Transdermal systems, formulations, and methods for the therapeutic administration of hallucinogens

Abstract

A drug delivery system is provided for transdermally administering a hallucinogenic active agent to a subject to provide a continuous microdose plasma level of the active agent or its metabolites during an extended drug delivery period. The transdermal drug delivery system includes a drug reservoir containing a formulation including an active agent, a combination of a solubilizer-type permeation enhancer and a plasticizer-type permeation enhancer, and a pH stabilizer. The pH stabilizer causes the pH of the formulation at the system-skin interface and / or within the skin to be within 25% of the pKa of the active agent as the active agent is transported across the skin from the skin surface to the bloodstream. Formulations and methods of use are also provided.

Description

[Technical field]

[0001] Technical Field The present invention relates generally to the use of hallucinogens in medical therapy, and more specifically to the transdermal administration of hallucinogens for the prevention and treatment of various disorders, diseases, and other deleterious conditions. [Background technology]

[0002] background In recent years, there has been much research into the potential therapeutic use of hallucinogens, primarily extracted from mushrooms. Many of the naturally occurring hallucinogens are indoles, such as tryptamines, including 5-hydroxytryptamine (serotonin), and their derivatives. The basic structures of indole and tryptamine are shown below, using a standard numbering system to indicate the substitutable positions on the molecular structure: [ka]

[0003] Of the approximately 600 naturally occurring indole compounds, psilocybin is one of the most studied and has been identified as an attractive and potentially powerful agent in the treatment and management of numerous mental health conditions. Psilocybin has the following molecular structure: [ka]

[0004] The polarity of the phosphate group combined with the presence of the dimethylamino functionality renders the molecule zwitterionic in physiological pH environments. [ka]

[0005] Psilocybin can be found in over 200 species of mushrooms in the genus Psilocybe, including P. azurescens, P. cyanescens, P. cubensis, and P. semilanceata. Although taxonomically these species are all considered members of their respective species (most are P. cubensis), they can vary dramatically in appearance, conditions required for cultivation, and potency. See, for example, Stamets, Psilocybin Mushrooms of the World (Ten Speed ​​Press, 1995). These mushrooms contain many different psychoactive agents, primarily tryptamines, with psilocybin typically being found in the highest concentrations. Levels and ratios of other hallucinogenic compounds (mainly psilocin and baeocystin) vary between species. The rare species P. azurescens is the most powerful of the mushrooms in the Psilocybe genus, as it contains the highest concentrations of psilocybin and psilocin, while P. cubensis is the species commonly referred to as the "magic mushroom."

[0006] The pharmacokinetics, pharmacology, and metabolism of psilocybin in humans are well known and well characterized (see, e.g., Bauer, “The Pharmacology of Psilocybin and Psilocin,” Psychedelic Science Review (March 13, 2019); Passie et al. (2002), “The pharmacology of psilocybin,” Addiction Biology 7(4):357-64; Brown et al. (2017), “Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults,” Clin. Pharmacokinet. 56(12):1543-54; and Dinis-Oliveira (2017), “Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance,” Drub Metab. Rev. 49(1):84-91). Psilocybin has been widely used in Phase 2 clinical trials conducted in academic settings. The major effects of psilocybin and other drugs derived from mushrooms of the Psilocybe genus include changes in perception, emotion, thought, and sense of self, characterized by significant alterations in many (but not all) mental functions, including perception, mood, motivation, cognition, and self-experience. Early clinical studies have established preliminary efficacy in the treatment of obsessive-compulsive disorder (OCD), substance use disorder, depression, and anxiety.

[0007] The clinical safety of psilocybin has been extensively studied as both a monotherapy and adjunctive therapy in adult populations. Psilocybin has been administered via oral and / or intravenous delivery and has been studied in both open-label and double-blind controlled trials; see Usona Institute Investigational New Drug Profile for IND number 129532 (December 17, 2018). In the aforementioned studies, oral dosages ranged from 0.014 mg / kg to 0.6 mg / kg (approximately 1 mg to 40 mg for the average human), and this dosage was administered in a single dose or divided into multiple spaced doses. The effects of psilocybin were shown to be dose-dependent, although other factors such as personality structure and situation appear to alter its overall effect. Most test subjects experience noticeable changes in mood, perception, thinking, and self-experience, but at higher doses, it can produce acute adverse drug reactions characterized by intense dysphoria and / or anxiety / panic.

[0008] Despite the interest of many researchers in the potential pharmaceutical applications of psilocybin, there are numerous obstacles to successfully utilizing psilocybin as a medicine. For example, significant physiological and psychological adverse events can occur when psilocybin is administered orally or intravenously to patients. Oral administration of mushrooms of the genus Psilocybe can, for example, cause severe gastrointestinal disorders; see Bauer (2019), supra. With regard to psychological side effects, psilocybin is well known to lead to paranoia, panic, and psychosis at high doses in some individuals. There are also several other safety-related issues.

[0009] Furthermore, when psilocybin is administered orally or intravenously, it must be converted to its active metabolite (the 4-hydroxy analog of psilocybin (psilocin)) in the brain to achieve the desired therapeutic effect; zwitterionic psilocybin is highly soluble in water and cannot cross the blood-brain barrier or other physiological membranes. In contrast to psilocybin, psilocin can cross the blood-brain barrier. It has been confirmed that the effects of psilocybin on the CNS are only observed after its conversion to psilocin (see, for example, Horita and Weber, ``Dephosphorylation of psilocybin in the intact mouse,'' Toxicology and Applied Pharmacology 4(6):730-737). Thus, psilocybin is a prodrug of the active molecular form, psilocin. [ka]

[0010] Alkaline phosphatase (ALP) is the primary enzyme that dephosphorylates psilocybin (a rapid reaction that occurs in the intestinal mucosa). Other phosphatases dephosphorylate psilocybin in the intestine, kidney, and blood. However, ALP concentrations vary dramatically from patient to patient depending on age, underlying medical conditions, and / or ongoing medical treatments (e.g., chemotherapy). Due to the variability in ALP concentrations, the resulting psilocin concentrations will also vary. Thus, administration of psilocybin by others has resulted in unpredictable and inconsistent therapeutic effects, as well as potentially dangerous side effects as described above.

[0011] Although some researchers have suggested that oral administration of psilocybin is safe, users have reported unwanted systemic reactions and other adverse events as mentioned above; the most important adverse event is an unwanted "bad trip" experience (i.e., unpleasant psychotropic effects). This can occur when the dosage and / or the patient's ALP concentration are very high. Another frequently underdiscussed severe pathological condition is the serotonin (5-HT) syndrome (SS, serotonin toxicity or hyperserotonemia), which results from excessive serotonergic activity in the brain. SS is one of the most important neurotoxicity syndromes and generally develops due to an overdose of serotonergic antidepressants or an interaction between several serotonergic drugs. Depending on the degree of toxicity, SS manifests clinically as three characteristic symptoms: neuromuscular, autonomic, and psychiatric symptoms, which range from mild to fatal and can develop rapidly within a few hours of drug administration. Early symptoms of SS typically include tachycardia, trembling, diaphoresis, dilated pupils, tremor, and hyperreflexia. As serotonin toxicity progresses to mild to moderate severity, hypertension, fever, and mental status changes, including confusion, hypomania, anxiety, and agitation, occur. Finally, severe cases of SS include muscular rigidity, hypertonia, hyperpyrexia, seizures, and coma.

[0012] Alternative parenteral routes of administration may be considered to address the aforementioned limitations, with the transdermal route being of particular interest insofar as it seeks to administer low doses of the drug continuously to avoid known adverse effects. It would avoid the GI system so that GI side effects are avoided, and would also avoid the psychological and neurological side effects associated with higher doses and / or higher patient ALP concentrations. However, psilocybin cannot pass through the skin. Furthermore, since the active metabolite, psilocin, is a polar molecule with charges localized on the hydroxyl and amino functional groups, it would also be expected to be a poor candidate for transdermal administration. It is well known in the transdermal drug delivery field that charged molecules (which may be zwitterions, cations or anions associated with counterions, or polar molecules with localized charges) tend not to pass through the skin. Thus, charged molecules are generally not considered candidates for transdermal administration. See, for example, Tanwar et al. (2016), ''Transdermal Drug Delivery: A Review,'' Int. J. Pharm Sci Res 7(6):2274-90. Thus, there is a need in the art for methods by which hallucinogens such as psilocin can be administered, after which such compounds can be safely and effectively administered to patients in a therapeutic setting. The present invention addresses the aforementioned need in the art. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Tanwar et al., Int. J. Pharm Sci Res (2016) 7(6):2274~90 Summary of the Invention [Means for solving the problem]

[0014] Summary of the Invention Psilocybin (zwitterion), as explained above, cannot cross the blood-brain barrier to achieve a therapeutic effect in the brain. The same can be said about the transdermal administration possibility of psilocybin, insofar as charged drugs show little or no skin permeability. One would similarly assume that psilocin, being small and with a charge localized on the 4-hydroxyl group and typically with an electron transfer on the nitrogen atom, would not be a candidate for transdermal drug delivery. However, to one's surprise, it has now been found that psilocin is not only a viable candidate for transdermal drug delivery, but can actually pass through the stratum corneum and upper layers of the skin, and thus can be administered transdermally to achieve the desired therapeutic effect.

[0015] The transdermal delivery of psilocin and other hallucinogens described herein and in the claims allows for controlled blood concentration levels, thereby achieving therapeutic effects while avoiding the "peaks and valleys" of the concentration profile, where high "peaks" may be associated with "bad trip" experiences, and "valleys" indicate no treatment at all. Furthermore, if cessation of treatment is indicated as a result of undesirable side effects, the transdermal system can be removed to immediately stop delivery, whereas oral products cannot be removed once administered, or injections cannot be undone. Additionally, the transdermal drug delivery provided herein avoids the gastrointestinal tract, thus avoiding unexpected effects due to variable alkaline phosphatase levels. This is particularly important in the treatment of children or the elderly, who may be seriously affected by high drug concentrations.

[0016] The present invention provides systems, methods, and formulations for transdermal administration of psilocin and other hallucinogens that avoid undesirable side effects when administered via oral or intravenous routes, provided that continuous delivery of subthreshold doses (also referred to in the art as "microdosing") of the hallucinogen is achieved by transdermal administration as provided herein. By providing psychedelic microdosing throughout the transdermal drug delivery period, the present invention is useful in any method in which hallucinogen microdosing provides a desired therapeutic or other effect, such as improved creativity, increased energy levels, stabilization of mood, and treatment of anxiety, depression, addiction, and other conditions.

[0017] Hallucinogens include, but are not limited to, serotonergic hallucinogens (eg, indolealkylamine compounds such as psilocin).

[0018] In one embodiment, then, the present invention provides a drug delivery system for transdermal administration of a hallucinogenically active agent to a subject through a localized area of ​​the subject's skin. The system has an outer surface and a bottom surface, and includes:

[0019] (a) a drug reservoir containing a formulation comprising:

[0020] (i) about 0.5% to about 40% by weight of a hallucinogenic active agent having a known pKa;

[0021] (ii) an enhancer composition comprising a skin permeation-enhancing effective amount of a combination of a solvent-type enhancer and a lipid-disrupting enhancer; and

[0022] (iii) a pH-adjusting effective amount of a pH adjusting agent that maintains the pH in said localized region within 25% of said pKa; and

[0023] (b) a backing layer, which may or may not be substantially impermeable to the formulation, and which serves as the exterior surface of the system during drug administration.

[0024] The system also includes a means for affixing the system to the skin, where the backing layer can be a skin contact adhesive that serves that purpose, or an additional element, such as a layer of skin contact adhesive (e.g., a rim), is laminated to the drug reservoir and serves to affix the system to the subject's skin during drug administration.

[0025] In one aspect of the embodiment, the hallucinogenic active agent is a polar and / or ionizable molecule, and the pH adjusting agent is selected to maintain the pH in the localized region within 15% of the pKa, and in some embodiments to maintain the pH close to the pKa of the active agent. The pH adjusting agent may be present in the drug reservoir if the formulation includes a liquid vehicle that is at least partially aqueous, or the active agent may be present in a water-containing layer of the skin where it is transported to the bloodstream, or both.

[0026] In another embodiment, the transdermal drug delivery system comprises a single layer adhesive system in which the drug reservoir is comprised of a skin contact adhesive that serves to affix the system to the skin in addition to containing the active agent formulation. The system includes a removable release liner that protects the bottom surface of the system during storage and prior to drug delivery.

[0027] In a further embodiment, the transdermal drug delivery system comprises an integral matrix system, where the drug reservoir again comprises a polymer matrix, but again does not serve as the means for affixing the system to the skin. Rather, a separate skin-contacting adhesive layer is laminated to the skin side of the drug reservoir.

[0028] In another embodiment, the drug reservoir comprises a sealed pouch that contains the formulation containing the active agent such that the system is a liquid reservoir system. In one design, the reservoir is placed between an outer backing layer and a heat-sealed membrane, where the heat-sealed membrane is laminated to a skin-contacting adhesive layer for attaching the system to the skin. The membrane can be selected to control the release rate of the drug from the system, the release rate of the enhancer from the system, or both. In another design, a microporous non-adhesive reservoir is used instead of the pouch in the previous embodiment, and the reservoir is directly contacted to the skin. A skin-contacting adhesive layer is incorporated between the outer backing layer and the microporous reservoir. To facilitate adhesion to the skin, the surface area of ​​the microporous reservoir is smaller than that of the skin-contacting adhesive layer, so that the skin-contacting adhesive layer extends beyond the outer edge of the reservoir, leaving uncovered (i.e., exposed) adhesive areas available for attaching the system to the skin.

[0029] In another embodiment, the formulation in the drug reservoir additionally comprises at least one excipient selected from a viscosity modifier, an emulsifier, a solubilizer, a preservative, an opacifier, a colorant, a flavoring, and a mild additive. An excipient of particular interest is a stabilizer for the formulation, which may be a stabilizer for the active agent, such as ascorbic acid or an ascorbate salt.

[0030] In further embodiments, the transdermal delivery system provides sustained release of the active agent over an extended drug delivery period ranging from about 6 hours to about 84 hours (e.g., from about 8 hours to about 24 hours).

[0031] In still further embodiments, the hallucinogen is present in an amount effective to provide a blood level in the range of 0.5 ng / ml to about 5.0 ng / ml during the extended drug delivery period.

[0032] In another embodiment, there is provided a drug delivery system for transdermal administration of psilocin to a localized region of the skin of a subject, said system having an outer surface and a bottom surface, comprising:

[0033] (a) a drug reservoir containing a formulation comprising:

[0034] (i) about 0.5% by weight to about 40% by weight of psilocin;

[0035] (ii) a buffering agent in an amount to adjust / maintain a pH in the range of 7.20 to 9.74 in the local region; and

[0036] (iii) 0.5% to 15% by weight of a monoamine oxidase inhibitor; and

[0037] (b) a backing layer that serves as the outer surface of the aforementioned system during drug administration; where

[0038] (c) the drug reservoir is comprised of a skin contact adhesive that serves as a means for attaching the system to the skin of the subject; or

[0039] (d) A layer of skin contact adhesive material is laminated to said drug reservoir and serves as a means for affixing said system to the skin of said subject.

[0040] In one aspect of the embodiment, the formulation additionally comprises an active agent stabilizer (including an oxygen scavenger) to protect the psilocin from oxygen-induced degradation and / or oxygen-induced reactions during storage and prior to drug delivery. The active agent stabilizer may be ascorbic acid or an ascorbate salt, and typically comprises about 0.5% to about 15% by weight of the formulation.

[0041] In another aspect of the embodiment, the pH adjusting agent is selected to change the pH in the localized region of the active agent to approximate the pKa of psilocin, which is 8.47. If the psilocin formulation includes a liquid vehicle that is at least partially aqueous, or the psilocin may reside in a water-containing layer of the skin after it is released into the skin, or both, the localized region of psilocin may reside in a drug reservoir.

[0042] In a further embodiment, the present invention provides a drug delivery system for transdermal administration of psilocin to a subject through a localized area of ​​the subject's skin, said system having an outer surface and a bottom surface, comprising:

[0043] (a) a drug reservoir containing a formulation comprising:

[0044] (i) 2.5% by weight to 25% by weight of psilocin;

[0045] (ii) 1.0% to 15% by weight of sodium bicarbonate;

[0046] (iii) 1.0% to 15% by weight of ascorbic acid, and

[0047] (iv) 1.0% to 15% by weight of a monoamine oxidase inhibitor; and

[0048] (b) a backing layer that serves as the outer surface of the aforementioned system during drug administration; where

[0049] (c) the drug reservoir is comprised of a skin contact adhesive that serves as a means for attaching the system to the skin of the subject; or

[0050] (d) A layer of skin contact adhesive material is laminated to said drug reservoir and serves as a means for affixing said system to the skin of said subject.

[0051] In aspects of the foregoing embodiments, the transdermal system used to administer the hallucinogen to the subject can provide a total flux of active agent J released from the system across the skin. T is obtained, and the total flux J T is the system flux, i.e., the patch flux (J P ) is primarily determined by

[0052] In another embodiment, the transdermal delivery system is a patch Flux JP The active agent is released through the skin flux J S are transported across the skin by J S :J P The ratio ranges from about 2:1 to about 100:1.

[0053] In another embodiment, a modular transdermal drug delivery system is used to deliver the hallucinogenically active agent in the aforementioned formulation, where the components of the system are similar to those described in U.S. Patent Application Publication No. 2020 / 0268681 A1 to Kochinke, which is incorporated herein by reference.

[0054] In another embodiment, the invention provides a method of administering a hallucinogen to a subject by applying any of the transdermal systems of the aforementioned formulations to a localized area of ​​the subject's skin and allowing the system to remain in place throughout the extended drug delivery period.

[0055] In one aspect of the embodiment, the hallucinogenically active agent is administered to the subject at continuous microdosing levels.

[0056] Administering a hallucinogenically active agent to a subject at continuous microdosing levels using the transdermal system of the present invention.

[0057] In a further embodiment, the present invention provides a method of administering a hallucinogenically active agent to a subject at continuous microdosing levels using the formulations of the present invention.

[0058] In a further embodiment, the present invention provides a method of administering a hallucinogen to a subject to provide a desired beneficial effect by transdermally administering the hallucinogen using the transdermal system of the present invention.

[0059] In another embodiment, the present invention provides a method of administering a hallucinogen to a subject to provide a desired beneficial effect by transdermally administering the hallucinogen using the formulations of the present invention.

[0060] In aspects of the foregoing embodiments, the desired beneficial effect is a therapeutic effect.

[0061] In another embodiment, neocortical 5-HT 2A A method is provided for administering a hallucinogen to a subject to increase receptor occupancy to a desired level, the method comprising the steps of:

[0062] 5-HT throughout the drug delivery period 2A Administering a hallucinogen transdermally to a subject in a manner effective to provide a plasma level of said agent or a metabolite thereof corresponding to a desired level of receptor occupancy.

[0063] In one aspect of the embodiment, the hallucinogen is administered to the subject by applying a transdermal drug delivery system to the skin of the subject, wherein the drug delivery system is a patch Flux J. P The active agent is released through the skin flux J S are transported across the skin by J S :J P The ratio ranges from about 2:1 to about 100:1.

[0064] In another aspect of the embodiment, the skin flux J of the drug across the skin is S Rather, the patch flux of drug released by the system J P The total flux J is mainly determined by T administering a hallucinogen to the subject by applying a transdermal drug delivery system to the skin of the subject so as to provide

[0065] wherein the system comprises an effective amount of a hallucinogen; a skin permeation enhancing effective amount of a combination of a solvent-type enhancer and a lipid disrupting enhancer; and a pH adjuster.

[0066] Additional objects, advantages and salient features of the illustrative embodiments of the invention will become apparent to those skilled in the art from the following description. [Brief description of the drawings]

[0067] [Figure 1] FIG. 1 shows a schematic comparison of the plasma concentration profile of an active agent or its metabolites delivered via macrodose delivery to that observed with microdose delivery.

[0068] [Diagram 2] FIG. 2 shows a schematic of a simple adhesive system for transdermal administration of an active agent of the present invention.

[0069] [Diagram 3] FIG. 3 illustrates a schematic of an integrated matrix system for transdermal delivery of an active agent of the present invention.

[0070] [Figure 4] FIG. 4 shows a schematic of a fluid reservoir system for transdermal administration of an active agent of the present invention, in which the fluid reservoir comprises a cavity enclosed by a heat-sealed membrane and an airtight outer backing layer.

[0071] [Diagram 5] FIG. 5 shows a schematic of a liquid reservoir system for transdermal administration of an active agent of the present invention, in which a microporous reservoir is loaded with a formulation containing the active agent to be delivered.

[0072] [Figure 6] FIG. 6 is a graph showing the cumulative mass released over time from the transdermal psilocin systems prepared in Examples 2 and 3.

[0073] [Figure 7] FIG. 7 is a graph showing skin flux over time obtained using the transdermal psilocin systems prepared in Examples 2 and 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] Detailed Description of the Invention 1. Definitions and Terminology:

[0075] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. Specific terms of particular importance for describing the present invention are defined below.

[0076] Unless otherwise clear from the context, in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural. Thus, for example, reference to a "pharmacologically active agent" or simply "active agent" includes a single such agent, as well as two or more such agents; a "pharmacologically acceptable carrier" refers to a combination of pharma- ceutical acceptable carriers, as well as a single pharma- ceutical acceptable carrier; a "formulation" and a "vehicle" include two or more formulations and vehicles, respectively, and so forth.

[0077] The term "active agent" refers to any compound, complex, or composition that exhibits a desired pharmacological, physiological, psychoactive, or other beneficial effect. For example, in certain embodiments, the active agent may be a pharmacologically active agent that exerts a therapeutic effect in the treatment of an adverse physiological condition. The term also includes, for example, an agent that interacts with the body or a part of the body to obtain a desired condition. It should also be understood that in certain embodiments, the active agent need not be a pharmacologically active agent or have a pharmaceutical effect, as long as the effect that the active agent has is believed to be beneficial to the subject to whom the active agent is administered.

[0078] When referring to an active agent, whether specific to a particular compound (e.g., psilocin) or class of compounds (e.g., hallucinogens), the terms used to refer to such agents are intended to include not only the specific molecular entity, but also its pharma- ceutically acceptable, pharmacologically active analogs and derivatives, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, hydrates, crystalline forms, enantiomers, stereoisomers, and other such derivatives, analogs, and related compounds.

[0079] A "hallucinogenic" active agent, as the term is used herein, refers to a pharmacologically active agent that tends to produce alterations in the subject's perception, emotions, cognition, and motivation, and that may cause hallucinogenic effects at high doses. With the present invention, hallucinogenic effects and other adverse effects are avoided without compromising therapeutic efficacy. The hallucinogenic active agent administered herein increases brain entropy within or slightly beyond the critical range defined by Carhart-Harris (2018), "The Entropic Brain-Revisited," Neuropharmacology 142:167-178.

[0080] By "transdermal" delivery, applicant intends to include both transdermal (or "percutaneous") administration and transmucosal administration (i.e., delivery in which a pharmacologically active agent passes through the skin or mucosal tissue into the bloodstream, thereby providing a systemic effect). "Topical" delivery generally refers to delivery of an active agent to the skin surface, and thus to the topmost region of the skin, where the agent does not penetrate into the bloodstream, resulting in a local rather than a systemic effect. Although the systems of the present invention are applied "topically" insofar as they are applied to a body surface, depending on the active agent and the components of the formulation that includes the active agent (such as one or more permeation enhancers), drug delivery can be either transdermal or topical, and thus either systemic or topical, although systemic drug delivery is generally preferred herein. Thus, unless otherwise specified herein, reference to a "transdermal system" includes a system that can be used for either transdermal or topical delivery, and reference to "transdermal delivery" includes methods that can be adapted for either transdermal or topical drug administration.

[0081] As used herein, the terms "treating," "treatment," and "therapeutic" refer to the administration of a pharmaceutical agent or composition to a subject to obtain a desired pharmacological or physiological effect, and thus include administration for therapeutic and / or prophylactic purposes. Treatment of a condition in a subject already suffering from the condition generally includes reducing the severity, number, and / or frequency of symptoms, eliminating the symptoms and / or underlying causes, and ameliorating or correcting damage. In the context of prophylaxis, treatment refers to the administration of a pharmaceutical agent or composition to a subject who does not yet suffer from a particular condition but has been identified as suspected of (i.e., at risk of developing) a particular condition, where the prophylactic effect includes partial or complete prevention of the condition or its symptoms.

[0082] The terms "effective amount," "therapeutically effective amount," and "therapeutically effective concentration" of an active agent, combination of active agents, or pharmaceutical formulation refer to a nontoxic but sufficient amount or concentration to obtain the desired result. The exact amount required will vary from subject to subject, depending on factors such as the age, weight, and general health of the subject, the particular condition being treated, the severity of the condition, the particular active agent, and, of course, the judgment of the physician.

[0083] The effective amount of the hallucinogenic active agent in the systems and formulations of the present invention is such that a "microdose" of the active agent is administered to the subject over a prolonged drug delivery period. The term "microdose" herein, referring to a preferred dose of the hallucinogen, refers to a dose less than a "macrodose" (i.e., a dose that produces a hallucinogenic experience), generally being at most about 20%, or at most about 15%, or at most about 10% of a macrodose. Generally, but not necessarily, a microdose is less than a threshold dose (meaning the lowest dose at which a subject experiences mental and / or physical changes caused by a psychoactive agent). Depending on the particular active agent used, a microdose can be less than 100 mg, less than 75 mg, less than 50 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 500 μg, less than 250 μg, less than 200 μg, less than 150 μg, less than 100 μg, less than 50 μg, less than 25 μg, and less than 20 μg, etc.

[0084] "Pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable (i.e., the material may be incorporated into the pharmaceutical compositions provided herein and does not cause any substantial undesirable biological effects or interact in a deleterious manner with any other components of the composition). When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it means that the carrier or excipient has met the required standards of toxicological and manufacturing testing, and / or has been included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration and has received "Generally Recognized as Safe" ("GRAS") status.

[0085] As used herein, "subject" or "individual" or "patient" refers to any subject desiring treatment, and generally refers to the recipient of the treatment to be administered according to the present invention.

[0086] "Drug delivery period" refers to the period during which an active agent is delivered from a transdermal system or formulation to the skin of a subject, and is generally an extended period ranging from about 6 hours to about 84 hours (e.g., about 8 hours to about 24 hours).

[0087] "Optional" or "optionally present," as in "optional additive" or "optionally present additive," means that the subsequently described component (e.g., additive) may or may not be present, such that the description includes the component when it is present and when it is not.

[0088] The term "substantially" indicates the possibility of slight deviations from the recited chemical or physical properties, allowing for differences of up to about 20%, or up to about 10%, or up to about 5% between the actual chemical or physical properties and the recited chemical or physical properties. The term "substantially homogeneous" refers to a material in the form of a mixture of two or more components that is substantially homogeneous throughout the material, for example, where any two discontinuous regions within the material differ by up to about 20%, or up to about 10%, or up to about 5% with respect to the chemical or physical properties of the material (such as the presence or absence of the component, particle size, concentration of the component, degree of hydrophilicity or lipophilicity, density, or crystallinity).

[0089] Similarly, the terms "approximately" and "about" are intended, in any context, to mean a possibility of variation of up to about 20%. Generally, the term means a possibility of variation of up to about 10%, or up to about 5%.

[0090] Chemical Substituents and Compound Terminology:

[0091] As used herein, the phrase "having a structure" is not intended to be limiting and is used in the same manner as the term "comprising" is generally used.

[0092] The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group typically, but not necessarily, containing 1 to about 24 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, and decyl, as well as cycloalkyl groups such as cyclopentyl and cyclohexyl). Generally, but also not necessarily, alkyl groups herein contain 1 to about 18 carbon atoms, preferably 1 to about 12 carbon atoms. The term "lower alkyl" contemplates alkyl groups of 1 to 6 carbon atoms. Preferred lower alkyl substituents contain 1 to 3 carbon atoms, with particularly preferred such substituents containing 1 or 2 carbon atoms (i.e., methyl and ethyl). "Substituted alkyl" refers to an alkyl substituted with one or more substituents, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl in which at least one carbon atom is replaced with a heteroatom, as further detailed below. Unless otherwise indicated, the terms "alkyl" and "lower alkyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

[0093] The term "aryl" as used herein, unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused to each other, directly linked, or indirectly linked (such as different aromatic rings are bonded to a common group such as a methylene or ethylene moiety). Preferred aryl groups contain 5 to 24 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms. Examples of aryl groups contain one aromatic ring or two fused or linked aromatic rings (e.g., phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, and benzophenone). "Substituted aryl" refers to an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to an aryl substituent in which at least one carbon atom is replaced with a heteroatom, as further detailed below. Unless otherwise specified, the term "aryl" includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

[0094] The term "cyclic" refers to an alicyclic or aromatic substituent which may or may not be substituted and / or which may or may not contain heteroatoms and which may be monocyclic, bicyclic, or polycyclic.

[0095] The term "alicyclic" is used in the conventional sense to refer to aliphatic, as opposed to aromatic, cyclic moieties, which may be monocyclic, bicyclic, or polycyclic.

[0096] The term "heteroatom-containing," as in "heteroatom-containing alkyl group" (also referred to as "heteroalkyl" group) or "heteroatom-containing aryl group" (also referred to as "heteroaryl" group), refers to a molecule, linkage, or substituent in which one or more carbon atoms are replaced with an atom other than carbon (e.g., nitrogen, oxygen, sulfur, phosphorus, silicon, or selenium, typically nitrogen, selenium, oxygen, or sulfur, preferably nitrogen or selenium, or both nitrogen and selenium). Similarly, the term "heteroalkyl" refers to an alkyl substituent that contains a heteroatom, the term "heterocyclic" refers to a cyclic substituent that contains a heteroatom, the terms "heteroaryl" and "heteroaromatic" refer to "aryl" and "aromatic" substituents that contain heteroatoms, respectively, and the like. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, and N-alkylated aminoalkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, and the like; examples of alicyclic groups containing heteroatoms are pyrrolidino, morpholino, piperazino, piperidino, and the like.

[0097] "Hydrocarbyl" refers to monovalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, more preferably 1 to about 18 carbon atoms, and most preferably about 1 to 12 carbon atoms, including straight-chain, branched-chain, cyclic, saturated, and unsaturated species such as alkyl, alkenyl, and aryl groups. "Substituted hydrocarbyl" refers to a hydrocarbyl substituted with one or more substituents, and the term "heteroatom-containing hydrocarbyl" refers to a hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term "hydrocarbyl" should be interpreted to include hydrocarbyl moieties that are substituted and / or contain heteroatoms.

[0098] "Substituted," as in "substituted alkyl," "substituted aryl," "substituted hydrocarbyl," and the like, as implied by some of the above definitions, means that at least one hydrogen atom bonded to a carbon (or other) atom in an alkyl, aryl, or other moiety has been replaced with one or more non-hydrogen substituents. Examples of such substituents include additional hydrocarbyl groups (e.g., C1-C 24 Hydrocarbyl, C1-C 12 hydrocarbyl, C1-C8 hydrocarbyl, and C1-C6 hydrocarbyl); functional groups such as halo, hydroxyl, sulfhydryl, C1-C 24 Alkoxy, C2-C 24 Alkenyloxy, C2-C 24 Alkynyloxy, C5-C 24 Aryloxy, acyl (C2-C 24 Alkylcarbonyl (-CO-alkyl) and C6-C 24 Arylcarbonyl (-CO-aryl), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C6-C 24 Aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X (wherein X is halo), C2-C 24 Alkylcarbonate (-O-(CO)-O-alkyl), C6-C 24 Arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)-NH2), mono-(C1-C 24 Alkyl) substituted carbamoyl (-(CO)-NH(alkyl)), di-(C1-C 24 Alkyl) substituted carbamoyl (-(CO)-N(C1-C 24 Alkyl)2), mono-(C6-C 24 aryl) substituted carbamoyl (-(CO)-NH-aryl), di-(C6-C 24 aryl) substituted carbamoyl (-(CO)-N(aryl)2), di-N-(alkyl), N-(C6-C 24aryl) substituted carbamoyl, thiocarbamoyl (-(CS)-NH2), carbamide (-NH-(CO)-NH2), cyano (-C≡N), isocyano (-N+≡C - -), cyanate (-OC≡N), isocyanate (-O-N+≡C - -), isothiocyanato (-SC≡N), azido (-N=N + ≡N - ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH2), mono-(alkyl)-substituted amino, di-(alkyl)-substituted amino, mono-(C5-C 24 Aryl)-substituted amino, di-(C5-C 24 Aryl)-substituted amino, C2-C 24 Alkylamide (-NH-(CO)-alkyl), C6~C 24 Arylamide (-NH-(CO)-aryl), imino (-CR=NH, where R=hydrogen, alkyl, C5-C 24 Aryl, C6-C 24 Alkaryl, C6~C 24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, C1-C 24 Alkyl, C5-C 24 Aryl, C6-C 24 Alkaryl, C6~C 24 aralkyl, arylimino (-CR=N(aryl), where R=hydrogen, C1-C 24 Alkyl, C5-C 24 Aryl, C6-C 24 Alkaryl, C6~C 24 aralkyl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1~C 24 Alkylsulfanyl (-S-alkyl; also known as "alkylthio"), arylsulfanyl (-S-aryl; also known as "arylthio"), C1-C 24 Alkylsulfinyl (-(SO)-alkyl), C5-C 24 Arylsulfinyl (-(SO)-aryl), C1-C 24 Alkylsulfonyl (-SO2-alkyl), C5~C24 Arylsulfonyl (-SO2-aryl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), and phosphino (-PH2); and hydrocarbyl moieties C1-C 24 Alkyl (preferably C1-C 18 Alkyl, more preferably C1-C 12 alkyl, most preferably C1-C6 alkyl), C2-C 24 Alkenyl (preferably C2-C 18 Alkenyl, more preferably C2-C 12 alkenyl, most preferably C2-C6 alkenyl), C2-C 24 Alkynyl (preferably C2-C 18 Alkynyl, more preferably C2-C 12 alkynyl, most preferably C2-C6 alkynyl), C5-C 24 Aryl (preferably C5-C 14 Aryl), C6~C 24 Alkaryl (preferably C6-C 18 Alkaryl), and C6-C 24 Aralkyl (preferably C6-C 18 aralkyl).

[0099] Additionally, the aforementioned functional groups may be further substituted, where a particular group permits, with one or more additional functional groups or one or more hydrocarbyl moieties (such as those specifically listed above). Similarly, the aforementioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties (such as those specifically listed above).

[0100] When the term "substituted" precedes a list of possible substituents, it is intended that the term apply to every member of said group. For example, the phrase "substituted alkyl, alkenyl, and aryl" should be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl." Similarly, when the term "heteroatom-containing" precedes a list of possible heteroatom-containing groups, it is intended that the term apply to every member of said group. For example, the phrase "heteroatom-containing alkyl, alkenyl, and aryl" should be interpreted as "heteroatom-containing alkyl, substituted alkenyl, and substituted aryl."

[0101] 2. Overview:

[0102] Transdermal administration of pharmacologically active agents is a convenient route of administration for a variety of indications. As previously explained, delivery of active agents via the transdermal route allows for continuous entry of therapeutic agents into the systemic circulation, eliminating the pulsatile administration peaks that are problematic for many drugs, particularly hallucinogens.

[0103] The transdermal absorption process has been described as follows: "When a drug system is applied superficially, the drug passively diffuses from its carrier or vehicle into the superficial tissues of the skin, specifically and most importantly the stratum corneum and the sebum-filled pilosebaceous ducts. Net mass transfer continues through the entire thickness of the stratum corneum and ducts into the viable epidermis and dermal strata. Thus, a concentration gradient is established across the skin, which essentially terminates at the outer extent of the skin's microcirculation in the dermal layer. The systemic circulation acts as a "sink" for the drug, maintaining the drug at a concentration near zero at the plane where it reaches the capillaries and is diluted into the systemic system. Once the drug enters the systemic circulation, it is distributed very rapidly, providing a reasonable rate of systemic metabolism and excretion (i.e., there is generally systemic accumulation). Thus, some drugs may have relatively high epidermal concentrations due to the fact that the epidermis does not have a direct blood supply and the concentration gradient from the outer surface to the microcirculation is directly across the epidermis. ” Flynn et al., Eds., Modern Pharmacokinetics (Marcel Dekker, 1979) at p.263.

[0104] In order to deliver therapeutic agents through the skin so that systemic effects are achieved, the morphological and physicochemical properties of the skin must be considered.Skin is highly impermeable to most molecules based on molecular size, hydrophilicity, lipophilicity, and charge.For example, large molecules are difficult to administer transdermally, and as mentioned above, polar and charged molecules do not pass through the skin, so they are not considered to be the best candidates for transdermal delivery.

[0105] For the reasons mentioned above, various techniques are adopted to promote the passage of active agents through the skin for systemic delivery.One approach that is widely used and adopted herein is the use of chemical permeation enhancers to promote the permeation of drugs across the skin by increasing the partition of drugs into the barrier domain of the stratum corneum.Penetration enhancers have several mechanisms of action, such as increasing the disruption of the bilayer and intercellular lipids of the stratum corneum and increasing the wetting of the stratum corneum to improve the solubility of certain drugs.In the case of polar charged drugs, electrical enhancement techniques (including iontophoresis and electroporation) are used; passive transdermal delivery using chemical enhancers has not achieved optimal results.

[0106] In one embodiment, the present invention provides systems, formulations, and methods for transdermal administration of hallucinogens (such as ionizable, ionized, and / or polar molecules), in which the aforementioned agents are combined with pH adjusters, combinations of two enhancers, stabilizers, and, if necessary, pharma- ceutically acceptable liquid vehicles. Although many hallucinogens have undesirable side effects when administered via oral or intravenous routes, the aforementioned hallucinogens can be administered according to the present invention without significant adverse effects, so long as continuous delivery of subthreshold doses (also referred to in the art as "microdoses") of the hallucinogen is achieved by the transdermal administration provided herein. In the transdermal context, achieving microdosing delivery is done by ensuring that blood concentrations of the active agent are maintained below a predefined upper limit above which adverse effects may occur. This is primarily ensured by the amount of drug incorporated into the system, i.e., the drug loading level, and the selection of both the system and formulation components. Ideally, the total input flux of drug through the skin from the system into the bloodstream, J, is 100%. T is controlled primarily by the patch and not the skin: the present invention provides a much smaller flux from the patch than the skin can absorb (i.e., the patch controls the delivery of the drug to the skin and the skin has only a small effect on the permeation resistance).

[0107] J T is (J P xJ S ) / (J P +J S ) where J P is the flux of drug from the transdermal system or "patch" (into water), and J S is the flux of the drug across the skin, where flux will be understood to be the release rate (from the system) or transport rate (through the skin) per unit area. The following example will clarify the concept.

[0108] (1)J P =10J S →J T =(10J S xJ S ) / (11J S )=10 / 11 J S ~J S (Skin - Controlled Release)

[0109] (2)J S =10J P →J T =(10J P xJ P ) / (11C)=10 / 11J P ~J P (System-Controlled Release)

[0110] Equation 2 is J S But, for example, J P If J is 10 times T is approximately J P Conversely, if the flux from the system is much greater than the skin can absorb, the total input rate into the bloodstream is determined by the skin. Equation 1 shows that J P J S If it is much larger (say, 10 times) than T ~J SIt is shown that. A preferred patch controlled delivery is achieved by (a) increasing the permeability of the skin and (b) utilizing a polymer barrier to control the delivery flux from the system to the skin. This delivery is then achieved by the selection of a barrier or control membrane of the liquid reservoir system that is heat sealable to the backing material and has a preferred permeability to the enhancer and / or drug. For example, if the solvent-enhancement flux determines the drug flux through the skin, an ethylene-vinyl acetate membrane with the appropriate vinyl acetate content and thickness can be selected to construct the liquid-reservoir system. For example, ALZA / Ciba Geigy's Estraderm® uses this ethanol flux control to regulate estradiol flux into the body. If the membrane has the desired permeability to ethanol but too much permeation resistance to the drug, the drug can be incorporated into the adhesive layer. The adhesive layer can be selected to provide little or no resistance to the drug transport and / or solvent enhancer. If the adhesive layer provides resistance to the solvent flux, the membrane characteristics must be tailored to provide low permeation resistance. The adhesive layer may also contain plasticizer-type skin permeation enhancers, which may not be able to penetrate the membrane at the desired rate. These plasticizer-type skin permeation enhancers have a dual function such that they can be used to adjust the tack and cohesive properties of the pressure sensitive adhesive.

[0111] The transdermal system of the present invention includes a formulation in which the active agent is included in a "therapeutically effective" amount (i.e., an amount effective to achieve its intended purpose). This means that during the drug delivery period, the active agent is released from the transdermal system, enters and passes through the skin, and ultimately enters the bloodstream to obtain a therapeutically effective blood level of the active agent and / or its active metabolites. The preferred mode of administration, as suggested above, is via microdosing, in which small amounts of the active agent are released periodically, preferably and more typically continuously, from the transdermal system to the skin at a predetermined flux that correlates with the desired pharmacological effect. This is in contrast to "macrodosing," which is typically administered when an individual takes a hallucinogen orally, or in some other manner in which the entire dose results in a substantially immediate release into the individual's bloodstream. Determining the therapeutically effective amount for any particular active agent is within the capabilities of one of ordinary skill in the art.

[0112] The aim is to achieve a desired brain activity score associated with a desired therapeutic effect. This follows from the Carhart-Harris entropic brain hypothesis; see Carhart-Harris (2018), supra. Carhart-Harris postulates that our brain states can be indexed by the magnitude of a specific measure of brain entropy, determined, for example, by fMRI, EEC, or MEG. In our normal state of mind, Carhart-Harris indicates that brain entropy is within a certain range, called the "critical zone," which corresponds to more or less wakefulness and consciousness, such that the entropy or complexity of brain activity is neither too ordered nor too disordered. When in a state of sleep, sedation, or anesthesia, entropic brain activity drops below the critical zone. However, when a standard "macrodose" of hallucinogens is taken, entropy shifts upward and beyond the critical zone, toward greater "conscious satisfaction, mental flexibility, and emotional instability," but with the impairment of analytical and convergent thinking. Administration of hallucinogens in accordance with the present invention, by continuous microdosing, elevates brain activity within or slightly above the critical zone, but avoids the upper supercritical zone.

[0113] The intensity of the psychedelic effects has been quantified; see Madsen et al. (2019), “Psychedelic Effects of Psilocybin Correlate with Serotonin 2A Receptor Occupancy and Plasma Psilocin Levels,” Neuropsychopharmacology 44(7):1328-1334. Madsen et al. measured the subjective intensity of the psychedelic experience (assessed using a Likert scale) following oral administration of psilocybin to human subjects and the effect of 5-HT 2A -R occupancy % (brain 5-HT compared to baseline as measured by positron emission tomography scan) 2A The researchers determined the relationship between the 5-HT binding (%) and plasma psilocin levels. 2A -R occupancy is an important determinant of hallucinogenic experiences, and plasma psilocin concentration is associated with increased neocortical 5-HT 2A As described in more detail below, the present invention has been found to correlate with the % 5-HT occupancy of a subject (see FIG. 3 of Madsen et al.). 2A It is possible to adjust the level of -R occupancy % to an optimum range.

[0114] 3. Activator:

[0115] The hallucinogens administered transdermally using the present invention are generally serotonergic hallucinogens (serotonin 5-HT 2A These are either psychoactive hallucinogens (hypertensives) or empathogenic psychedelic agents (serotonin releasing agents).

[0116] Examples of serotonergic hallucinogens include, but are not limited to, the following:

[0117] Alkylated tryptamines, such as psilocin, bufotenin, N,N-dimethoxytryptamine (DMT), baeocystin, aeruginasin, 5-methoxy-DMT, 5-bromo-DMT, N-methyl-N-ethyltryptamine (NET), N-methyl-N-isopropyltryptamine (MiPT), N-methyl-N-propyltryptamine (MPT), N,N-diethyltryptamine (DET), N-ethyl-N-isopropyltryptamine (EiPT), N-methyl-N-butyltryptamine (NBT), N-propyl-N-isopropyltryptamine, N,N- Dipropyltryptamine, N,N-diisopropyltryptamine, N,N-diallyltryptamine, N,N-dibutyltryptamine, N-ethyltryptamine, N-methyltryptamine, trimethyltryptamine, α-methyltryptamine, α-ethyltryptamine, α,N-DMT, α,N,N-trimethyltryptamine, ethosybin, metosin, ethosin, meprosin, miprosin, deprosin, iprosin, daltosin, lucigenol, psilomethoxine, psiracetin (O-acetylpsilocin), methacetin, ethacetin, ipracetin, and their derivatives;

[0118] Benzofurans, such as dimemebfe and 5-methoxy-N,N-diisopropylbenzofuranethylamine;

[0119] Ibogoids, such as ibogaine and voacangine;

[0120] Lysergamides, such as lysergic acid diethylamide (LSD), lysergic acid amide, N1-methyl-lysergic acid diethylamide, N-acetyl-lysergic acid diethylamide, lysergic acid ethylamide, lysergic acid methyl ester, lysergic acid 2,4-dimethylazetide; lysergic acid piperidine, N,N-dimethyl-lysergamide, lysergic acid β-propanolamide, lysergic acid 1-butanolamide, and other lysergic acid and lysergamide derivatives and analogs; and

[0121] Phenethylamines, such as mescaline, lophophine, isomescaline, cyclopropylmescaline, escaline, trisescaline, isoproscaline, methallylscaline, buscaline, 3-methoxy-4-ethoxyphenethylamine (MEPEA), β-methoxymescaline, and 2,5-dimethoxy, 4-substituted phenethylamines.

[0122] Another group of hallucinogenically active agents which can be administered transdermally according to the present invention are empathogens (i.e. serotonin releasing agents) which include:

[0123] Substituted amphetamines and substituted methylenedioxy-phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 2,3-MDA, 5-methyl-MDA, 3-methoxy-MDA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-ethylenedioxy-N-methylamphetamine (EDMA), p-methoxyamphetamine, and p-methoxymethamphetamine; and

[0124] Substituted cathinones, such as methylone, ethylone, euthyronine, and pentylone.

[0125] A further group of hallucinogens that can be administered using the present invention are the N-methyl-D-aspartate receptor antagonists, in particular ketamine.

[0126] In another embodiment, the systems, formulations, and methods of the present invention transdermally deliver hallucinogenic indolealkylamines, where the term "indolealkylamine" refers to the hallucinogenic indolealkylamine itself, as well as its hallucinogenic analogs or derivatives. Hallucinogenic indolealkylamines are analogs of 5-hydroxytryptamine (5-HT or serotonin), a monoamine neurotransmitter well known for its ability to affect both mood and behavior. Examples of indolealkylamines suitable for use herein are hallucinogenically active agents having the molecular structure of formula (I): [ka] During the ceremony,

[0127] R 1 is amino, monosubstituted amino, disubstituted amino, amido, -LR 6 where L is an optionally substituted, optionally heteroatom-containing -(CH2) n n is an integer ranging from 1 to 6 inclusive; R 6 is amino, monosubstituted amino, disubstituted amino, or a 5- or 6-membered alicyclic or aromatic N-heterocycle, or R 1 and R 2 together form a cyclic group containing at least one nitrogen atom;

[0128] R 2 is H or R 1 together with form a cyclic group;

[0129] R 3 , R 4 , and R 5 H and OR 7 where R 7 is H, C1-C6 hydrocarbyl, or phosphonato, or R 3 and R 4 , or R 4 and R 5 taken together form a cyclic group.

[0130] More typically:

[0131] R 1 has the structure -(CH2) n -R 6 where n is an integer ranging from 2 to 4 inclusive, and R 6 is selected from amino, mono(alkyl)-substituted amino, and di(alkyl)-substituted amino;

[0132] R 2 is H;

[0133] R 3 and R 4 is independently selected from H and OH;

[0134] R 5 H and OR 8 where R 8 is H or lower alkyl.

[0135] In one embodiment, R 2 and R 5 Both are H and R 6 is the structure -N(R 9 R 10 ), where R 9 and R 10 is independently selected from H and lower alkyl, such that the compound has the structure of formula (II): [ka]

[0136] In one group of such compounds, R 4 is H, and the indole alkylamine of formula (II) has the structure of formula (III): [ka] In the formula, R 3 is H or OH; n is an integer ranging from 2 to 4 (inclusive), and R 9and R 10 is as defined above (i.e., independently selected from H and lower alkyl). n is 2, and R 9 and R 10 is methyl, the indole alkylamine of formula (III) is 3 When is OH, it is psilocin, and R 3 When is H, it will be recognized as N,N-dimethyltryptamine (DMT).

[0137] R 3 and R 5 When is H, the indole alkylamine has the structure of formula (IV): [ka] In the formula, R 4 is selected from H and OH; n, R 9 , and R 10 is as defined for formula (II) and (III). The indole alkylamine of formula (II) is 4 is hydroxyl, n is 2, and R 9 and R 10 When is methyl, it is bufotenin (a structural isomer of psilocin).

[0138] The hallucinogenic indolealkylamines may be administered as monotherapy or in combination with one or more other active agents.

[0139] Additional activators:

[0140] Any additional active agent(s) co-administered with the hallucinogen may serve the same purpose as the hallucinogen or may serve a different purpose. In some cases, synergy may be observed with respect to therapeutic efficacy. In some cases, synergy may be observed with respect to reduction in side effects observed with any one of the co-administered active agents. In some cases, synergy allows for a reduction in the dosage of one or more co-administered active agents.

[0141] In the case of combination therapy, the additional active agent(s) may be co-administered simultaneously by incorporation into the same drug delivery system, or the additional active agent(s) may use a separate transdermal system or be administered via an alternative route (e.g., orally or intravenously, etc.) Thus, co-administration of two or more active agents via "combination therapy" may occur simultaneously, or the two or more active agents may be administered sequentially at different times.

[0142] Additional active agents that may be administered in combination with hallucinogens include analgesics, anesthetics, anti-arthritic agents, anti-cancer agents (including antineoplastic agents), anticonvulsants, antidepressants, antidiabetic agents, antidiarrheal agents, antihistamines, hyperlipidemic agents, antihypertensive agents, anti-infective agents, such as antibiotics and antivirals, anti-inflammatory agents, anti-migraine preparations, antiemetics, antineoplastic agents, antioxidants, antiparkinsonian agents, antipyretics, antispasmodics, anxiolytics, herbal medicines, hormoneolytics, muscle relaxants, steroids, and tranquilizers.Typically, preferred additional active agents are selected from anti-inflammatory agents, antivirals, anti-cancer agents, antiapoptotic agents, neuroprotective agents, and antioxidants.

[0143] Specific pharmacologically active drug classes of interest that may be administered in conjunction with a hallucinogen include, by way of example and not limitation, the following:

[0144] Monoamine oxidase (MAO) inhibitors represent a further class of active agents that are advantageously co-administered with hallucinogens.MAO inhibitors are particularly interesting for hallucinogens that are metabolized by MAO (e.g., psilocybin and bufotenin).Examples of MAO inhibitors include non-selective MAO-A / MAO-B inhibitors, such as isocarboxazid, hydracarbazine, phenelzine, and tranylcypromine; selective MAO-A inhibitors, such as bifemelane, moclobemide, pirlindole, and toloxatone; reversible MAO-A inhibitors, such as harmine, harmaline, and d-1,2,3,4-tetrahydroharmine; and selective MAO-B inhibitors, such as rasagiline, selegiline, and safinamide. Any MAO inhibitor should be incorporated into the drug reservoir or in a separate formulation along with the MAO-reactive active agent, typically at a concentration ranging from about 0.5% to about 15% by weight (e.g., 1.0% to about 10% by weight).

[0145] Cannabinoid: The term "cannabinoid" refers to compounds found in the Cannabis genus of the cannabis plant family (including the species Cannabis sativa, Cannabis indica, and Cannabis ruderalis), or their naturally occurring or chemically synthesized metabolites, derivatives, or analogs.Cannabinoids have been established to have any of a wide range of pharmacological usefulness, and are included in more than one of the above categories.

[0146] Examples of cannabinoids that can be administered transdermally in combination with hallucinogens using the systems, formulations, and methods of the present invention include tetrahydrocannabinol (THC), dronabinol (i.e., the pure isomer (-)-trans-Δ 9-THC), cannabichromanone, cannabichromene (CBC), cannabichromenic acid, cannabichromevarin (CBCV), cannabichromevaric acid, cannabicitran (CBT), cannabicoumaronone (CBCON), cannabicyclol (CBL), cannabicyclol acid, cannabicyclovaline, cannabidiol (CBD), cannabidiol monomethyl ether, cannabidiol dimethyl ether, cannabidiol dimethylheptyl, cannabidiol dimethylheptyl-7-acid, dimethylheptylpentylcannabidiol (DMHP-CBD), cannabidiolic acid, cannabidiol chol, cannabidivarin (CBV), cannabidivalic acid, cannabielsoin (CBE), cannabielsoinic acid, cannabifuran, cannabigerol (C BG), cannabigerol monomethyl ether (CBGM), cannabigerolic acid, cannabigerolic acid monomethyl ether, cannabigerovarin (CBGV), cannabigerovaric acid, cannabiglendol, cannabinodiol, cannabinodivarin, cannabinol (CBN), cannabinolic acid, cannabinol methyl ether, cannabiolcol, cannabilipsol, cannabitetrol, cannabiditriol, 10-O-ethyl-cannabidiol, cannabivalichromene, cannabivarin, dehydrocannabifuran, 1,2-dihydroxyhexahydrocannabinol, 1,2-dihydroxyhexahydrocannabinol acetate, dimethylheptylpyran, isotetrahydrocannabivarin, levonantradol, nabilone, rimonabant, Δ 9 -Tetrahydrocannabinolic acid, Δ 9 -Tetrahydrocannabinol, Δ 9 -Tetrahydrocannabiolcholic acid, Δ 9 -Tetrahydrocannabivarin, Δ 9 -Tetrahydrocannabivaric acid, 8,11-dihydroxy-Δ 9 -Tetrahydrocannabinol, 8,9-dihydroxy-Δ 6a,10a -Tetrahydrocannabinol, Δ 8 -Tetrahydrocannabinol, Δ 8 -Isotetrahydrocannabinol, Δ 8-Tetrahydrocannabinolic acid, 10-oxo-Δ 6a,10a -Tetrahydrocannabinol (OTHC), HU-210 (1,1-dimethylheptyl-11-hydroxy-Δ 8 -THC), HU-331 (3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone), JWH-018 (1-pentyl-3-(1-naphthoyl)indole), and other JWH cannabinoids, such as JWH-073 (John W. Huffman, Clemson University, Clemson, SC), AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole) and other AM cannabinoids (Alexandros Makriyannis, Northeastern University, Boston MA), and CP-55,940 (2-((1S,2S,5S)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)-5-(2-methyloctan-2-yl)phenol; Pfizer). As analgesics, these compounds have been proposed for use in treating neuropathic or chronic pain associated with fibromyalgia, rheumatoid arthritis, acute inflammation, and cancer. See, for example, A. Hazekamp (2010), ''Review on Clinical Studies with Cannabis and Cannabinoids,'' Cannabinoids 5 (Special Issue): 1-21. Other cannabinoids that can be administered in combination with hallucinogens will be apparent to those skilled in the art upon reference to the relevant texts, journals, and patent literature. See, for example, Wurzer et al., U.S. Patent Application Publication No. 2014 / 0271940A1, incorporated herein by reference.

[0147] Anti-inflammatory agents: These include nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen, apazone, diclofenac, difenpyramide, diflunisal, etodolac, indomethacin, ketorolac, meclofenamate, nabumetone, phenylbutazone, piroxicam, sulindac, and tolmetin; and steroids. doxorubicin anti-inflammatory agents include, for example, hydrocortisone, hydrocortisone-21-monoesters (e.g., hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydrocortisone-21-propionate, hydrocortisone-21-valerate), hydrocortisone-17,21-diesters (e.g., hydrocortisone-17,21-diacetate, hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21-dibutyrate), alclometasone, dexamethasone, flumethasone, prednisolone, and methylprednisolone.

[0148] Antioxidants: Antioxidants useful herein are preferably, but not necessarily, biologically active antioxidants that are naturally occurring compounds, chemically synthesized naturally occurring compounds, modified naturally occurring compounds, and / or compounds approved by the FDA or other regulatory agencies as safe for consumption. Exemplary, but not limited to, antioxidants include ascorbic acid, vitamin E (tocopherol and tocotrienol), carotenoids (e.g., beta-carotene, lycopene, lutein, and zeaxanthin), ubiquinol (coenzyme Q), glutathione, uric acid, and lipoic acid, as well as the synthetic antioxidants propyl gallate, tertiary butyl hydroquinone, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT). For other antioxidants that can be delivered with hallucinogens, see Kebede et al. (2019), “Application of Antioxidants in the Food Processing Industry: Options to Improve the Extraction Yields and Market Value of Natural Products,” Adv. Food Tech. Nutr. Sci. Open J. 5(2):38-49, the disclosure of which is incorporated herein by reference.

[0149] Another group of active agents that can be co-administered with hallucinogens are compounds found in Antrodia camphorata mushrooms. The components of Antrodia camphorata include terpenoids, benzenoids, lignans, benzoquinone derivatives, and other compounds. Specific and representative Antrodia camphorata compounds useful herein are as follows:

[0150] Terpenes and terpenoids, such as humulene (α-caryophyllene), myrcene, pinene (including α-pinene and β-pinene), anthrocin, 19-hydroxylabd-8(17)-en-16,15-olide, 3β,19-dihydroxylabd-8(17), 11E-dien-16,15-olide, 13-epi-3β,19-dihydroxylabd-8(17), 1 1E-dien-16,15-olide, 19-hydroxylabda-8(17)-13-dien-16,15-olide, 14-deoxy-11,12-didehydroandrographolide, 14-deoxyandrographolide, pinusolidinic acid, anthocin A, anthocin B (anthocic acid A), anthocin C, anthocin D (anthocic acid F), anthocin E, anthocin F, anthocin G, anthocin tosine H (Zanthic acid C), anthocine I (Zanthic acid B), anthocine K, methyl anthocinate A, methyl anthocinate B, zanthic acid D, methyl anthocinate G, methyl anthocinate H, zanthic acid E, dehydroebric acid, dehydrosulfurenic acid, 15α-acetyl-dehydrosulfurenic acid, ebric acid, sulfurenic acid, versisponic acid D, ebricol (24-methylenedihydrolanosterol), 3β,15α-dihydroxy-lanosta-7,9(11),24-trien-21-oic acid, 3β-hydroxy-lanosta-7,9(11),24-trien-21-oic acid, β-sitosterol, β-sitostenone, stigmasterol, ergosterol, ergosta-4,6,8(14)22-tetraen-3-one3, and epi-friederinol;

[0151] Benzenoids, such as 1,4-dimethoxy-2,3-methylenedioxy-5-methylbenzene, 1,4-dimethoxy-2,3-methylenedioxy-5-benzoate, 1,6-dimethoxy-2,3-methylenedioxy-4-benzoic acid, anthrocamphin A, anthrocamphin B, 2,3,4,5-tetramethoxybenzoyl chloride, anthrodioxolanone, and isobutylphenol;

[0152] Lignans, such as (+)-sesamin, 4-hydroxysesamin, and (-)-sesamin;

[0153] Benzoquinone derivatives, such as 5-methyl-benzo(1,3)-dioxole-4,7-dione, 2-methyoxy-5-methyl(1,4)benzoquinone, and 2,3-dimethoxy-5-methyl(1,4)benzoquinone;

[0154] Derivatives of succinic and maleic acid, for example, trans-3-isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]pyrrolidine-2,5-dione, trans-1-hydroxy-3-(4-hydroxyphenyl)-4-isobutylpyrrolidine-2,5-dione, 3R * ,4S * -1-Hydroxy-3-isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]pyrrolidine-2,5-dione (Anthrodin D or Camphorataimide E), cis-3-(4-hydroxyphenyl)-4-isobutyldihydrofuran-2,5-dione, 3-(4-hydroxyphenyl)-4-isobutyl-1H-pyrrole-2,5-dione, 3-(4-hydroxyphenyl)-4-isobutylfuran-2,5-dione (Anthrocinnamomin C), 3-isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]pyrrolidine-2,5-dione nyl]furan-2,5-dione (Anthrodin A or Camphorata anhydride A), Dimethyl 2-(4-hydroxyphenyl)-3-isobutylmaleate, 3-isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]-1H-pyrrole-2,5-dione (Anthrodin B or Camphorataimide B), Anthrocinnamomin D, 3-isobutyl-4[4-(3-methyl-2-butenyloxy)phenyl]-1H-pyrrole-1-od-2,5-dione (Anthrodin C or Camphorataimide C), Anthrocinnamomin A, 3R * ,4S * -1-hydroxy-3-isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]pyrrolidine-2,5-dione (androcin E or camphorataimide D), and anthrocinnamomin B; and

[0155] Other compounds not included within the following groups include 2,2',5,5'-tetramethoxy-3,4,3',4'-bi-methylenedioxy-6,6'dimethylbiphenyl, alpha-tocospiro B, methyl oleate, antroquinonol, adenosine, cordycepin, 2,4,5-trimethoxybenzaldehyde, antroquinonol B, 4-acetyl-antroquinonol B, 2,3-(methylenedioxy)-6-methylbenzene-1,4-diol, and 2,4-dimethoxy-6-methylbenzene-1,3,diol.

[0156] See Geethangili et al. (2009), "Review of Pharmacological Effects of Antrodia camphorata and Its Bioactive Compounds," Evidence-based Complementary and Alternative Medicine 2011:1-17.

[0157] In another embodiment, the above-mentioned Antrodia camphorata mushroom components are used instead of hallucinogens and administered as monotherapy.These compounds are identified as alternatives to current cancer treatments and immune-related disease treatments.The co-administration of Antrodia camphorata components with cannabinoids is also envisaged.

[0158] It should also be noted that constituents of Antrodia camphorata mushroom, particularly the terpenoids, act as lipid-disrupting permeation enhancers and can be advantageously used as plasticizer-type permeation enhancers herein.

[0159] Other additional active agents that may be co-administered with the hallucinogens include, by way of example, the following:

[0160] Antibacterial agents: tetracycline antibiotics and related compounds (e.g., chlortetracycline, oxy-tetracycline, demeclocycline, methacycline, doxycycline, minocycline, and roli-tetracycline); macrolide antibiotics, e.g., erythromycin, clarithromycin, and azithromycin; streptogramin antibiotics, e.g., quinupristin and dalfopristin; beta-lactam antibiotics (penicillins (e.g., penicillin G, penicillin VK, ), antistaphylococcal penicillins (e.g., cloxacillin, dicloxacillin, nafcillin, and oxacillin), broad-spectrum penicillins (e.g., aminopenicillins, e.g., ampicillin and amoxicillin, and antipseudomonal penicillins, e.g., carbenicillin), cephalosporins (e.g., cefadroxil, cefepime, cephalexin, cefazolin, cefoxitin, cefotetan, cefuroxime, cefotaxime, ceftazidime, and ceftriaxone), and carbapenems, e.g., aminoglycoside antibiotics, such as streptomycin, gentamicin, tobramycin, amikacin, and neomycin; glycopeptide antibiotics, such as teicoplanin; sulfonamide antibiotics, such as sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, and sulfamethoxazole; quinolone antibiotics, such as ciprofloxacin, cyclosporine, and cyclosporine; loxacin, nalidixic acid, and ofloxacin; antimycobacterial agents such as isoniazid, rifampin, rifabutin, ethambutol, pyrazinamide, ethionamide, aminosalicylic acid, and cycloserine; systemic antifungal agents such as itraconazole, ketoconazole, fluconazole, and amphotericin B; and other antibacterial agents such as chloramphenicol, spectinomycin, polymyxin B (colistin), bacitracin, nitrofurantoin, and methenamine.

[0161] Anticonvulsants: azetazolamide, carbamazepine, clonazepam, clorazepate, ethosuximide, ethotoin, felbamate, lamotrigine, mephenyloin, mephobarbital, phenyloin, phenobarbital, primidone, trimethadione, vigabatrin, topiramate, and benzodiazepines.

[0162] Antianxiety and tranquilizers: Benzodiazepines (e.g., alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam), buspirone, chlordiazepoxide, and droperidol.

[0163] Anticancer and Antineoplastic Agents: Paclitaxel; Docetaxel; Camptothecin and their analogs and derivatives (e.g., 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, irinotecan, topotecan, and 20-O-β-glucopyranosylcamptothecin); Taxanes (e.g., baccatin, cephalomannine, and their derivatives); Carboplatin; Cisplatin; Interferon α-2a, Interferon β-glucosamine; Interferon alfa-2b, interferon alfa-n3, and other agents in the interferon family; levamisole; altretamine; cladribine; tretinoin; procarbazine; dacarbazine; gemcitabine; mitotane; asparaginase; porfimer; amifostine; mitotic inhibitors (including the podophyllotoxin derivatives teniposide and etoposide); and the vinca-alkaloids vinorelbine, vincristine, and vinblastine.

[0164] Antiviral agents: These include antiherpes agents such as acyclovir, famciclovir, foscarnet, ganciclovir, idoxuridine, sorivudine, trifluridine, valacyclovir, and vidarabine; antiretroviral agents such as didanosine, stavudine, zalcitabine, tenovovir, and zidovudine; and other antiviral agents including amantadine, interferon-α, ribavirin, and rimantadine.

[0165] Agents for treating neurodegenerative diseases: Active agents for treating Alzheimer's disease and Huntington's disease include donezepil, physostigmine, and tacrine (for treating Alzheimer's disease), and fluoxetine and carbamazepine (for treating Huntington's disease).Antiparkinsonism drugs useful herein include amantadine, apomorphine, bromocriptine, levodopa (especially levodopa / carbidopa combination), pergolide, ropinirole, selegiline, trihexyphenidyl, trihexyphenidyl hydrochloride, and anticholinergic agents.ALS is generally treated with anticonvulsants (antispasmodics), such as baclofen, diazepam, tizanidine, and dantrolene.

[0166] Neuroprotective agents: glutamate blockers and NMDA channel blockers, such as magnesium sulfate; free radical scavengers, such as tempol, hydroxystilbenes, and oxyreservatrol; COX-2 inhibitors, such as flavocoxide, valdecoxib, and celecoxib; beta blockers, such as propranolol, metoprolol, and atenolol; statins, such as atorvastatin, mevastatin, rosuvastatin, and simvastatin; melatonin; and erythropoietin.

[0167] Apoptosis inhibitors: These are compounds that inhibit the initiation or progression of a cell through the apoptotic process and include inhibitors of c-Myc, Bax, p53, tBid, and BCL, as well as caspase inhibitors and other enzymes involved in the apoptotic pathway. Examples of apoptosis inhibitors include: 5-[(4-ethylphenyl)methylene]-2-thioxo-4-thiazolidinone; 4'-methoxyflavone; 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine; 1H-benzimidazole-1-ethanol, 2,3-dihydro-2-imino-alpha-(phenoxymethyl)-3-(phenylmethyl)-monohydrochloride; N-[4-[(4-aminophenyl)thio]phenyl]-4-[[(4-methoxyphenyl)sulfonyl]amino]-butanamide; 2-pyridin-2-yl-4H-1,3-benzothiazin-4-one; 4-chloro-3-[ [(3-nitrophenyl)amino]sulfonyl]-benzoic acid; combretastatin A4; cyclic pifithrin-α-hydrobromide; fastentin; ferrostatin-1; 3-[6-[[4-(trifluoromethoxy)phenyl]amino]-4-pyrimidinyl]benzamide (GNF-2); 2-(1H-indol-3-yl)-3-pentylamino-maleimide (IM-54); ischemin; liproxstatin-1; calpain inhibitor III; N-ethylmaleimide; 4-chloro-2-[3-(3-trifluoromethyl-phenyl)-ureido]benzoic acid; necrostatin-1; and 3-(5-fluoro-1H-indol-3-yl)-2-mercapto-2-propenoic acid.

[0168] 4. Drug delivery systems:

[0169] The hallucinogenic active agent is delivered transdermally to a subject using a topically applied formulation or a transdermal drug delivery system provided herein. As noted above, the desired concentration of the administered agent (or its metabolites) is controlled by the transdermal system insofar as the flux from the system dominates the total flux of the active agent from the system through the skin into the bloodstream. This feature of the invention can facilitate controlled blood concentration levels over time, eliminating "peaks" and "valleys."

[0170] (a) Surface-applied formulations:

[0171] In one embodiment, the transdermal drug delivery system comprises a formulation containing an active agent to be applied to the skin, for example, using a device for applying an intended (or "metered") dose of a liquid formulation to the skin. For example, a roll-on type applicator (such as those described in U.S. Patent Nos. 8,419,307 and 9,289,586 to Bayly et al.) can be used as a metered-dose spray device.

[0172] The formulation includes a hallucinogenic active agent, a composition of a skin permeation enhancer, and a pH adjusting agent. The formulation is applied to a topical area of ​​the skin of a subject to administer a dose of the active agent to be delivered over a drug delivery period typically ranging from 6 to 84 hours (e.g., 8 to 24 hours). Upon evaporation or absorption of the enhancer composition, the direct enhancing effect of the enhancer composition ceases. Transport of drug remaining on the application area or already present in the skin can then be reactivated by reapplication of the enhancer composition in the absence of additional active agent. This process is continued to enhance delivery of drug already present in and on the skin.

[0173] The concentration of active agent in the formulation is selected to provide a unit dose of active agent in each application, and the unit dose is selected to provide a therapeutically effective blood level of the active agent or its metabolites during the drug delivery period.

[0174] The enhancer composition used in this embodiment comprises a combination of a solvent-type skin permeation enhancer and a plasticizer-type skin permeation enhancer, also referred to as a lipid disrupting agent.

[0175] Solvent-type promoters include C2-C6 alcohols, such as ethanol, isopropanol, 1,2-butanediol, and propylene glycol; ethers, such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; ketones, such as acetone; esters, such as ethyl acetate and ethyl formate; hydrocarbon solvents, such as pentane; amines and other nitrogen compounds, such as urea, N,N-dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; alkanones, such as acetone; organic acids, especially ascorbic acid, citric acid, and succinic acid; and sulfoxides, such as dimethyl sulfoxide (DMSO) and decyl methyl sulfoxide (C 10 Such enhancers include, but are not limited to, ethanol, methyl ether, methyl stearate, methyl ethyl ...

[0176] Plasticizer-type enhancers include, for example, surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethyl-ammonium bromide, benzalkonium chloride, poloxamers (e.g., Pluronic® 231, 182, 184), and polysorbates (e.g., Tween® 20, 40, 60, 80); polyethylene glycol and its esters, such as polyethylene glycol monolaurate (PEGML); fatty alcohols, fatty acids, and esters of fatty acids, such as oleic acid (OL), oleyl alcohol (OA), milliglycerides, and the like. isopropyl laurate (IPM), methyl laurate, ethyl laurate, propylene glycol monolaurate, propylene glycol dilaurate, glycerol monolaurate, lauryl lactate, methyl laurate; glycerol phospholipids (including lecithin); higher alcohols, such as 2-phenoxyethanol (PHE), undecanol, hexanol, octanol, and benzoyl alcohol, and salicylaldehyde (SA); terpenes and terpenoids, such as isomenthone, humulene, and other terpenes and terpenoids, such as Kang et al. (2013), "Terpenes and Improvement of Transdermal Drug Delivery" in Ramawat, eds., Natural Products (Springer, Berlin); vegetable oils such as safflower oil, cottonseed oil, corn oil, almond oil, castor oil, jojoba oil, linseed oil, and the like; mineral oils and their components; and other solvents such as isomenthone, the ether / ester combinations described in U.S. Pat. No. 5,053,227, and 1-dodecylazacycloheptan-2-one (Azone®).

[0177] The formulation additionally comprises a pH adjusting agent, which may be, for example, a buffer system. Suitable buffer systems include phosphate buffers and bicarbonate buffers. Also, depending on the active agent, the pH adjusting agent may be a weak acid, such as ascorbic acid, citric acid, formic acid, or acetic acid. The purpose of the pH adjusting agent is to maintain a pH in the local region of the active agent that is close to the pKa of the drug, generally within about 25% of the pKa, typically within about 15% of the pKa. In the case of psilocin, which has a pKa of 8.47, phosphate buffers, especially pyrophosphate buffers, are suitable, as is sodium bicarbonate. Also, pyrophosphate buffers are suitable pH adjusting agents for LSD, which has a pKa of 7.8, and DMT, which has a pKa of 8.4. In the case of bufotenin, which has a pKa of 9.67, phosphate buffers can also be used, but a buffer that provides a slightly higher pH may be preferred.

[0178] The pH adjusting agent increases the concentration of the non-ionized form of a polar or ionizable active agent that exists in equilibrium with the ionized form by approaching the pKa of the active agent. When the formulation includes an aqueous liquid carrier in addition to the aforementioned components, the pH adjusting agent maintains the pH of the formulation close to the pKa of the active agent. It will be appreciated that upon delivery to the skin in the absence of a liquid carrier, the pH adjusting agent maintains the pH in the region of the active agent (i.e., within the various layers of the skin) in a manner that favors the non-ionized form of the drug.

[0179] The formulation may additionally contain a stabilizer to stabilize the active agent, thereby preventing the active agent from decomposing or reacting during storage and use. For example, some compounds, such as psilocin, undergo undesirable reactions in the presence of oxygen, since the phenolic hydroxyl group makes the molecule unstable and susceptible to radicalization and oligomerization; see, for example, Lenz et al. (2020), Injury-Triggered Blueing Reactions of Psilocybe Magic Mushrooms, Angew Chem Int Ed Engl 59(4):1450-1454. Thus, a suitable stabilizer for psilocin and other oxygen-reactive active agents is an antioxidant. Antioxidants that may be advantageously incorporated into the formulation in such cases include those identified in the previous section. Preferred antioxidants are those that serve an additional purpose in the formulation (reducing the complexity of the formulation). Ascorbic acid and ascorbate salts are examples of suitable oxidizing agents inasmuch as they act not only as oxygen scavengers but also as pH adjusters and solvent-type skin permeation enhancers.

[0180] The formulation typically comprises about 0.5% to about 40% by weight of the active agent, more typically about 1% to about 20% by weight (e.g., about 1% to about 10% by weight), while the permeation enhancer composition typically comprises about 1% to about 30% by weight of the formulation, e.g., 1% to about 25% by weight (e.g., 5% to about 25% by weight). In addition to the enhancer composition, a liquid vehicle may also be included. Depending on the active agent to be delivered and the components of the enhancer composition selected, the liquid vehicle may be hydrophilic or hydrophobic.

[0181] The formulation may also include one or more conventional additives (i.e., excipients, such as viscosity modifiers (i.e., thickening or thinning agents), crystallization inhibitors, emulsifiers, solubilizers, preservatives, opacifiers, colorants, and fragrances). Additionally, the pharmaceutical formulation may include a mild additive, such as glycerin, to minimize or eliminate the possibility of skin irritation or damage that may result from a particular active agent or other components of the system.

[0182] In one embodiment, biocompatible polymers are incorporated into the formulation, which dry to form a film on the skin to seal the skin, thereby increasing skin moisturization. Such polymers include poloxamers (e.g., Pluronic® block copolymers, available from BASF Corporation), acrylic acid polymers and copolymers (e.g., poly(acrylic acid, e.g., available from Lubrizol Corporation under the trade name Carbopol®), cosmetically acceptable film-forming polymers, including but not limited to: sulfopolyesters, e.g., those commercially available as EastmanAQ® polymers; silicone resins and silicone resin gums, e.g., trimethylsiloxylates, optionally mixed with cyclopentasiloxane, dimethicone, and polypropylsilsesquioxane, available from Dow Chemical Co. as DOWSIL® resins and resin gums; silicone acrylates; ethylcellulose polymers; hydrophobic carboxylated acrylic acid copolymers; and starches and modified starches (e.g., STRUCTURE® XL from Nouryon).

[0183] In another embodiment, the formulation includes one or more inhibitors of any enzyme that may cause undesired or premature degradation of the specific active agent (e.g., MAO inhibitors for drugs metabolized by MAO, such as psilocybin, psilocin, and bufotenin). Suitable MAO inhibitors are exemplified in the previous section.

[0184] In a variation of this embodiment, the active agent or a fraction thereof is encapsulated in liposomes or ethosomes (i.e., liposomes containing a certain amount of ethanol). See Nounou et al. (2008), "Liposomal Formulation for Dermal and Transdermal Drug Delivery: Past, Present, and Future," Recent Patents on Drug Delivery & Formulation 2:9-18; Pilch et al. (2018), "Liposomes with an Ethanol Fraction as an Application for Drug Delivery," Int. J. Mol. Sci. 19:3806; and Somwanshi et al., "Development and Evaluation of Novel Ethosomal Vesicular Drug Delivery System of Sesamum indicum L. Seed Extract," Asian J. Pharmaceut. 12(4). The disclosures of the latter two references are incorporated herein by reference to disclose ethosomes encapsulating drugs and ethosomal dispersions, respectively. Proliposomes, niosomes, proniosomes, transfersomes, and protransfersomes can be used in a similar manner, but ethosomes are generally preferred. See Modi et al. (2012), "Transfersomes: New Dominants for Transdermal Drug Delivery," Am. J. PharmTech Res. 2(3).By incorporation of a fraction of the total hallucinogen into ethosomes or the like (e.g., 10%-90%, 10%-85%, or 20%-75% by weight), the sustained release of the active agent after penetration into the skin will be extended beyond what would otherwise be the end of the drug delivery period; the greater the fraction of the active agent that is incorporated into ethosomes or lithosomes or the like, the longer the drug delivery period will be.

[0185] When the active agent administered is psilocin, the photosensitivity of the drug is countered by covering the application area with an opaque or metallized material after administration, which can be a thin film or layer on the skin contact adhesive base layer or on its edge or periphery. An opaque fabric product can be suitable. The potential chemical instability of the drug in the presence of oxygen is addressed by incorporating an oxygen scavenger into the formulation (e.g., any of the ascorbic acid, enzyme or enzyme combinations, polyunsaturated fatty acids, or antioxidants described in the previous section as additional active agents).

[0186] In a variation of this embodiment, the formulation containing the active agent may be applied to an area of ​​the skin of a subject using a metered dose transdermal spray. The formulation is composed of the same components as the roll-on formulation, unless an aerosolization device is used, in which case the components are incorporated into a volatile vehicle instead of the carrier suggested above.

[0187] In one embodiment, a topically administrable formulation for transdermal administration of a hallucinogenically active agent to a subject comprises:

[0188] (a) about 0.5% to about 40% by weight of a hallucinogenic active agent having a known pKa;

[0189] (b) a skin-permeation-enhancing effective amount of an enhancer composition comprising a solvent-type enhancer and a lipid-disrupting enhancer;

[0190] (c) a pH-adjusting effective amount of a pH adjusting agent that maintains the pH within 25% of the pKa within the localized area of ​​skin to which said formulation is applied topically; and, optionally,

[0191] (d) Stabilizers.

[0192] For example, the formulation may include:

[0193] (a) from about 1.0% to about 25% by weight of a hallucinogenic active agent having a known pKa;

[0194] (b) a skin-permeation-enhancing effective amount of an enhancer composition comprising a solvent-type enhancer and a lipid-disrupting enhancer;

[0195] (c) a pH-adjusting effective amount of a pH adjusting agent that maintains the pH within 15% of the pKa within the localized area of ​​skin to which said formulation is applied topically; and

[0196] (d) about 1.0% by weight to about 10% by weight of ascorbic acid or a salt thereof.

[0197] (b) Transdermal patch:

[0198] In another embodiment, the formulation containing the active agent, the active agent, the combination of the solvent type enhancer / plasticizer type enhancer, and the pH adjuster, is incorporated into a drug reservoir in a layered transdermal delivery system, i.e., a patch. The transdermal system preferably includes a sealed, typically opaque or metallized backing layer, where the backing layer serves as the outer surface of the system after application of the patch to the skin of the subject. This type of backing layer prevents light from penetrating the patch and potentially destabilizing photosensitive drugs such as psilocin. During storage and before use, the system also includes a removable release liner that covers and protects the skin-facing side of the adhesive matrix before use.

[0199] The backing layer is typically, but not necessarily, the primary structural element of the transdermal system after assembly of the laminate, and can be selected to provide a device with physical characteristics such as flexibility, drape, and, if necessary, occlusion. The material selected to serve as the backing layer should be stable under storage conditions, chemically inert to any components of the adhesive layer laminated to it, and incapable of absorbing the formulation and formulation components contained within the transdermal drug delivery system. The backing is preferably made of one or more sheets or films of flexible elastomeric material that serve as a protective covering to prevent loss of drug and / or vehicle by passage over the top surface of the assembled system. Additionally, the backing material can be selected to provide the device with a degree of occlusion such that the covered skin area is moistened upon application. The material used for the backing layer must enable the assembled transdermal system to follow the contours of the skin and to fit comfortably over areas of the skin such as joints or other bends, areas normally subjected to mechanical strain, and further, there must be little or no chance of the system peeling off from the skin due to differences between the flexibility or elasticity of the skin and that of the system.

[0200] Examples of materials useful for the backing layer are polyester, polyethylene, polypropylene, polyurethane, polyetheramide, and ethylene-vinyl acetate copolymer (EVA).Backing layers can be commercially obtained, for example, from 3M Corporation under the Scotchpak™ and CoTran™ brands, including polyester film backings (3M Scotchpak™ 9754, 9757 and 9758), polyester film laminate backings (3M Scotchpak™ 1012, 9723, 9730, 9733, 9735 and 9738), polyurethane nonwoven backings (3M CoTran™ 9700), polyurethane monolayer film backings (3M CoTran™ 9701), and polyethylene monolayer film backings (3M CoTran™ 9718, 9719, 9720 and 9722).

[0201] The backing layer generally ranges in thickness from about 10 microns to about 300 microns, preferably from about 15 microns to about 250 microns, and can optionally be pigmented, metallized, or provided with a matte finish suitable for writing.

[0202] (i) Simple adhesive system:

[0203] In one embodiment, the transdermal patch is a simple adhesive system, also referred to as a "drug-in-adhesive" system. A simple adhesive system is shown in Figure 2, where the drug reservoir 1 doubles as the skin contact adhesive (SCA) layer and contains a polymer matrix that helps to affix the system to the skin during drug delivery. The drug reservoir, which contains the components of the formulation described in the previous section, is laminated directly to the outer backing layer 3.

[0204] Suitable skin contact adhesives are generally pressure sensitive adhesives (PSAs) and preferably comprise viscoelastic polymers, which may be selected from, for example, polysiloxanes (silicones), polyisobutylenes (PIBs), polyacrylates, polyurethanes, and tackifying rubbers other than PIBs, such as polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and mixtures thereof. In addition to the elastomeric polymer, the PSA composition may also comprise tackifying resins, fillers, stabilizers, and / or antioxidants, and crosslinkers, all of which are selected to provide the desired degree of tack, peel adhesion, skin adhesion, and cohesive strength.

[0205] The skin-contacting surface of the SCA reservoir is protected during storage and prior to use by a removable release liner, as shown in FIG. 2 as element 5. Release liners are typically composed of polyester or other polymers treated with a silicone coating, a fluorosilicone coating, or a coating of other fluoropolymers. Commercially available release liners include Syl-Off® products (available from Dow Corning Corporation), products from Tribex Corporation, and 3M Scotchpak™ products. For an illustration of this type of transdermal drug delivery system, see Rastogi et al. (2012), ''Transdermal Drug Delivery System: An Overview,'' Asian J Pharmaceut. 6(3):161-170, p. 167, FIG. 3(c). The disclosure of Rastogi et al. is incorporated herein by reference.

[0206] (ii) Integrated matrix systems:

[0207] In another embodiment, the transdermal drug delivery system used herein is an integral matrix system, where again the drug reservoir is a polymer matrix loaded with a formulation containing an active agent, but in this case does not double as a means for attaching the system to the skin. An integral matrix system is shown in FIG. 3. The matrix reservoir 7 may or may not be comprised of a skin contact adhesive. Rather, a separate skin contact adhesive layer 9 is laminated to the underside of the drug reservoir. Materials other than SCA suitable for the matrix reservoir in this embodiment include, but are not limited to, polyurethanes, acrylic acid polymers and copolymers, poly(lactide-co-glycolide) (PLGA), and other materials known to those skilled in the art. Rastogi et al. (2012) show this type of matrix system in FIG. 3(b) on page 167. In FIG. 3, a preferably occlusive outer backing layer is shown at 3 and a release liner is shown at 5.

[0208] (c) Liquid Reservoir System (LRS):

[0209] In these types of systems, the formulation containing the active agent described in the previous section is incorporated into a liquid drug reservoir instead of an adhesive matrix type reservoir. In a first embodiment, designated herein as LRS-m (m=membrane) and illustrated in FIG. 4, the transdermal system for drug administration has a reservoir 11 in the form of a pouch or cavity for containing the liquid formulation, where the reservoir is disposed between a heat-sealed lower membrane 13 and an occlusive outer backing layer 15. The heat-sealed membrane, which serves as the release "rate-controlling membrane", is immediately inside a lower layer 17 that serves as the bottom surface of the system and contains a skin contact adhesive that adheres to the skin of the subject during drug administration. In FIG. 4, the release liner is shown at 3. In this embodiment, the release rate of the enhancer composition and / or the active agent can be controlled by the membrane such that delivery to the patient is controlled by the transdermal system and not the skin. Drugs can be included in the adhesive layer as well as in the drug reservoir, where the membrane permeability is designed to control the flux of solvent-type enhancers, which in turn correlates with the flux of the drug through the skin. Suitable membrane materials include, by way of example, polyethylene, polypropylene, ethylene vinyl acetate copolymers, ethylene copolymers, ethylene oxide copolymers, polyamides, cellulose derivatives, polyurethanes, polyether block amide copolymers, and polyvinyl acetate. Some membranes can be microporous (e.g., those made from microporous polyethylene or polypropylene).

[0210] In another embodiment shown in Figure 5, the active agent-containing formulation is incorporated into a microporous reservoir 19 laminated to an outer backing material 21, which is preferably sealed as before and opaque or metallized to prevent light from reaching the photosensitive agent. This is called the LRS-b (Band-Aid) system. The microporous reservoir loaded with the drug / enhancer formulation is covered with a release liner 3 during storage and prior to use, as described above. In this case, the LRS-b can be loaded with the active agent-containing formulation immediately prior to application to the skin of the subject.

[0211] LRS-m and LRS-b patches are illustrated in Figure 3(a) (where the LRS-m system is referred to as the "reservoir system") and Figure 3(d) (where the LRS-b system is referred to as the "microreservoir system") on page 167 of Rastogi et al. (2012).

[0212] (d) Modular Transdermal Delivery System:

[0213] In another embodiment, a modular transdermal delivery system is used to deliver a formulation containing an active agent to the skin of a subject.Suitable modular transdermal delivery systems are described in U.S. Patent Application Publication Nos. 2020 / 0268681A1, 2020 / 0146998A1, 2018 / 0311180A1, 2018 / 0311181A1, and 2018 / 0296498A1, all to Frank Kochinke, the entire disclosures of which are incorporated herein by reference.These modular systems are advantageous in clinical trials when evaluating different formulations, inasmuch as they obviate the need for large-scale manufacturing settings to produce clinical supplies.The components of the modular patch can be pre-prepared and assembled and loaded by researchers, manufacturers, or end users.

[0214] 5. Method of use and indications

[0215] As explained above, the objective of the present invention is to administer a hallucinogenic active agent to a subject to achieve a desired therapeutic effect without the undesirable adverse effects that can occur when administering a macrodose. See Figure 1, which shows the plasma concentration profile obtained using the transdermal microdosing method of the present invention compared to the plasma concentration profile obtained using a conventional immediate release delivery involving administration of a macrodose of the drug.

[0216] In one embodiment, the present invention provides a 5-HT 2AThe present invention provides a method for transdermally administering a hallucinogen such as psilocin to a subject to increase the 5-HT occupancy rate to a level in the range of about 5% to about 60% (e.g., in the range of about 20% to about 50%). 2A The -R% occupancy range is achieved using a transdermal system that continuously delivers active agent to achieve and maintain a plasma psilocycin concentration in the range of about 1.0 μg / L to about 7.5 μg / L (e.g., 1.5 μg / L to about 5.0 μg / L).

[0217] The method is carried out in the method of use for treating mental health conditions in subjects.Examples of mental health conditions that can be treated herein include traumatic brain injury and stroke, moderate traumatic brain injury (mTBI), opioid withdrawal, addiction, smoking cessation, attention deficit hyperactivity disorder (ADHD), dementia, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), social phobia, obesity, and anorexia. These include, but are not limited to, bulimia, pain, mania, generalized anxiety disorder (GAD), agoraphobia, specific phobia, panic disorder, separation anxiety disorder, acute stress disorder, adjustment disorder, reactive attachment disorder, somatic symptom disorder, illness anxiety disorder, anorexia nervosa, bulimia nervosa, rumination disorder, restless legs syndrome, obsessive-compulsive disorder, postpartum depression, schizophrenia, tic disorders (including Tourette's syndrome), dysthymia (mild chronic depression), alcohol use disorder, seasonal affective disorder, major depressive disorder (treatment-resistant depression), body dysmorphic disorder, depression in Alzheimer's disease or dementia, dementia with Lewy bodies, Parkinson's disease dementia, bipolar disorder types 1 and 2, post-concussion headache, and depression in terminally ill patients.

[0218] In another embodiment, the present invention is used to treat an inflammatory and / or autoimmune condition in a subject. Exemplary such conditions include neuropathy, sarcoma, Parkinson's disease, Parkinson's psychosis, cluster headache, irritable bowel syndrome, chronic obstructive pulmonary disease, asthma, migraine, atherosclerosis, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baro's disease, Bechet's disease, and others. disease), benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital cardiac conduction disorders, Coxsackie myocarditis, Crest syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EOE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell Myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schönlein purpura (HSP), Herpes gestationis or Pemphigoid of pregnancy (PG), Sweat gland suppuration (HS) (Acne contralateralis), Hypogammaglobulinemia, IGA nephropathy, IGG4-associated sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes mellitus (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Lignin conjunctivitis, Linear IgA disease (LAD), Lupus, Chronic Lyme disease, Meniere's disease, Microscopic polyangiitis (MPA),Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus erythematosus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), pancreatic cancer, ... Leigh-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestin syndrome Teron dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome ( These include SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), unclassifiable connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease.

[0219] Specific indications of interest that can be treated using the systems, formulations, and methods of the present invention include: neuropathic pain; post-traumatic stress disorder (PTSD); obesity; depression and anxiety (including end-of-life anxiety); traumatic pain; neurodegenerative diseases, e.g., Alzheimer's disease; cluster headaches; and alcoholism.

[0220] Experimental section: Example 1 Preparation of psilocin The following manufacturing method allows for the rapid isolation of psilocin from hallucinogenic mushrooms by simultaneous extraction of psilocin and psilocybin. Dilute acetic acid is used as the solvent since both compounds are highly soluble in acetic acid and only small amounts of interfering substances are extracted. Heating the acid extract completely dephosphorylates psilocybin to psilocin. Addition of base is followed by rapid extraction into ether to avoid any possible decomposition of psilocin at pH above 7. The method, extraction, and dephosphorylation steps produce reasonably pure psilocin from small amounts of mushroom material.

[0221] Protocol: 1. Grind a representative sample of 2-10 g of dried mushrooms into a fine powder with a mortar and pestle. 2. Mix the powder with 100 mL of dilute acetic acid in a 250 mL beaker. Readjust the pH to 4 using glacial acetic acid. 3. After standing for 1 hour, place the beaker in a boiling water bath for 8-10 minutes or until the internal temperature of the acid mixture reaches 70C. 4. Remove the beaker and cool to room temperature under running water. 5. The acid mixture is then separated from the mushroom powder by suction filtration using glass wool. 6. The filtrate is brought to pH 8 with concentrated ammonium hydroxide and rapidly extracted with two 50 mL portions of diethyl ether. The mixture should be gently stirred rather than shaken to prevent emulsification. 7. Dry the ether over sodium sulfate, filter, and evaporate under nitrogen without heat. 8. Crude psilocin will appear as a greenish residue. Recrystallize from chloroform / n-heptane (1:3) to obtain white crystals.

[0222] Neocortical 5-HT associated with optimal therapeutic outcomes 2ATo confirm receptor occupancy levels, studies are conducted with human volunteers in which the volunteers are administered a hallucinogen transdermally using the transdermal systems, formulations, and methods of the present invention. Plasma levels of the active agent or its metabolites are determined at regular time intervals and correlated with each volunteer's subjective drug experience. A preferred method is a modification of the evaluation performed and described by Madsen et al. (2018), where the transdermal system or formulation is used instead of oral drug administration. Optimal plasma levels and associated 5-HT 2A The receptor occupancy level is determined, and then the transdermal system is engineered to provide active agent release throughout the drug delivery period such that optimal plasma levels are achieved and are approximately constant throughout drug delivery. This can be accomplished by using any or all of the following techniques: increasing or decreasing the drug loading in the formulation / reservoir; increasing or decreasing the amount of enhancer; varying the enhancer to active agent ratio; testing different enhancer compositions and pH adjusters; incorporating various optional excipients such as viscosity adjusters and active agent stabilizers; or using a rate-controlling membrane to increase or decrease the release rate to the desired range.

[0223] Specifically, in the case of psilocin, the findings of Madsen et al. 2A This provides a starting point for identifying optimal plasma psilocin levels that correlate with receptor occupancy levels. According to our studies, the skin flux of psilocin is 1 μg / cm 2 / hr~10μg / cm 2 / hr range, average 5μg / cm 2 / hr. Patch area 50cm 2 For 55 μg / cm, the dose per hour of input ranges from 50 μg / hr / patch to 500 μg / hr / patch. At this patch size, the upper limit of the hourly input is close to that of the 1 mg intravenous application. Daily doses range from 1.2 mg / day / patch to 12 mg / day / patch. 2 / hr skin flux, the hourly input is 250 μg / hr / patch and the daily dose is 6 mg / day / patch. Transdermal systems suitable for achieving the aforementioned delivery profiles can be constructed as described above.

[0224] Example 2 Transdermal Psilocin System A Psilocin (0.129 g) was added to 3.043 g of ethanol. This ethanol / psilocin solution was then added to 3.034 grams of Duro-Tak® 87-4098 adhesive. The final mixture in the vial was placed on a roller for 6 hours.

[0225] The solution was poured onto a 3M® Fluoropolymer Release Liner Film 9755. A casting knife with a gap width of 330 um was used to evenly distribute the adhesive containing Psilocin. The casting solution was left to dry for 6 hours. After drying, a 3M Polyester Backing Film 1109 was placed on top of the dried solution. Surface area 1 cm 2 Patches were punched out and utilized for in vitro diffusion studies. The patch thickness was 130 μm and the loading of psilocin was 4.12%.

[0226] The cast adhesive solution had approximately 4% by weight of psilocin after drying. It should be noted that the weight can vary, for example, from 2% to about 15% by weight. The Duro-Tak adhesive used was an acrylate copolymer-based adhesive, although other adhesives, particularly acrylate adhesives, can also be used.

[0227] Skin from patient 1 (male, 30 years old) was used for in vitro diffusion studies in Franz cells. 2 A disk of 1cm was punched out. 2 A patch of 1cm 2A skin disc was placed on top of the membrane; this was then placed in the membrane. Samples were taken every hour to test for psilocin diffusion. The temperature of the water used as the receptor medium was 32°C and the pH was maintained at 7.4 using PBS buffer. A flow rate of 12 mL / min was used. Two tests, designated A1 and A2, were performed in parallel.

[0228] The cumulative mass released was plotted as a function of time for the first 6 hours and is shown in Figure 6 along with the results obtained for the transdermal system of Example 3 below. The skin flux over time was plotted and is shown in Figure 7 along with the flux obtained for the transdermal system of Example 3.

[0229] Example 3 Transdermal Psilocin System B The procedure of Example 2 was repeated, except that the psilocin loading of the patch was 3.89%. The same process was used to evaluate the cumulative released mass and skin flux, and each test was performed twice, designated B1 and B2. The results obtained for transdermal psilocin tests A1, A2, B1, and B2 are shown in Figures 6 and 7, respectively, as shown above.

[0230] Each transdermal system exhibited a lag time of about 2 hours, as can be seen in Figure 6. Figure 7 shows that the flux was approximately 70 μg / cm 2 This data shows that the patch size is approximately 25 cm when made using the formulation parameters of Examples 2 and 3. 2 It can be estimated that this transdermal system will deliver approximately 42 mg of psilocin per day.

Claims

1. 1. A drug delivery system for transdermal administration of a hallucinogenically active agent to a subject through a localized area of ​​the subject's skin over an extended drug delivery period, the system having an outer surface and a bottom surface; (a) Below: (i) from about 0.5% to about 40% by weight of said hallucinogenically active agent having a known pKa; (ii) a skin permeation enhancing effective amount of an enhancer composition comprising a solvent-type enhancer and a lipid-disrupting enhancer; and (iii) a pH-adjusting effective amount of a pH adjusting agent that maintains the pH in said localized region within 25% of said pKa; a drug reservoir containing a formulation comprising: (b) a backing layer that serves as the outer surface of the system during drug administration; and (c) a means for applying the system to the localized area of ​​the subject's skin. Including, the system.

2. The system of claim 1 , wherein the drug reservoir comprises a polymer matrix.

3. The system of claim 2 , wherein the polymer matrix is ​​comprised of a skin contact adhesive that serves as the means for affixing the system to the localized area of ​​the subject's skin.

4. 10. The system of claim 1, wherein the means for attaching the system to the skin of the subject comprises a layer of skin contact adhesive laminated to the drug reservoir and serving as the bottom surface of the system during drug administration.

5. The system of claim 1 , wherein the drug reservoir comprises a sealed pouch and the formulation is in liquid form.

6. The system of claim 1 , wherein the drug reservoir comprises a microporous drug reservoir loaded with the formulation.

7. The system of claim 1 , wherein the formulation additionally comprises a pharma- ceutically acceptable liquid vehicle.

8. The system of claim 1 , wherein the hallucinogen comprises a polar molecule.

9. The system of claim 1 , wherein the pH adjuster adjusts the pH in the localized region to within 15% of the pKa.

10. The hallucinogen is serotonin 5-HT ２Ａ The system of claim 1 , comprising a receptor agonist.

11. The serotonin 5-HT ２Ａ The system of claim 10, wherein the receptor agonist is selected from tryptamines, phenethylamines, and lysergamides.

12. The serotonin 5-HT ２Ａ The system of claim 11, wherein the receptor agonist is selected from psilocin, bufotenin, N,N-dimethyltryptamine, and lysergic acid diethylamide.

13. The serotonin 5-HT ２Ａ The system of claim 12, wherein the receptor agonist is psilocin.

14. 2. The system of claim 1, wherein the hallucinogen comprises an empathogenic compound selected from 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxyethylamphetamine.

15. The system of claim 1 further comprising at least one additional active agent.

16. 16. The system of claim 15, wherein the at least one additional active agent is selected from an anti-inflammatory agent, an antibacterial agent, an antiviral agent, an anti-cancer agent, an anti-apoptotic agent, a neuroprotective agent, and an antioxidant.

17. 16. The system of claim 15, wherein the at least one additional active agent comprises a cannabinoid.

18. The system of claim 13, further comprising a monoamine oxidase inhibitor in an amount effective to inhibit the degradation of the psilocin in the skin.

19. 16. The system of claim 15, wherein the at least one additional active agent comprises a compound found in Antrodia camphorata mushroom.

20. The system of claim 15 , wherein the at least one additional active agent comprises a terpene or a terpenoid.

21. The system of claim 1 , wherein the formulation additionally comprises a stabilizer for the active agent.

22. 10. The system of claim 1, wherein the formulation additionally comprises at least one excipient selected from a viscosity modifier, an emulsifier, a solubilizer, a preservative, an opacifier, a colorant, a flavoring, a crystallization inhibitor, and a mild additive.

23. The system of claim 1, wherein the long-term drug delivery period ranges from about 6 hours to 84 hours.

24. 24. The system of claim 23, wherein the long-term drug delivery period ranges from about 8 hours to about 24 hours.

25. 10. The system of claim 1, wherein said hallucinogenic active agent is present in an amount effective to provide a blood level ranging from 0.5 ng / ml to about 5.0 ng / ml during said extended drug delivery period.

26. 10. The method of claim 1, wherein the formulation comprises from about 1.0% to about 30% by weight of the hallucinogen.

27. 10. The system of claim 1, wherein the formulation comprises from about 5.0% to about 25% by weight of the hallucinogen.

28. 1. A topically administrable pharmaceutical formulation for transdermal delivery of a hallucinogenically active agent to a subject, said formulation comprising: (a) from about 0.5% to about 40% by weight of said hallucinogenic active agent having a known pKa; (b) a skin permeation-enhancing effective amount of an enhancer composition comprising a solvent-type enhancer and a lipid-disrupting enhancer; and (c) a pH adjusting agent; an effective amount of a pH adjusting agent that maintains the pH within 25% of the pKa in the localized area of ​​skin to which the formulation is applied topically.

13. A pharmaceutical formulation comprising:

29. 1. A drug delivery system for transdermally administering psilocin to a subject through a localized area of ​​the skin of the subject, the system having an outer surface and a bottom surface; (a) Below: (i) about 0.5% to about 40% by weight of psilocin; (ii) a buffering agent in an amount to adjust / maintain a pH in the range of 7.20 to 9.74 in said localized region; and (iii) 0.5% to 15% by weight of a monoamine oxidase inhibitor; a drug reservoir containing a formulation comprising: (b) a backing layer that serves as the outer surface of the system during drug administration. where (c) the drug reservoir is comprised of a skin contact adhesive that serves as a means for attaching the system to the skin of the subject; or (d) a layer of skin contact adhesive material is laminated to the drug reservoir and serves as a means for affixing the system to the skin of the subject. system.

30. 30. The system of claim 29, wherein the formulation further comprises 0.5% to 15% by weight of ascorbic acid or a pharma- ceutically acceptable base addition salt thereof.

31. 1. A drug delivery system for transdermally administering psilocin to a subject through a localized area of ​​the skin of the subject, the system having an outer surface and a bottom surface; (a) Below: (i) 2.5% to 25% by weight of psilocin; (ii) 1.0% to 15% by weight of sodium bicarbonate; (iii) 1.0% to 15% by weight of ascorbic acid, and (iv) 1.0% to 15% by weight of a monoamine oxidase inhibitor; a drug reservoir containing a formulation comprising: (b) a backing layer that serves as the outer surface of the system during drug administration. where (c) the drug reservoir is comprised of a skin contact adhesive that serves as a means for attaching the system to the skin of the subject; or (d) a layer of skin contact adhesive material is laminated to the drug reservoir and serves as a means for affixing the system to the skin of the subject. system.

32. 32. The transdermal delivery system of any one of claims 1-27 and 29-31 for use in a method for treating a subject suffering from a disease or disorder responsive to continuous microdosing delivery of a hallucinogen, said method comprising applying said transdermal delivery system to a localized area of ​​the skin of said subject and allowing said system to remain in place throughout a prolonged drug delivery period.

33. 33. The system of claim 32, wherein the disease or disorder is selected from neuropathic pain; traumatic pain; post-traumatic stress disorder (PTSD); obesity; depression; anxiety; neurodegenerative diseases; cluster headache; and alcoholism.

34. 30. The formulation of claim 28, for use in a method for treating a subject suffering from a disease or disorder responsive to continuous microdosing delivery of a hallucinogen, the method comprising applying the formulation to a localized area of ​​the skin of the subject and allowing the formulation to remain coated and in place throughout a period of extended drug delivery.

Images