methylamino)butan-1-ol, isononyl isononanoate, glycol palmitate, 3,5-bis(1 ,1-dimethylethyl)-4-hydroxy-benzoic acid, 2,4-bis(1 ,1-dimethylethyl)phenyl ester, tridecyl behenate, arachidyl behenate, 4-hydroxybenzoic acid, 2-methylpropyl ester, menthanediol, 1-amino-3-phenoxy-2-propanol, diethyl DL-aspartate, D-alpha-tocopheryl nicotinate, 7-dehydrocholesterol, pyridoxine tripalmitate, hydroxypropyl tetrahydropyrantriol, tetrabromophenol blue, 4-ethyl-1,3-dioxolan-2-one, N,N-dioctylmethylamine, N-(2-hydroxyethyl)-1 ,3-diaminopropane, genistein, isopropyl sorbate, glycol oleate, methoxydiglycol methacrylate, myristamidopropyl dimethylamine, curcumin, farnesol, tripropylenetetramine, (R)-camphor, methyl 4-methylsalicylate, nootkatone, orphenadrine citrate, kanamycin B, methyl 2,4-dihydroxy-3,6-dimethylbenzoate, ruscogenin, astaxanthin, 2-pinanol, betulin, 1 ,3-dioxan-5-ol, 1,4,8,11-tetraazaundecane, glaucine, ellagic acid, mangiferin, inulin lauryl carbamate, dyphylline, pentaethylene glycol, chlorophyll A, tangeretin, indigo, 1 ,6-hexanediamine, N,N'-dibutyl-, N-benzoyl-2'-deoxy-cytidine, crotamiton, 2,9-dimethyl-1 ,10-phenanthroline, procyanidin, ninhydrin, cinchonidine, 3-octanol, acetate, glucamine, tristearyl phosphate, ethanone, 1-(2,5-dihydroxyphenyl)-, luteolin, 2-nitro-N-(2-hydroxyethyl)aniline, ethyl hydroxypyrone, c.i. pigment red 149, cis-2-pinanol, arbutin, tobramycin sulfate, N-(3-aminopropyl)diethanolamine, tioxolone,nicotinaldehyde, nordihydroguaiaretic acid, kojic acid, resveratrol, estradiol, stearone, quinidine sulfate, (S)-3-(hexadecyloxy)propane-1 ,2-diol, 4-pentylphenyl 4-octyloxybenzoate, D-ribose, D-sorbitol, L-ascorbic acid, dibenzoxazoyl naphthalene, thymidine, 3-nitro-4-aminophenoxyethanol, methyl diisopropyl propionamide, totarol, allantoin galacturonic acid, 4,4-dimethyloxazolidine, trimethyl phosphate, raffinose, 2,3-butanediol, 3-(4-hydroxy-4-methylpentyl)cyclohex-3-ene-1-carbaldehyde, benzoic acid, 4-hydroxy-, 2-ethylhexyl ester, alpha, 4-dimethyl-alpha-(4-methyl-3-pentenyl)-3-cyclohexene-1 -methanol, deceth-6, tetrandrine, dl-alpha-tocopherol nicotinate, matrine, chlorophyll b, kaempferol, hesperidin, hesperetin, cholesteryl butanoate, poly(oxy-1,2-ethanediyl), alpha-isooctadecyl-omega-hydroxy-, ethyl butylacetylaminopropionate, etocrylene, 3,6-dith ia- 1 ,8-octanediol, polypropylene glycol oleyl ether, permethrin, genistein glucoside, lauryl stearate, dimethyl isosorbide, esculin, 1 -dodecanol, 2-octyl-, 2-heptylundecanol, l-erythrulose, ribonolactone, 1,2,4-trihydroxybenzene, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-, 1,2-pentanediol, anhydroxylitol, glyceryl dimyristate, perilla alcohol, sorbeth, trilinolein, glycerol trioctanoate, propylene glycol didecanoate, trilaurin, phenoxypropanediol, butyl glucoside, 2,4,5,6-pyrimidinetetramine sulfate (1 :1), tetrahydropyranyloxy phenol, tetramethylolglycoluril, 3-((2-ethylhexyl)oxy)-1-propanamine, cetyl palmitate, lactamide mea, gamma-tocopherol, myrcenol, sorbitan, monoisooctadecanoate, palmitamide mea, alpha-bromocinnamaldehyde, benzoic acid, 2-ethylhexyl ester, batilol, decyl d-glucopyranoside, 1,3-dioxolane-4-methanol, ethylhexyl methoxycinnamate, stearyl stearoyl stearate, raspberry ketone, betahistine mesylate, ethylene dodecanedioate, 3-methyl-5-phenyl-1 -pentanol, beta-methyl-benzenepentanal, ethyl ricinoleate, naphazoline HCI, isohexyl palmitate, paeonol, 2-methyl-5-hydroxyethylaminophenol, sericoside, beclomethasone dipropionate, isopropyl nicotinate, lauraminopropylamine, 3-iodo-2-propynyl butylcarbamate, phytosphingosine, phenoxyethylparaben, tristearin, tripalmitin, trimyristin, chlorhexidine, glyceryl stearate citrate, betamethasone dipropionate, tripropylene glycol n-butyl ether, sucralose, bis(2-ethylhexyl) malate, 4-terpineol, betahistine, epirubicin, sclareolide, pyridoxine tris-hexyldecanoate, 3-methoxy-3-methyl-1-butanol, quinidine, camphanediol, leptospermone, alpha-adenosine, 1-acetoxy-2-methylnaphthalene, chlorobutanol, D-fructose, 29H,31 H-phthalocyanine, benzylidenephthalide, lactic acid, 2-octyldodecyl ester, methyl 9-undecylenate, ethinylestradiol, beta-hydroxy-benzenepropanoic acid, ethyl ester, stevioside,progesterone, ergosterol, cholesterol, hydroxydecyl ubiquinone, terrein, menadione, 1 ,2-butanediol, tert-butyl methacrylate, theophylline, pyridoxine HCI, (R)-2-amino-1-butanol, lactitol, maltitol, melibiose, adenosine, inosine, 2-decyl-1 -tetradecanol, gamma-terpineol, octyl 4-(dimethylamino)benzoate, decyl beta-D-glucopyranoside, D-xylose, ethyl dihydroxypropyl paba, alpha-tocopheryl acetate, isostearyl neopentanoate, uridine, kanamycin a, alpha-tocopherol, dodecyl beta-D-glucopyranoside, hexadecyl 2-ethylhexanoate, stearyl ethylhexanoate, darutoside, 2-dodecyl-tetradecanol, 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate, laurocapram, Z-9-octadecenoic acid, isodecyl ester, menthyl lactate, oleyl glyceryl ether, piperlonguminine, 2-ethylhexyl pelargonate, beta-lactose, pentaerythritol tetraacetate, 3-methylamino-4-nitrophenoxyethanol, alpha-lactose monohydrate, D-(-)-pantolactone, glucoheptonolactone, 2,2-dimethylpropanoic acid, isodecyl ester, behenamidopropyl dimethylamine, cholesterol acetate, alpha-d-glucopyranose, pentaacetate, brucine sulfate heptahydrate, phloridzin, phloretin, quinine sulfate dihydrate, 1 ,2,4-triacetoxybenzene, trehalose dihydrate, ethyl nicotinate, peg / ppg dimethyl ether, tribenzoin, chimyl alcohol, mangostin, dibromopropamidine diisethionate, oxytetracycline dihydrate, diisopropyl oxalate, dipropyl oxalate, 3-aminopropane-1,2-diol, pentaerythrityl tetrabehenate, 2-amino-1 -propanol, (S)-2-octanol, ethyl pyruvate, hydrogenated tallowamine, cocamine, bioflavonoids, methyl cocoate, methyl dicocamine, dihydrogenated tallow methylamine, dimethyl cocamine, glyceryl monococoate, hydrogenated ditallowamine, simmondsia chinensis seed oil, tallow amine, peg tallow aminopropylamine, coconut amine ethoxylate ether (5eo), 2,2'-iminobis-, ethanol, N-coco alkyl derivs., N-tallowalkyl-1 ,3-propanediamine, N-(tallow alkyl)dipropylenetriamine, N-coco-1 ,3-propylenediamine, propylene glycol distearate, methyl glucoside propoxylate, octocrylene, triarachidin, triheptanoin, phloroglucinol trimethyl ether, pentaerythrityl tetraisostearate, glycerol tridecanoate, myristyl propionate, ethyl thioglycolate, glycol dilaurate, dimethyl maleate, diisostearyl adipate, hexyl salicylate, magnesium laureth sulfate, glycol distearate, dimethyl adipate, lauryl lactate, methylglucamine, ethyl palmitate, 3-ethoxy-1-propanamine, octane-1 ,8-diol, palmitamide, distearyl ether, cetyl acetate, 1-pentadecanol, dicaprylyl ether, 1-eicosanol, erucyl alcohol, isoamyl laurate, silicone oil, basic fuchsine, alcohols, d 2-15, lactose, isobutyl methyl tetrahydropyranol, pyridoxine dipalmitate, dibutyl lauroyl glutamide, polyglyceryl diisostearate, tetrahydrofurfuryl acetate, myristyl acetate, methyl di-t-butyl hydroxyhydrocinnamate,pinoresinol diglucoside, ppg benzyl ether myristate, pigment red 190, D-chiro-inositol, pentaerythrityl hydrogenated rosinate, dmdm hydantoin, pigment red 22, 5-oxo-L-proline, (1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl ester, isomalt, isobutyl stearate, c.i. pigment red 23, pyridoxine, maltol isobutyrate, hydroxymethyl dioxoazabicyclooctane, salicylamide, cytidine, thymine, stearyl heptanoate, isooctadecanoic acid, monoester with 1,2,3-propanetriol, 1 -docosanol, pyridoxal, panthenyl ethyl ether, pentaerythrityl tetra-di-t-butyl hydroxyhydrocinnamate, 1,6-dioxacycloheptadecan-7-one, DL-mevalonolactone, xanthohumol, isoamyl allylglycolate, ethyl 2,2-dimethylhydrocinnamal, diethoxynonadiene, amines, tri-d 4-18-alkyl, cetearyl alcohol, dipentaerythrityl hexa c5-9 acid esters, peg / ppg butyl ether dimethicone, bis(16-methylheptadecyl) hydroxybutanedioate, 5-butyl-5-ethyltetrahydro-2H-pyran-2-one, 2,4-dimethyl-3-cyclohexene carboxaldehyde, trimethylpentanediyl dibenzoate, teprenone, 5-oxo-D-proline, (1 R,2S,5R)-5-methyl-2-(l-methylethyl)cyclohexyl ester, amides, coco, N-(2-hydroxyethyl)-, cocamidopropyldimethylamine, ethyl hydroxymethyl oleyl oxazoline, diethylene glycol rosinate, isooctadecanoic acid, 1 -methylethyl ester, linoleamide mea, methyl rosinate, glycerides, coco mono- and di-, ethoxylated, lauryl alcohol, ethoxylated, propoxylated, ethoxylated methyl beta-d-glucoside, retinol, tocotrienol, isooctyl tallate, cocamide mipa, benzoic acid, d 2-15-alkyl esters, polydextrose, alcohols, d 2-14, ethoxylated, propoxylated, polybeta-alanine, ppg butyl ether dimethicone, pentaerythrityl tetracaprylate / tetracaprate, trimethyl pentanyl diisobutyrate, d-glucopyranose, oligomeric, decyl octyl glycosides, trimethylolpropane triisostearate, stearoxy dimethicone, propylene glycol dicaprylate / dicaprate, alcohols, c8-10, ethoxylated, coconut diethanolamide, xylobiose, silica dimethyl silylate, triethylene glycol hydrogenated rosinate, amines, tri-c8-10-alkyl, diethyl 2,4,6-trioxoheptanedioate, heptanoic acid, ester with 2,2-dimethyl-1 ,3-propanediol, methacrylic acid, 2-ethylhexyl ester, polyglyceryl-10 decalinoleate, n-(tallowalkyl)tripropylenetetraamine, methyl soyate, alcohols, c16-18 and c18-unsaturated, ethoxylated, alcohols, c9-11 , propoxylated, d-glucopyranoside, methyl, octadecanoate (2:3), alcohols, c6-12, ethoxylated propoxylated, wheat germ glycerides, hydrogenated palm kernel oil, 1 ,2,3,4,5,6,7,8-octahydro-5,5-dimethylnaphthalene-2-carbaldehyde, 1 ,2-hexanediol, 1 ,2-hexadecanediol, dodecyl-beta-D-maltoside, 2-octyldodecyl 2-ethylhexanoate, ethyl 10-undecylenate, 2-octylamine, distearyl thiodipropionate, polyoxyethylene isohexadecyl ether, oleylacetate, diisopropyl adipate, gamma-caprolactone, d-mannitol, benzoic acid, p-hydroxy-, decyl ester, bis-hydroxyethyl tromethamine, 4-(2-methylbutyl)phenyl (S)-4-(octyloxy)benzoate, maltose, xanthine, uric acid, dimethylamino methylpropanol, 1 ,2,4-benzenetricarboxylic acid, mixed branched tridecyl and isodecyl esters, 1 -(4-(1 ,1-dimethylethyl)phenyl)-3-(4-methoxyphenyl)-1 ,3-propanedione, quinidine mono-D-gluconate, p-toluenesulfonamide, delta-decalactone, retinyl propionate, dipentaerythrityl hexaheptanoate / hexacaprylate / hexacaprate, troxerutin, 3,5,5-trimethyl-hexanoic acid, 2-ethylhexyl ester, octenidine, 2,5-thiophenediylbis(5-tert-butyl-1 ,3-benzoxazole), cytosine, gerotine, triethylhexyl citrate, ethyl 5-oxo-L-prolinate, isoamyl p-methoxycinnamate, N-oleyl-1 ,3-propanediamine, 6, 7,8,9-tetrahydro-5h-cyclohepta[b]pyridine, 1 ,4-piperazinedipropanamine, nerolidol, tetradecyl 2-ethylhexanoate, beta-carotene, 2-dodecylhexadecanol, di-hema trimethylhexyl dicarbamate, 2,2-bis(((2-ethyl-1-oxohexyl)oxy)methyl)propane-1 ,3-diyl bis(2-ethylhexanoate), adenine, carbitol acrylate, sodium carbomer, melatonin, caprylic / capric glycerides, guanine, triethylhexanoin, octyldimethylamine, propylene glycol dicaprylate, didecylmethylamine, 2-(3-pentyl)pyridine, hexanoic acid, 2-ethyl-, 2-ethylhexyl ester, ethambutol, phytantriol, 2-hydroxy-2-methylpropiophenone, polypropylene glycol 1 -oxopropyl tetradecyl ether, diisopropyl sebacate, dipropylene glycol salicylate, n-acetyl-beta-d-glucosamine, riboflavin tetraacetate, isobornyl methacrylate, 3,7,11 ,15-tetramethyl-2-hexadecen-1-ol, myristamide dea, palmitamide dea, tocoquinone, 3-methylpentane-1 ,3,5-triol, cetearyl dimethicone, polymer with vinyl cyclohexene oxide, beta-cyclodextrin, 3-lauryloxy-1 -propylamine, 3-decoxypropane-1 -amine, camphor, sphinganine, stearamidopropyl dimethylamine, bromothymol blue, 4,4'-(3h-2,1-benzoxathiol-3-ylidene)bis(2,6-dibromo-3-methyl-phenol, S,S-dioxide, quassin, 1 -adamantanol, decyloxazolidinone, DL-alpha-tocopheryl acetate, tetramethrin, hypocrellin a, phenoxyisopropanol, phenolphthalein, procyclidine, dibromantin, dm hydantoin, isoamyl cinnamate, ethyl methylphenylglycidate, geranyl tiglate, (R)-(+)-alpha-terpineol, tromethamine, octyl isovalerate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, tributyl citrate, 1 ,1,1-tris(hydroxymethyl)propane, tripentaerytritol, tris(2-ethylhexyl) phosphate, diazolidinyl urea, 3,7-dimethyloctan-3-ol, linalool, cetylhydroxyproline palmitamide, octyldodecyl ricinoleate, DL-pantolactone, oxytetracycline, dihydrolanosterol, lanosterol, kojic dipalmitate, 2,5-di-t-pentylhydroquinone, (E)-beta-ionone, retinyl palmitate, terpineol, helianthus annuus seed oil, soybean oil, safflower oil, oleaeuropaea fruit oil, linum usitatissimum seed oil, cottonseed oil, cocos nucifera seed butter, ricinus communis seed oil, brassica campestris seed oil, malt extract, menhaden oil, montan cera, elaeis guineensis butter, basic violet 1 , triticum vulgare germ oil, myroxylon pereirae resin, cedar leaf oil, terpineol acetate, sorbitan sesquioleate, thymus vulgaris oil, sesamum indicum seed butter, ionone, mentha pulegium herb oil, cuminum cyminum fruit oil, cymbopogon martini herb oil, citrus paradisi seed oil, commiphora myrrha gum oil, cucurbita pepo seed oil, vetiveria zizanoides root oil, lavandula hybrida herb oil, mustela oil, galbanum oil, lanolin alcohol, ichthammol, p-toluenesulfonamide, n-ethyl-, saponins, methyl hydrogenated rosinate, pentaerythrityl rosinate, glyceryl rosinate, vitamin b6, dimethyl imidazolidinone, dihydrocholesterol, saccharin, clarithromycin, dexpanthenol, musk ketone, Z-3,4,5,6,6-pentamethyl-3-hepten-2-one, 2-methyl-3-(3,7,11 ,15-tetramethylhexadec-2-enyl)-1 ,4-naphthoquinone, isooctadecanoic acid, 2-ethylhexyl ester, dioctyldodecyl lauroyl glutamate, stearyl acetate, dipeptide diaminobutyroyl benzylamide diacetate, methylcyclopentadecenone, 2-(1-oxobutoxy)-1 ,2,3-propanetricarboxylic acid, 1 ,2,3-trihexyl ester, vanillyl butyl ether, acetyl tetrapeptide-3, decanedioic acid, 1 -methyl 10-(1 ,2,2,6, 6-pentamethyl-4-piperidinyl) ester, methyl glucose dioleate, ethyl gallate, beta-sitosterol, naphazoline, 1 ,5-dihydroxy naphthalene, cholesteryl isostearate, theobromine, tetradecanoic acid, isohexadecy ester, 2-amino-4-hydroxyethylaminoanisole, 2-amino-4-hydroxyethylaminoanisole sulfate, 2-octyldodecyl myristate, riboflavin, dimethylmethoxy chromanol, orphenadrine, alcohols, c12-14-secondary, ethoxylated, alpha-arbutin, isononanoic acid, mixed esters with dipentaerythritol, heptanoic acid and pentaerythritol, methoxyisopropyl acetate, decyl isostearate, itraconazole, zingiber officinale root extract, phytonadione, cetyl isononanoate, acetylated castor oil, dichlorophenyl imidazoldioxolan, benzophenone-7, dimethyl hydroxymethyl pyrazole, phenylethyl resorcinol, N-(3-aminopropyl)-N-tallowalkyl trimethylene diamines, 1,2-benzenedicarboxylic acid, 2-butoxy-2-oxoethyl butyl ester, solvent red 24, dibutyl ethylhexanoyl glutamide, 3-o-ethyl ascorbic acid, benzoxiquine, menthoxypropanediol, glycol salicylate, DL-mannitol, inositol, xylitol, octyldodecyl erucate, o-toluenesulfonamide, tetradecanoic acid, isotridecyl ester, 2-tert-butylcyclohexyl acetate, 2,5-di-tert-butylhydroquinone, (2-methoxymethylethoxy)-propanol acetate, phenyl methyl pyrazolone, hydroxypinacolone retinoate, menthyl salicylate, DL-menthyl acetate, erythorbic acid, chlorothymol, DL-menthol, 4-acetylresorcinol, karaya gum, ceratonia siliqua gum, gelatin, casein, 4-(1 ,1 ,3,3-tetramethylbutyl)phenol, ethoxylated, tocophersolan, peg / ppg copolymer, butoxypolypropylene glycol, dextrin, buteth, peg phenyl ether, glycols, polyethylene, monolaurate, polyethylene glycols monohexadecyl ether, glycols, polyethylene, monooleate, polyethylene glycol monooleyl ether, glycols, polyethylene, monostearate, polyoxyl stearyl ether, octyldodecyl stearoyl stearate, glycogen, inulin, carbomer 934, atelocollagen, polyglyceryl oleate, hemoglobin, polyglyceryl stearate, zein, polymethyl methacrylate, polyethylene glycol monododecylphenyl ether, methyl hydroxyethylcellulose, (1 ,1 ,3,3-tetramethylbutyl)phenol, ethoxylated, polyoxyethylene polyoxypropylene monobutyl ether, polyglycerol, hexanoic acid, 2-ethyl-, d 2-15-alkyl esters, poly(oxypropylene) glycol monoallyl ether, ppg / smdi copolymer, polyoxyethylene isotridecyl ether, polypropylene glycol bis(2-aminopropyl) ether, 1 ,3-propanediol, 2,2-dihydroxymethyl-, propoxylated, sodium carboxymethyl starch, gluconolactone, 2-methyl-oxirane, polymer with oxirane, ether with 1 ,2,3-propanetriol (3:1), oxyethylated, oxypropylated hexadecanol, cholesteryl chloride, diethylaminomethylcoumarin, beta-sitosteryl acetate, coumarin, N,N-diethyl-m-aminophenol, fatty acids, coco, 2-ethylhexyl esters, ethyl olivate, 6-methyl coumarin, glycol dioleate, 4,4'-biphenol, 3-hexenol, methyl behenate, veratryl alcohol, 1-(2-naphthalenyl)-ethanone, hydroxymethyl dioxolanone, methyl eugenol, eugenyl acetate, triisocetyl citrate, acetyl decapeptide-3, methyl nicotinate, o-tolyl biguanide, 2-octyldodecyl isooctadecanoate, pentaerythrityl tetraisononanoate, stearamide dea, oleic acid diethanolamide, 2-hydroxyoctacosyl 12-hydroxyoctadecanoate, ethyl benzoate, alpha-methylbenzyl acetate, 2-hydroxypropanoic acid, c12-15-alkyl esters, isopropyl benzoate, propylene glycol diethylhexanoate, phenyl benzoate, behenamide mea, tridecyl trimellitate, 4-hydroxybenzoic acid, propyl ester, benzyl 4-hydroxybenzoate, 1-(1-naphthalenyl)-ethanone, dimyristyl tartrate, Butyl p-aminobenzoate, benzoic acid, 4-hydroxy-, butyl ester, benzyl nicotinate, 2-phenylethyl benzoate, t-butylphenyl imidazolylphenyl sulfonamide, hydroxycyclohexyl phenyl ketone, 1 ,2,3-benzotriazole, 2-(8-heptadecenyl)-4,5-dihydro-1 H-imidazole-1 -ethanol, 2-aminobutanol, dihydroxyacetone, dimethyl urea, orlistat, fenticlor, eugenol, isoeugenol, allantoin, shellac cera, alpha-terpineol, niacinamide, epigallocatechin gallate, trehalose, diethyl caprylamide, 4-hydroxybenzoic acid, methyl ester, glyceryl dibehenate, neryl butyrate, erythritol, isobornyl acrylate, diethyl phthalate, doxycycline, bifonazole, triacetin, glycofurol,1 ,6-hexanediol, glucosyl ceramide, glycol ethylhexanoate, methoxy PEG maleimide and combinations and derivatives thereof. An especially preferred non-ionic surfactant is sorbitan stearate.

[0040] Suitable ionic or non-ionic co-surfactants generally include a 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, oleic acid, 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, 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, stearylamine, 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, polypropylene glycol, and derivatives and combinations thereof. Especially preferred ionic or nonionic co-surfactants are PEG sorbitan monolaurate, cholesterol, and stearylamine.

[0041] The total amounts of primary nonionic surfactant and optional secondary nonionic or ionic 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 niosome weight.

[0042] Suitable inhibitors of a metabolic enzyme pertaining to psychedelics can be added to the composition. Suitable inhibitors generally can be selected from monoamine oxidase inhibitors including but not limited to harmaline, moclobemide, brofaromine, methylene blue, pirlindole, caroxazone, metralindole, minaprine, eprobemide, harmine, rosiridin, esuprone, CX157, amiflamine, befloxatone, sercloremine, tetrindole, cimoxatone, isocarboxazid, hydracarbazine, phenelzine, tranylcypromine, bifemelane, moclobemide, pirlindole, rasagiline, selegiline, safinamide, linezolid, furazolidone, benmoxin, iproclozide, iproniazid, mebanazine, iproniazid, nialamide, octamoxin, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, toloxatone, procarbazine, tilianin, 7,8-dichloro-1 ,2,3,4-tetrahydroisoquinoline, clorgiline, lazabemide, milacemide, mofegiline, pargyline, pivhydrazine, procaine, viloxazine, CX157, and derivatives and combinations thereof. An especially preferred inhibitor of a metabolic enzyme pertaining to psychedelics is tilianin.

[0043] The total amounts of inhibitors of a metabolic enzyme pertaining to psychedelics, combined, are generally within a range from about 1 - 10 wt%,preferably an amount within the range of 1 - 5 wt%, and more preferably an amount within the range from about 0.1 - 1 wt%, and optimally within the range of 0.01 - 0.1 wt% of the total niosome weight.

[0044] 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.

[0045] 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 niosomes taken orally by the patient.

[0046] 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.

[0047] 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.

[0048] 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 anddissociative 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 deficit disorders; 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 legsyndrome; 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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).

[0054] 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

[0055] 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, one or 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.

[0056] The term "pharmaceutical composition" means a composition according to the invention combined with at least one additional, pharmaceutically acceptable carrier.

[0057] 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 ofadministration 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.

[0058] 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.

[0059] 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 the recipient; 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.

[0060] 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 200mg. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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 from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.

[0066] 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.

[0067] Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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, orsolubilizer. 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).

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] An effective dosage can be administered in one or more administrations. For the purposes of this invention, an effective dosage of drug, composition, orpharmaceutical 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

[0080] 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.

[0081] 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.

[0082] 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 disordersincluding 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.

[0083] 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.

[0084] 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 health care 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.

[0085] 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.

[0086] 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 behaviorpatterns 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

[0087] Our testing was done with 5-MeO-DMT which is not regulated as a controlled substance, but which behaves in formulation in ways that are similar to controlled psychedelics.

[0088] Described herein are studies that were performed to develop an encapsulating niosomal composition and its method of manufacture for psychedelics. The experimental design provided multiple compositions of different ratios of primary non-ionic surfactants, and non-ionic or ionic co-surfactant(s). These compositions were initially prepared by creating a thin film of the surfactant(s), the psychedelic agent, and an inhibitor of metabolic enzymes pertaining to psychedelics. The thus created niosomes are prepared by hydration of the thin-film with an aqueous medium to create coarse-sized particles followed by high-shear mixing and high-pressure homogenization (microfluidic processing) to form stable, nanosized niosomes. The niosomes showed high colloidal stability under physical and chemical stressors, as well as upon storage.

[0089] The niosomes produced in our examples show enhanced stability under physical and chemical duress, as well as upon storage where the niosomes remained colloidally stable over 4 months storage at 4 °C in the formulation.

[0090] Cytotoxicity assays on three cell lines reveal negligible toxicity of formulated 5-MeO-DMT and tilianin at therapeutic concentrations.

[0091] 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 sorbitan stearate as the non-ionic surfactant, and PEG sorbitan monolaurate, cholesterol, and stearylamine as the co-surfactants.

[0092] For our primary surfactant, 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.

[0093] The resulting niosomes were characterized by dynamic light scattering (DLS) to determine the average diameter of particles as well as to measure changes in polydispersity index and surface charge (^-potential). Particles were imaged using a transmission electron microscope after appropriate sample preparation.

[0094] The niosomes were stress tested under different chemical and physical environments mimicking commercial production and storage conditions to evaluate their long-term stability. The average particle sizes, polydispersity index, and -potentials for our niosomes were promising under this stress testing.

[0095] Biological assays were used to evaluate the effect of our niosomes on cells. Cytotoxicity was evaluated using immortalized human embryonic kidney cells and cancer cells.

[0096] The niosomes were prepared using the thin-film hydration method.Sorbitan stearate, PEG sorbitan monolaurate, cholesterol, and stearylamine were co-dissolved in a 2:1 (v / v) mixture of chloroform and methanol at a molar ratio of 2:2:2:0.4. The final molar concentration of the surfactants was maintained at least 100 times higher than their respective critical micelle concentrations (CMCs). 5-MeO-DMT and tilianin were added at varying molar ratios of 0:0, 2:0, 2:0.1 , and 2:1. The mixture was subjected to rotary evaporation in a BUCHI Rotavapor R-300 (Flawil, Switzerland) until a thin, uniform film formed at the bottom of the roundbottom flask. To eliminate any residual organic solvents, the flask was either placed under high vacuum for 15 minutes or left at room temperature overnight. The dried film was then hydrated with HPLC-grade water at 67 °C for 1 or 2 hours under vigorous stirring. Thin-film hydration typically produces large, heterogeneous, multilamellar niosomes. Therefore, additional processing steps are required to homogenise the dispersion and reduce vesicle size. To achieve this, shear mixing was carried out using an IKA T18 Digital ULTRA-TURRAX® disperser (IKA-Werke GmbH & Co. KG, Staufen, Germany) operating at 9,000 rpm for 60 seconds. Size reduction and homogenisation of multilamellar niosomes were further achieved using a Nano DeBEE high-pressure homogeniser (BEE International, Massachusetts, USA) for 8 cycles at an operating pressure of 15,000 - 30,000 psi using the Z8 nozzle (0.2 mm aperture size), producing smaller, more uniformly distributed vesicles with reduced lamellarity. Following high energy processing, the formulations are filtered using 0.22 pm syringe filters. Directly following, the formulation was stored in the fridge (4 °C) for long term storage.

[0097] To determine particle size distributions in the niosomes, DLS, also known as photon correlation spectroscopy, was applied. This technique generated Z-average diameters of the dispersed lipid phase particles (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 Instruments Ltd., UK). The Z-average diameters of the dispersed phase particles were calculated from the autocorrelation function of the intensity of light scattered from the particles.

[0098] As Table 1 shows, the niosomes form particles with average particle sizes of <100 nm, a narrow range of nanoparticle sizes, and high surface charge that experiences a flip from positively to negatively charged once 5-MeO-DMT is encapsulated within the formulation. We expect that this basic formulation will produce particles having an average particle 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.Stress Tests

[0099] The niosomes of the present invention that were produced upon high-energy processing of the pre-constituted coarse niosomes. The formulations were stress-tested to examine the effect of storage times, heat, freeze / thaw cycles, and chemical additives on particle stability. The results show that the present niosome composition offered high stability in response to these stressors and none of the stressors examined could induce destabilization in the thus created niosomes.

[0100] 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.

[0101] Testing of the niosomes containing 5-MeO-DMT and tilianin proved that the particles are extremely stable even in the presence of highly alkaline and acidic stressors, as well as in the presence of salt, sugars, preservatives, high heat, and extended heating for 24 h and no colloidal destabilization phenomena is observed visually. See Table 2:

[0102] Cytotoxicity evaluation: our tests show a dilution dependent cytotoxicity of niosomes containing 5-MeO-DMT and tilianin. The results determined that the formulation was non-toxic at therapeutic concentrations.Experimental Details - Materials

[0103] All materials were purchased from Sigma Aldrich (St. Louis, MO, USA) unless otherwise stated and used as received. Stearylamine, sorbitan stearate, cholesterol, was purchased from Aaron Chemicals (San Diego, CA, USA). PEG sorbitan monolaurate was purchased from Bio Basic (Markham, ON, Canada). HPLC-grade water (EMD Millipore, Burlington MA, USA) was used in all experiments. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was purchased from Aaron Chemicals (San Diego, CA, USA). 5-MeO-DMT and tilianin were 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+).

[0104] Three different cell lines were used for the cytotoxic evaluation of the tested formulation:

[0105] HEK293: Rat lung cell line (https: / / www.atcc.org / products / crl-1573)

[0106] GBM U87: Glioblastoma cancer cells (https: / / www.atcc.org / products / htb-14)

[0107] HepG2: Liver cancer cells (https: / / www.atcc.org / products / hb-8065) Preparation of the 5-MeO-DMT and tilianin niosomes

[0108] The niosomes were prepared using the thin-film hydration method.Sorbitan stearate, PEG sorbitan monolaurate, cholesterol, and stearylamine were co-dissolved in a 2:1 (v / v) mixture of chloroform and methanol at a molar ratio of 2:2:2:0.4. The final molar concentration of the surfactants was maintained at least 100 times higher than their respective critical micelle concentrations (CMCs). 5-MeO-DMT and tilianin were added at varying molar ratios of 0:0, 2:0, 2:0.1 , and 2:1. The mixture was subjected to rotary evaporation in a BUCHI Rotavapor R-300 (Flawil, Switzerland) until a thin, uniform film formed at the bottom of the roundbottom flask. To eliminate any residual organic solvents, the flask was either placed under high vacuum for 15 minutes or left at room temperature overnight. The dried film was then hydrated with HPLC-grade water at 67 °C for 1 or 2 hours under vigorous stirring. Thin-film hydration typically produces large, heterogeneous,multilamellar niosomes. Therefore, additional processing steps are required to homogenise the dispersion and reduce vesicle size. To achieve this, shear mixing was carried out using an IKA T18 Digital ULTRA-TURRAX® disperser (IKA-Werke GmbH & Co. KG, Staufen, Germany) operating at 9,000 rpm for 60 seconds. Size reduction and homogenisation of multilamellar niosomes were further achieved using a Nano DeBEE high-pressure homogeniser (BEE International, Massachusetts, USA) for 8 cycles at an operating pressure of 15,000 - 30,000 psi using the Z8 nozzle (0.2 mm aperture size), producing smaller, more uniformly distributed vesicles with reduced lamellarity. Following high energy processing, the formulations are filtered using 0.22 pm syringe filters. Directly following, the formulation was stored in the fridge (4 °C) for long term storage.

[0109] Long-term storage: To examine the effect of long-term storage on the colloidal and chemical stability of the niosomes containing 5-MeO-DMT and tilianin, 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. Measurements were performed immediately after high pressure homogenization, and after that, once every seven days for up to 4 months.

[0110] Flash heating: 1 g of the niosome composition was placed in a preheated water bath, and the internal temperature of the formulation was maintained at 80 °C for 1 minute. This protocol is a more extreme version of the high-temperature short-time pasteurization process (typically, 71.5 °C for 15 s) that fruit juices and milk beverages are subjected to in the industry. The formulation was then allowed to cool to room temperature, and a part of it was diluted for DLS study.

[0111] Additives: in a representative experiment, varying masses of CaCl2-2H2O, sucrose, and potassium sorbate were added individually to 1 g portions of the compositions 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 niosomes, given that they are not expected to degrade 5-MeO-DMT in any meaningful way. Any drop in 5-MeO-DMT or tilianin for these experiments may be attributed to colloidal events leading to instability rather than to chemical transformations.

[0112] Cell culture: The human hepatocellular cell line HepG2, and the human embryonic kidney HEK-293 cell lines (ATCC) were cultured in Dulbecco's Modified Eagle's Medium (DMEM, Sigma-Aldrich) supplemented with 10% FBS (Gibco) and 1% penicillin / streptomycin (Sigma-Aldrich) at 37 °C in an incubator humidified with 5% CO2 atmosphere. The human glioblastoma cell line U87 (ATCC) were cultured in Minimal Essential Medium (Sigma-Aldrich) supplemented with 10% fetal bovine serum (Gibco) and 0.5% penicillin / streptomycin (Sigma-Aldrich) at 37°C and 5% CO2-humidified incubator, all three cell lines are adherent and were subcultured twice per week at 70-80% confluency using standard concentrations of trypsin— EDTA (ethylenediaminetetraacetic acid).

[0113] Cell viability was assessed using the MTT, a widely used colorimetric method for evaluating cytotoxicity. MTT is a water-soluble tetrazolium salt that is reduced by mitochondrial dehydrogenase enzymes in metabolically active (viable) cells to form insoluble purple formazan crystals. The amount of formazan produced is directly proportional to the number of living cells. HEK-293, HepG2, and U87 cells were seeded into 96-well plates at densities of 7x103, 6x103, and 6x103cells per well, respectively, and incubated for 24 h at 37 °C allowing them to adhere and proliferate. Negative control and blank wells were included in all experiments. The negative control consisted of untreated cells cultured in complete medium, while blank wells contained culture medium without cells to account for background absorbance. The culture medium was then replaced with 100 pL of fresh medium containing various concentrations of niosome (100, 50, 25, 10, 5, and 1 pM), and the cells were incubated for an additional 24 h. Following treatment, the medium was carefully aspirated and 100 pL of MTT solution (1 mg / mL) was added to each well. The plates were incubated for 4 h at 37 °C in a humidified atmosphere containing 5% CO2. After incubation, the MTT solution was removed, and the resulting formazan crystals were dissolved in 100 pL of dimethyl sulfoxide per well. The absorbance was measured at 570 nm using a microplate reader (SpectraMax M5e, Molecular Devices, USA). Cell viability (%) was calculated relative to untreated control cells using the following formula (OD = optical density):

[0114] 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.Cell viability (Patent Citations

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Claims

1. CLAIMS1. A niosome composition comprising bilayered, non-ionic surfactant vesicles that include: (a) a therapeutic amount of one or more psychedelic agents, (b) a primary nonionic surfactant, and (c) optionally, an inhibitor of a metabolic enzyme pertaining to said one or more psychedelic agents.

2. A niosome composition as in claim 1 wherein said primary nonionic surfactant comprises sorbitan stearate.

3. A niosome composition as in claim 1 further comprising a secondary cosurfactant that comprises PEG sorbitan monolaurate, cholesterol, and / or stearylamine.

4. A niosome composition as in claim 1 further comprising said inhibitor of a metabolic enzyme.

5. A niosome composition as in claim 4, wherein said inhibitor comprises a monoamine oxidase inhibitor.

6. A niosome composition according to claim 5 wherein said monoamine oxidase inhibitor comprises tilianin.

7. A niosome composition according to claim 1 wherein said one or more psychedelic agents comprise 5-MeO-DMT, 4-MeO-DMT, 4-AcO-DMT (4-acetoxy-dimethyltrypamine, LSD, psilocybin, psilocin, mescaline, ibogaine, octanoyl bufotenin, and / or bufotenin.

8. A niosome composition according to claim 7 wherein said one or more psychedelic agents comprises ibogaine, octanoyl bufotenin, or 5-MeO-DMT.

9. A niosome composition according to claim 8 wherein said one or more psychedelic agents comprises 5-MeO-DMT.

10. A niosome composition according to claim 1 having an average particle size that is within a range from about 10 nm to less than 300 nm.

11. A niosome composition according to claim 10 wherein the average particle size is within a range from about 50-250 nm.

12. A niosome composition according to claim 11 wherein the average particle size is within a range from about 30-200 nm.

13. A niosome composition according to claim 1 in liquid form and having a concentration of one or more psychedelic agents in an amount within a range from about 0.1-1000 mg / ml.

14. A niosome composition according to claim 13 comprising a concentration of one or more psychedelic agents in an amount within a range of 1-100 mg / ml.

15. A process for the manufacture of the niosome vesicles by a process that comprises:dissolving: (i) a therapeutic amount of one or more psychedelics, (ii) a primary non-ionic surfactant, (iii) optionally, one or more ionic or non-ionic co-surfactant(s), and (iv) an inhibitor of a metabolic enzyme pertaining to psychedelics in an organic solvent to form a first composition;removing the organic solvent from said first composition to form a thin-film; hydrating said thin film with an aqueous medium to form coarse-sized particles; andprocessing the coarse sized particles with high-shear conditions and microfluidic processing in a microfluidic production device to produce a niosome composition product that contains said one or more psychedelics.

16. A coarse sized particle composition comprising a therapeutic amount of one or more psychedelic agents and one or more surfactants that is made by a process that comprises:(a) dissolving: (i) a therapeutic amount of one or more psychedelics, (ii) a primary non-ionic surfactant, (iii) optionally, one or more ionic or non-ionic cosu rfactant(s), and (iv) an inhibitor of a metabolic enzyme pertaining to psychedelics in an organic solvent to form a first composition;(b) removing the organic solvent from said first composition to form a thin-film, and(c) hydrating said thin film with an aqueous medium to form coarse-sized particles.

17. A composition according to claim 16 wherein said primary surfactant comprises sorbitan stearate.

18. A composition according to claim 16 further comprising a co-surfactant comprising PEG sorbitan monolaurate, cholesterol, and stearylamine.

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