Orally administrable formulation

Abstract

An orally administrable formulation of the present invention is provided, which comprises a hydrophilic polymer base having incorporated therein a pharmaceutical ingredient, the pharmaceutical ingredient comprising a pharmaceutical compound selected from a cannabinoid, a hallucinogenic compound, or a mixture thereof, and an absorption enhancer for improving absorption of the pharmaceutical agent across the oral mucosa.

Description

[Technical Field]

[0001] The present invention relates to orally administrable formulations useful for the delivery of pharmaceutical agents. [Background technology]

[0002] Many people worldwide suffer from mental and mood disorders such as depression, anxiety, obsessive-compulsive disorder, and post-traumatic stress disorder. Many of these disorders are thought to involve the patient's serotonin system, which involves the interaction between the neurotransmitter serotonin (often abbreviated as 5-HT) and the various subtypes of neurotransmitter serotonin receptors found in the human body.

[0003] While serotonin-targeting drugs are widely used and commercially successful, they often suffer from slow onset of action, serious side effects, and limited efficacy, resulting in dissatisfaction among users. Furthermore, these drugs are often harmful to users. For example, many people taking prescription serotonin-targeting drugs report suicidal thoughts, sexual dysfunction, fatigue, elevated blood pressure, blurred vision, abnormal heart rate, nausea, and weight gain.

[0004] In recent years, hallucinogenic compounds have returned to the mainstream of medical research. Hallucinogenic compounds such as (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), ibogaine, and mescaline have attracted significant interest due to their remarkable therapeutic efficacy for psychological distress and impressive safety profiles. The term "classic" hallucinogens generally refers to LSD, psilocybin, mescaline, ibogaine, DMT, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and is typically defined by an indole-containing molecular structure, as shown in Figure 1.

[0005] Psilocybin (also known as 4-phosphoryloxy-N,N-dimethyltryptamine or [3-(2-trimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate) is believed to be the most abundant psychoactive compound in many species of fungi. Psilocin (4-hydroxy-N,N-dimethyltryptamine) is believed to be the second most abundant psychoactive compound. When properly formulated and administered, psilocin and psilocybin have been shown to produce rapid effects and long-lasting changes in patients' moods. These effects are achieved with minimal side effects, low addictive potential, low abuse potential, and low risk of toxicity.

[0006] Major barriers to developing oral formulations of large molecules such as hallucinogens include low intrinsic permeability, intraluminal and cellular enzymatic degradation, rapid clearance, and chemical instability in the gastrointestinal (GI) tract. These issues also exist in formulations containing small organic drug molecules, but the solutions that work for small organic drug molecules are not easily applicable to formulations containing hallucinogens.

[0007] The oral route of administration for large molecules has attracted much more attention than other routes of administration. Furthermore, the oral cavity is easily accessible and convenient, and oral membranes, such as the sublingual and buccal mucosa, are relatively permeable, allowing for rapid absorption of orally administered drugs with acceptable bioavailability. However, the ability of a molecule to penetrate the oral mucosa is thought to be related to its size, lipid solubility, and charge, and the permeability of molecules greater than 1000 daltons is significantly reduced. Although several permeation enhancers have been shown to facilitate the mucosal administration of large drug molecules, few of these permeation enhancers have been approved for market launch due to their inadequate safety profiles, reduced mucosal barrier function, impaired mucociliary clearance, and irritating effects. Furthermore, permeation enhancers have a very bitter and unpleasant taste.

[0008] Therefore, it is desirable to develop effective formulations for the delivery of therapeutic compounds, such as, for example, hallucinogenic compounds. Summary of the Invention [Means for solving the problem]

[0009] Provided herein are novel orally administrable formulations.

[0010] In one aspect of the present invention, an orally administrable formulation is provided in which a pharmaceutical component, including a pharmaceutical agent or a mixture of pharmaceutical agents and an absorption enhancer, is incorporated into a hydrophilic polymer matrix.

[0011] In another aspect of the present invention, there is provided an orally administrable formulation comprising a pharmaceutical ingredient, including a pharmaceutical agent or a mixture of pharmaceutical agents, an enzymatic absorption enhancer, and a non-enzymatic absorption enhancer, incorporated into a hydrophilic polymer base.

[0012] These and other aspects of the invention are described herein. DETAILED DESCRIPTION OF THE INVENTION

[0013] Provided herein are novel orally administrable formulations comprising a hydrophilic polymer base admixed with a pharmaceutical ingredient comprising a pharmaceutical agent and an absorption enhancer combination.

[0014] Orally administrable formulations of the present invention may include any one or mixture of a variety of pharmaceutical agents, including, for example, one or more of the agents listed below.

[0015] The pharmaceutical agents contained in the compositions of the present invention are not particularly limited. Examples of pharmaceutical agents that may be incorporated into the formulations of the present invention include, but are not limited to: Antimicrobial agents, such as triclosan, cetylpyridinium chloride, domiphen bromide, quaternary ammonium salts, zinc compounds, sanguinarine, fluoride, alexidine, chlorhexidine, octenidine, EDTA, etc.; Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, naproxen, diclofenac, tolmetin sodium, and indomethacin; Antitussives, such as benzonatate, caramiphen edisylate, menthol, dextromethorphan hydrobromide, clofedanol hydrochloride, etc.; Decongestants, such as pseudoephedrine hydrochloride, phenylephrine, phenylpropanolamine, pseudoephedrine sulfate, etc.; Antihistamines, such as brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, diphenylpyraline hydrochloride, azatadine maleate, diphenhydramine citrate, doxylamine succinate, promethazine hydrochloride, pyrilamine maleate, tripelennamine citrate, triprolidine hydrochloride, acrivastine, loratadine, brompheniramine, dexbrompheniramine, cetirizine, levocetirizine, etc. Expectorants, such as guaifenesin, ipecac, potassium iodide, terpines, etc.; Antidiarrheal drugs, such as loperamide; H2 antagonists, such as famotidine and ranitidine; Proton pump inhibitors, such as omeprazole and lansoprazole; · Non-selective central depressants, such as aliphatic alcohols and barbiturates; Non-selective central stimulants, such as caffeine, nicotine, nicotine polacrilex, nicotine in combination with alkaline agents, strychnine, picrotoxin, pentylenetetrazole, etc.; Drugs that selectively modulate central nervous system functions, such as phenylhydantoin, phenobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, diazepam, benzodiazepines, phenacemide, feneturide, acetazolamide, sulthiame, bromides, etc.; Anti-Parkinson's medications, such as levodopa and amantadine; Antipyretic analgesics, such as salicylates, phenylbutazone, indomethacin, phenacetin, etc. Antipsychotics, such as chlorpromazine, methotrimeprazine, haloperidol, clozapine, reserpine, imipramine, tranylcypromine, phenelzine, MC-4 receptor antagonists, lithium, etc. · Hypnotics, sedatives, antiepileptics, stimulants; Vitamins and minerals; · Amino acids and peptides; ·Sildenafil citrate; ·PPY(3-36); decapeptide; KSL-W (acetate), fluor; Antidiabetic drugs, such as metformin, metformin HCl, glyburide, insulin secretagogues, insulin stimulants, lipid metabolism drugs, glucose metabolism drugs, insulin, cholesterol-lowering drugs such as statins, exenatide, GLP-1, etc.; Opioid analgesics, such as alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cocaine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, oxymorphone, hydromorphine, naltrexone, naloxone, 14-hydroxycodeinone, neopinone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphan ol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, diamorphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptadine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, μ agonist / μ antagonist mixtures, μ antagonist combinations, mixtures of the above drugs, and the like; the opioid analgesic may be in the form of a free base, a pharmaceutically acceptable salt, or a pharmaceutically acceptable complex; terpenes and / or terpenoids derived from plants or fungi, such as, but not limited to, myrcene, beta-caryophyllene, pinene, limonene, terpinolene, humulene, nerolidol, linalool, ocimene, guaiol, bisabolol, alpha-phellandrene, cadinene, camphene, camphor, citral, citronellol, delta-3-carene, eucalyptol, eugenol, gamma-terpinene, geraniol, humulene, nerol, nerolidol, ocimene, p-cymene, phytol, pulegone, terpineol, valencene, and mixtures or pharmaceutically acceptable salts thereof; "Cannabinoids" and "Cannabinoid Derivatives." As used herein, "cannabinoids" and "cannabinoid derivatives" refer to various compounds that act on cannabinoid receptors, such as cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), in cells to inhibit the release of neurotransmitters in the brain. Cannabinoids include endocannabinoids (cannabinoids naturally produced in humans and animals, e.g., arachidonoylethanolamide (anandamide), 2-arachidonoylglycerol (2-AG), and arachidonylglyceryl ether (nolazine ether)); phytocannabinoids (cannabinoids found in plants such as cannabis, e.g., tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN)); synthetic cannabinoids (artificially produced cannabinoids), and functionally equivalent derivatives and analogs thereof. Examples of cannabinoids include cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivaric acid (CBDVA), cannabinovarin (CBNV), cannabigerovarin (CBGV), cannabichromene (CBC); JWH-018, JWH-073, JWH-398, JWH-200, JWH-081, and 4-methyl-JWH-073. naphthoylindoles such as JWH-015, JWH-122, JWH-220, JWH-019, and JWH-007; phenylacetylindoles such as JWH-250 and JWH-203; benzoylindoles such as RCS-4, AM-694, and WIN48,098; cyclohexylphenols such as CP47,497-C8 and CP47,497; and HU-210 and 3-dimethylneptyl-11-carboxylic acid congener 8.Cannabinoids also include tetrahydrocannabinoids and their analogs, i.e., delta-9-tetrahydrocannabinol (THC or dronabinol) and functionally equivalent compounds, such as delta-8-tetrahydrocannabinol (D8-THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarinic acid (THCVA), nabilone, rimonabant (SR141716), JWH-018, JWH-073, CP-55940, dimethylheptylpyran, HU-210, HU-331, SR144528, WIN55,212-2, JWH-133, levonantradol, AM-2201, and the like. Mixtures of the above cannabinoids are also encompassed. "Functionally equivalent," with respect to cannabinoid analogs and derivatives, refers to compounds that bind to cannabinoid receptors and / or exhibit the same or comparable therapeutic effect (e.g., at least about 50% of the activity of the parent cannabinoid compound); Fungal polysaccharides, polysaccharide-protein complexes, or polysaccharide-peptide complexes (PSPs), glycoproteins, proteoglycans, α-glucans, β-glucans, heteroglycans, peptidoglycans, or lectins, which have therapeutic activities such as antitumor, immunomodulatory, antioxidant, anti-inflammatory, antimicrobial, and antidiabetic activities; · Biological response modifiers (BRMs), such as monoclonal antibodies, interferons, interleukins, tumor necrosis factors, colony-stimulating factors and vaccines; Hallucinogenic compounds, such as indole-containing hallucinogenic compounds. Examples of hallucinogenic compounds include tryptamine, phenethylamine, ketamine, ibotenic acid, muscimol, salvinorin A, and lysergamide, including, for example, DMT (N,N-dimethyltryptamine), which may be in the form of ayahuasca, 5-hydroxy-N,N-dimethyltryptamine (5-HO-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), LSD (lysergic acid diethylamide), mescaline (3,4,5-trimethoxyphenethylamine), ibogaine, PCP (phenylcyclohexylpiperidine), and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin), as well as analogs thereof, such as [3-[2-(methylamino)ethyl]-1H-indol-4-yl]dihydrogen phosphate (baeocystin), and and 4-hydroxy-N,N-dimethyltryptamine (psilocin), further including amphetamine, 3,4-methylenedioxyamphetamine (MDA), methylenedioxyethylamphetamine (MDEA), MDMA (3,4-methylenedioxymethamphetamine), and analogs or combinations thereof; and also including extracts and / or compounds extracted from other sources such as fungi of the genera Bromhemia, Bromhemia, Bromhemia, Bromhemia, Bromhemia, Bromhemia, Bromhemia, Bromhemia, and other plants, such as cacti, including, for example, phenethylamine alkaloid (e.g., mescaline)-containing extracts extracted from cacti of the genera Echinopsis or Lophophora.

[0016] The pharmaceutical agent of choice may be readily available commercially.

[0017] Alternatively, certain pharmaceutical agents may be synthesized chemically or biosynthetically using methods available in the art.

[0018] Plant-derived and fungal-derived compounds, such as cannabinoids and terpenes, may be obtained using established extraction methods or chemically synthesized. Cannabinoids and some terpenes may be extracted from plants of the Cannabis genus (e.g., Cannabis sativa, Cannabis indica, and Cannabis ruderali). Terpenes may also be extracted from other plants, such as tea, thyme, and sage, from fruits such as citrus fruits, and from fungi. Some of these compounds are commercially available. In another embodiment, plant material containing cannabinoids and / or terpenes may be directly incorporated into the formulations of the present invention, as described in U.S. Pat. No. 9,833,408, the contents of which are incorporated herein by reference.

[0019] Fungal compounds, such as hallucinogenic compounds, may be extracted from fungal products (e.g., mushrooms) and provided as a dry powder or a liquid extract in a solvent. Psilocybin may be extracted from mushroom material using alcohol and then crystallized. Another extraction protocol that may be used is the following: In a beaker, crushed mushrooms are mixed with dilute acetic acid and titrated with acid (e.g., concentrated (glacial) acetic acid) to a pH of 4. After incubation, the mixture is heated to 70°C. This heating step dephosphorylates psilocybin to produce psilocin. The acid mixture is separated from the raffinate, adjusted to pH 8, and extracted, for example, with diethyl ether. The extraction solvent is evaporated to yield a precipitate of psilocin, which may then be crystallized, for example, with a 1:3 mixture of chloroform and heptane, to yield a white powder.

[0020] In another embodiment, the fungal product may be dried and ground using established protocols and incorporated directly into the formulations of the present invention.

[0021] Hallucinogenic compounds may also be chemically or biochemically synthesized using known chemical synthesis methods and used in the formulations of the present invention.

[0022] A pharmaceutical ingredient may contain two or more pharmaceutical agents. In one embodiment, the two or more pharmaceutical agents may target a specific condition. Thus, treatment may be enhanced by each pharmaceutical agent treating a specific condition through the same or different mechanisms of action (multimodal). For example, a formulation of the present invention may be designed to treat pain using a multimodal approach and thus may contain a pharmaceutical ingredient including an opioid, an NSAID, acetaminophen, and / or an SSRI antidepressant. Alternatively, a formulation of the present invention may contain a combination of an analgesic compound, such as an opioid analgesic, with a second pharmaceutical agent, where the second pharmaceutical agent is selected from a cannabinoid, a terpene or terpenoid, and / or a hallucinogen, or may include two or more hallucinogens, and may be combined with a cannabinoid and / or a terpene. A combination of pharmaceutical agents that exhibits a synergistic effect is preferred, i.e., a combination that exhibits a therapeutic effect greater than the additive therapeutic effect of each pharmaceutical agent alone. In this regard, the dosage of at least one of the combined pharmaceutical agents is preferably reduced, for example, by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75% or more, compared to the dosage of the pharmaceutical agent used alone. Such a dosage reduction may also result in a more favorable or reduced side effect profile. In one embodiment, the dosage of the opioid analgesic is reduced by such a multimodal combination.

[0023] In another embodiment, multiple pharmaceutical agents may be combined in the formulations of the present invention to treat multiple aspects of a particular condition, such as pain or inflammation, and may further incorporate anti-tumor or other pharmaceutical agents. The combination of multiple pharmaceutical agents for treating multiple aspects of a particular condition may be selected to provide a therapeutic effect greater than the therapeutic effect of each pharmaceutical agent alone, as described above. Examples of pharmaceutical agents that may be combined include an anti-inflammatory agent such as diclofenac, acetaminophen, ibuprofen, ketoprofen, or naproxen (or other anti-inflammatory agents described herein), an opioid analgesic such as morphine, codeine, hydromorphone, oxycodone, or fentanyl (or other opioid analgesics such as those described herein), and a hallucinogen such as psilocybin (or other hallucinogens described herein). This combination may further include a cannabinoid or terpene, as listed above. An exemplary combination is diclofenac, psilocybin, and an opioid such as morphine or hydromorphone. This combination may be further enhanced by the addition of cannabinoids such as CBD.

[0024] The amount of single or multiple pharmaceutical agents (including combinations of pharmaceutical agents) in the formulations of the present invention will vary depending on the particular pharmaceutical agent selected, the form of pharmaceutical agent incorporated into the formulation, the condition being treated, and the effective dosage of each pharmaceutical agent. Typically, formulations of the present invention will contain about 0.1-40% by weight of a pharmaceutical agent, with 1-30% by weight being preferred. As those skilled in the art will readily appreciate, appropriate dosages of pharmaceutical agents will vary depending on the particular pharmaceutical agent. In one embodiment, the formulations of the present invention contain a cannabinoid in an amount of about 1-60 mg per dosage form. In another embodiment, the formulations of the present invention contain a hallucinogen in an amount of about 1-60 mg per dosage form.

[0025] In further embodiments, the formulations of the present invention preferably contain a therapeutically effective amount of a mixture of pharmaceutical agents, thereby complementing or enhancing the therapeutic effects of one or more pharmaceutical agents. In this regard, the amount of the pharmaceutical agent combination incorporated into the formulations of the present invention may be about 0.1-100 g, about 1-60-80 g, or about 5-50 g. As used herein, the term "about" refers to an amount that varies by ±10% from the amount stated herein. As will be readily understood by those skilled in the art, the amount of each pharmaceutical agent will vary depending on the therapeutically effective amount of each pharmaceutical agent. An exemplary multimodal combination includes 10-50 mg of diclofenac, 2-50 mg of psilocybin, and 10-30 mg of an opioid (e.g., morphine) or 1-10 mg of the opioid hydromorphone, and may further include 10-50 mg of CBD. Another exemplary combination is 25 mg of diclofenac, 10 mg of psilocybin, 20 mg of CBD, and 2 mg of hydromorphone.

[0026] The formulations of the present invention comprise a hydrophilic polymer base. The components of the hydrophilic polymer base may vary widely depending on the desired chewing and other sensory properties of the final product. Thus, the term "hydrophilic polymer base" refers to a base for the formulations of the present invention that is suitable for oral administration, contains a hydrophilic elastomeric polymer that is soluble in the oral cavity (i.e., in an aqueous solution) and may be chewable, and is combined with one or more ingredients that complement the properties of the hydrophilic polymer base. Thus, upon dissolution in the oral cavity, the hydrophilic polymer base releases a pharmaceutical agent, which is then absorbed through the oral mucosa. The hydrophilic polymer base may comprise a single hydrophilic elastomeric polymer or a combination of hydrophilic elastomeric polymers, and the content of each hydrophilic elastomeric polymer is approximately 1 to 40% by weight of the entire formulation of the present invention. The total content of the hydrophilic polymers in the entire formulation of the present invention is preferably 1 to 80% by weight, and may be, for example, 10 to 60% by weight.

[0027] The hydrophilic polymer base comprises one or more hydrophilic elastomeric polymers suitable for forming a gel in aqueous solution. As those skilled in the art will readily appreciate, the hydrophilic polymer selected will vary depending on the pharmaceutical agent to be delivered and its desired release characteristics, including, for example, immediate or sustained release, delayed release, pulsed release, extended release, controlled release, targeted release, or programmed release. Thus, to achieve immediate release, a rapidly dissolving hydrophilic polymer or combination of such polymers is selected for use in the formulations of the present invention, while to achieve sustained or delayed release, a slowly dissolving hydrophilic polymer or combination of such polymers is selected. To achieve a combination of immediate and delayed release of pharmaceutical agents, a formulation comprising multiple layers may be utilized. For example, a pharmaceutical agent to be rapidly released may be formulated in a layer comprising a rapidly dissolving hydrophilic polymer or combination thereof, and a pharmaceutical agent to be delayed released may be formulated in a layer comprising a slowly dissolving hydrophilic polymer or combination thereof.

[0028] Examples of suitable gel-forming elastomeric polymers include, but are not limited to, polyethylene glycol, polyacrylamide, polyacrylic acid, acrylic acid, polyacrylic acid copolymers, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, glycolide, polylactide, methyl methacrylate copolymers, carboxyvinyl polymers; polysaccharides such as pullulan, amylose, high amylose starch, hydroxypropylated high amylose starch, alginate, pectin, dextrin, dextran, chitin, chitosan, levan, elsinan, scleroglucan, and alternan; and combinations thereof. The amount of these elastomeric polymers is such that they dissolve, disperse, and swell in water to form an internal structure with weak cohesion, for example, a three-dimensional network that increases the volume of the water in which they are contained, thereby forming a dissolvable film or a dissolvable gel when orally administered.

[0029] Additional second film-forming agents that may be added to the hydrophilic polymer base to optimize tensile strength, stability, flexibility, solubility, and brittleness include agents such as xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, carrageenan gum, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and mixtures thereof. The amount of second film-forming agent varies depending on the amount and properties of the hydrophilic elastomeric polymer, and is typically 0.1 to 10% by weight of the total hydrophilic polymer base (excluding water).

[0030] The hydrophilic elastomeric polymer is preferably pullulan, and its content is in the range of about 1 to 80% by weight of the total hydrophilic polymer base, preferably about 25 to about 60% by weight, and more preferably about 30 to about 50% by weight of the total hydrophilic polymer base. Another preferred film-forming agent is a mixture of pullulan with alginate or hydroxypropylmethylcellulose, or a mixture of all of these. Preferred second film-forming agents include xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, gelatin, and / or carrageenan gum.

[0031] Plasticizers may be added to the hydrophilic polymer base to vary the consistency of the formulations of the present invention. Examples of plasticizers that may be added to the hydrophilic polymer base include n-butyl stearate; oleic acid; monoglyceryl, diglyceryl, or triglyceryl esters of saturated or unsaturated fatty acids, which are oleic acid, caprylic acid, butyric acid, capric acid, caproic acid, and lauric acid; mineral oil, liquid petroleum hydrocarbons, squalane, squalene, castor oil, and other ricinoleic acid derivatives; diethylene glycol, propylene glycol, and their derivatives; tributylacetyl citrate, tributyl citrate, lecithin, coconut oil, and the like. Examples of suitable plasticizers include, but are not limited to, oils, glyceryl tributyrate, zinc laurate, calcium stearate, propylene glycol monostearate, propylene glycol monolaurate, fatty acids, glycerin, butyl sebacate, butyl benzyl sebacate, diacetyl tartaric acid esters of mono- and diglycerides of edible fats and oils or edible lipid-forming acids; acetylated monoglycerides; petrolatum, stearyl citrate monoglyceride, limonene, polylimonene, butyl lactate, butyl oleate, and mixtures thereof. The content of the plasticizer in the formulation of the present invention may be in the range of about 0 to 60% by weight, for example, 1 to 50% by weight or 10 to 40% by weight, based on the total weight of the hydrophilic polymer base.

[0032] The hydrophilic polymer base may contain natural or synthetic resins. Examples of natural or synthetic resins include natural rosin esters (often referred to as ester gums), such as the glycerol ester of partially hydrogenated rosin, the glycerol ester of polymerized rosin, the glycerol ester of partially dimerized rosin, the glycerol ester of tall oil rosin, the pentaerythritol ester of partially hydrogenated rosin, the methyl ester of rosin, the methyl ester of partially hydrogenated rosin, and the pentaerythritol ester of rosin; synthetic resins, such as terpene resins derived from α-pinene, β-pinene, and / or d-limonene; and natural terpene resins. The content of the resin (including a combination of resins) in the formulation of the present invention may be 5 to 10 wt. % of the total hydrophilic polymer base.

[0033] The formulation of the present invention may contain a softener in addition to the plasticizer in the hydrophilic polymer base. Suitable softeners include, but are not limited to, glycerin, edible oil, mannitol, and sorbitol. The content of these waxes may range from about 1 to 10% by weight based on the total weight of the hydrophilic polymer base.

[0034] The hydrophilic polymer base of the formulation of the present invention may optionally contain one or more excipients / conditioners, examples of which include magnesium carbonate, calcium carbonate, sodium sulfate, limestone powder, silicates such as magnesium silicate and aluminum silicate, kaolin and clay, aluminum oxide, aluminum phosphate, silicon oxide, talc, titanium oxide, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, cellulose polymers such as wood fiber, mineral oils such as paraffin oil, plant saponins derived from soapberry, soybean, or broadleaf saponin, and combinations thereof. Preferably, the excipients are hydrophobic. The content of the excipients / conditioners in the hydrophilic polymer base is sufficient to obtain a polymer base with the desired consistency.

[0035] The hydrophilic polymer base of the formulation of the present invention may further comprise a water-soluble wax. Suitable waxes include microcrystalline waxes containing isoparaffinic (branched) hydrocarbons and naphthenic hydrocarbons, such as Microwax. TM 1750, Microwax TM 820, Paramelt® HMP (a blend of refined mineral waxes and hydrocarbon waxes with a high melting point and low oil content), Paramelt LMP (a microwax with a low melting point and low oil content), and microwax TM ZG. The wax content may be in the range of about 1 to 10% by weight based on the total weight of the hydrophilic polymer base.

[0036] The hydrophilic polymer base and optional additional base components (e.g., secondary film-forming agents, plasticizers, resins, softeners, excipients, and waxes) and their amounts determine the properties of the formulations of the present invention. Therefore, as will be readily apparent to those skilled in the art, these bases and base components and their amounts may be varied to obtain orally administrable formulations with desired properties, such as solubility and drug release profile.

[0037] In one embodiment, the orally administrable formulation of the present invention comprises a polymeric base comprising one or more hydrophilic elastomeric polymers in an amount ranging from about 45 to 85% by weight, preferably about 50 to 80% by weight, e.g., about 55%, 60%, 65%, 70%, or 75% by weight of the total polymeric base; a second film-forming agent in an amount ranging from about 5 to 15% by weight, based on the total polymeric base; and a plasticizer in an amount ranging from about 10 to 40% by weight, e.g., 15%, 20%, 25%, 30%, or 35% by weight, based on the total polymeric base. As used herein, the term "about" indicates a variation of up to about ±10% from the amounts recited herein.

[0038] In one embodiment, the orally administrable formulation of the present invention comprises a polymer base containing 50-80% by weight of one or more polysaccharide polymers. This polymer base may contain a non-polysaccharide polymer, such as hydroxypropyl methylcellulose, in an amount of 10% by weight or less based on the total polymer base. Polysaccharides that can be used include pullulan, amylose, high-amylose starch, hydroxypropylated high-amylose starch, alginate, pectin, dextrin, dextran, chitin, chitosan, levan, elsinan, scleroglucan, and alternan. Preferred polysaccharides include pullulan, starch, alginate, pectin, dextran, and dextrin. The polymer base may further comprise a second film-forming agent, such as xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, carrageenan gum and / or gelatin, in an amount of about 5-10% by weight of the total polymer base.

[0039] The pharmaceutical ingredients contained in the formulations of the present invention include a selected pharmaceutical agent, such as an analgesic (NSAID and / or opioid), a hallucinogenic compound, and / or a cannabinoid, and an absorption enhancer, which is then mixed with a hydrophilic polymer base. The pharmaceutical agent and the absorption enhancer can be mixed and then added to the hydrophilic polymer base, or the pharmaceutical agent and the absorption enhancer can be added separately to the hydrophilic polymer base. The absorption enhancer of the present invention can facilitate the absorption of a combination of pharmaceutical agents to achieve a synergistic effect of these pharmaceutical agents.

[0040] In one embodiment, an enzyme-based absorption enhancer is incorporated into the formulation of the present invention. Examples of enzyme-based absorption enhancers used in the formulation of the present invention include, but are not limited to, lipases such as pancreatic lipase (PL), pancreatic lipase-related protein 1 or pancreatic lipase-related protein 2 (PLRP1 / PLRP2), hepatic lipase, endothelial lipase, lipoprotein lipase, lysosomal lipase, gastric lipase, and lingual lipase. The content of the enzyme-based absorption enhancer in the formulation of the present invention is in the range of 25 to 170 U per liter of the formulation of the present invention, or 0.01 to 10% by weight of the total pharmaceutical ingredient, or 0.05 to 5% by weight of the total pharmaceutical ingredient.

[0041] In another embodiment, non-enzymatic absorption enhancers may be utilized. Examples of non-enzymatic absorption enhancers include bile acids. Examples of bile acids suitable for use in the formulations of the present invention include, but are not limited to, cholic acid or cholic acid derivatives such as deoxycholic acid, glycocholic acid, chenodeoxycholic acid, taurocholic acid, glycodeoxycholic acid, and taurodeoxycholic acid, or salts and mixtures thereof. Examples of salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorous acid; and those derived from non-toxic organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium; and those derived from non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine. Other salts include sulfate, citrate, phosphate, and tartrate salts. A preferred bile salt for use in the formulations of the present invention is sodium deoxycholate.

[0042] Additionally or alternatively, to further enhance absorption, the formulations of the present invention may contain one or more non-enzymatic absorption enhancers, such as polyoxyethylene ethers, polyoxyethylene esters, or polyoxyethylene alcohols; alkali metal alkyl sulfates, such as C8-C 22 Alkyl, preferably C 12 Examples of suitable surfactants include alkyl sulfates of alkali metals, such as alkyl(lauryl) and alkali metals such as sodium and potassium, such as sodium lauryl sulfate; lecithin, hyaluronic acid, pharmaceutically acceptable hyaluronate, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, oleic acid, linoleic acid, linolenic acid, monoolein, monooleic acid esters, monolauric acid esters, borage oil, evening primrose oil, chamomile extract, cucumber extract, menthol, trihydroxyoxocoloylglycine, lysine, polylysine, triolein, and polidocanol alkyl ether.

[0043] As used herein, the term "polyoxyethylene ether" (also called polyethylene glycol) includes several types of condensation polymers of ethylene glycol, including, but not limited to, HOCH2(CHOCH2), CH2OH(OCH2CH2), H(OCH2CH2), or OH(OCH2CH2), with an average molecular weight of 200 to 6000. Polyoxyethylene alcohols and polyoxyethylene esters are also suitable. Examples of suitable compounds include Brij TM Compounds, namely, Brij 30, Brij 52, Brij 56, Brij 58, Brij 72, Brij 76, Brij 700, Brij 721, Brij 92, Brij 93, Brij 96, Brij 97, Brij 98, Brij 99, etc. Polyoxyethylene ethers are preferred, with polyoxyethylene (9) lauryl ether being most preferred.

[0044] Examples of lecithins include phospholipon-H TMSaturated phospholipid, phospholipon-G TM These include unsaturated phospholipids, phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin, and lysolecithin.

[0045] In a further embodiment, the enzymatic absorption enhancer may be combined with a non-enzymatic absorption enhancer. For example, as described herein, the enzymatic absorption enhancer may be combined with bile acid or its salt, or another non-enzymatic absorption enhancer, such as polyoxyethylene ether, polyoxyethylene ester or polyoxyethylene alcohol; alkali metal alkyl sulfate; hyaluronic acid, or other absorption enhancer, to improve the absorption of one or more pharmaceutical agents in the formulation of the present invention.

[0046] The amount of absorption enhancer used in the formulation of the present invention may be in the range of 1 to 50% by weight based on the total weight of the formulation of the present invention, for example, 10 to 40% by weight, 5 to 30% by weight, or 1 to 10% by weight based on the total weight of the formulation of the present invention.

[0047] The orally administrable formulations of the present invention are prepared as follows: First, a selected polymer base and other base components, such as a secondary film-forming agent, plasticizer, resin, softener, excipient, wax, etc., are mixed with water in a sufficient amount (amount) of water, such as an amount sufficient to dissolve the hydrophilic polymer base component, under heating to obtain a clear solution. The resulting hydrophilic polymer base is then mixed with pharmaceutical ingredients, including the pharmaceutical agent (in a form suitable for use, e.g., extracted or unextracted form such as plant or fungal material), absorption enhancers, and other desired ingredients as described herein.

[0048] The formulations of the present invention may contain one or more buffering agents that promote the release of pharmaceutical agents from the formulation particles in the oral cavity and improve the bioavailability of pharmaceutical agents, such as cannabinoids, terpenes, and / or their derivatives. Suitable buffering agents include carbonates, such as monocarbonates, bicarbonates, and sesquicarbonates; glycerates; phosphates; glycerophosphates; acetates; gluconates or citrates of alkali metals, such as potassium and sodium, for example, trisodium citrate and tripotassium citrate; ammonium, Tris buffer, amino acids, and mixtures thereof. The buffering agent may be microencapsulated or may be in the form of granules coated with a polymer and / or lipid that is less soluble in saliva than the buffering agent. Such microencapsulation can control the dissolution rate of the buffering agent, effectively promoting the release of the pharmaceutical agent. The buffering agent is typically present in an amount of about 5% by weight or less based on the total formulation of the present invention.

[0049] The formulations of the present invention may contain one or more additional additives, including humectants, inorganic salts, antioxidants, protease inhibitors, emulsifiers, and colorants. Examples of humectants include, but are not limited to, propylene glycol and glycerol. Examples of inorganic salts include sodium, potassium, calcium, and zinc salts, particularly sodium chloride, potassium chloride, calcium chloride, zinc chloride, and sodium bicarbonate. Examples of antioxidants include tocopherol, deferoxamine mesylate, methylparaben, ethylparaben, ascorbic acid, and mixtures thereof. Examples of protease inhibitors include, but are not limited to, bacitracin, bacitracin derivatives such as bacitracin methylenedisalicylate, soybean trypsin, and aprotinin. Examples of emulsifiers include lecithin (e.g., E322, E342), polyglycerol polyricinoleate (e.g., PGPR, E476), citrate esters (e.g., E472c), ammonium phosphatide (e.g., E442), polyoxyethylene emulsifiers (e.g., TWEEN 80), sulfate emulsifiers (e.g., SLS, SDS, SLES), and sorbitan tristearate (e.g., STS, E492). The total content of such additional additives may be about 1-5% by weight of the entire composition. Bacitracin and its derivatives are preferably present in an amount of 1.5-2% by weight of the entire composition, and soybean trypsin and aprotinin are preferably present in an amount of about 1-2% by weight of the entire composition.

[0050] The formulations of the present invention may also contain antimicrobial agents. In one embodiment, the formulations of the present invention contain one or more essential oils that confer antimicrobial properties. The amount of essential oil selected for use in the formulations of the present invention is preferably an amount sufficient to confer antimicrobial effects without altering the physical properties of the formulations of the present invention, e.g., an amount ranging from 0.01 to 15% by weight (although amounts beyond this range may be used). Typically, oils such as thymol, methyl salicylate, and / or eucalyptol may be present in an amount of about 0.01 to about 4% by weight of the total formulation of the present invention, preferably about 0.50 to about 3.0% by weight of the total formulation of the present invention, and more preferably about 0.70 to about 2.0% by weight of the total formulation of the present invention. Menthol may be added in an amount ranging from about 0.01 to about 15% by weight of the total formulation of the present invention, preferably about 2.0 to about 10% by weight of the total formulation of the present invention, and more preferably about 3 to about 9% by weight of the total formulation of the present invention. The appropriate amount of a selected antimicrobial oil to include in the formulations of the present invention can be readily determined by one of ordinary skill in the art.

[0051] A saliva stimulant may be added to the formulation of the present invention. Examples of saliva stimulants include food acids such as citric acid, lactic acid, malic acid, succinic acid, ascorbic acid, adipic acid, fumaric acid, and tartaric acid. Preferred food acids are citric acid, malic acid, and ascorbic acid. The amount of saliva stimulant added to the formulation of the present invention may be in the range of about 0.01 to about 12% by weight, and preferably in the range of about 1 to about 10% by weight.

[0052] The formulation of the present invention may contain one or more additional agents, and the amount of each agent may be about 1 to 5% by weight of the total formulation of the present invention. Examples of the additional agents include solubilizing agents, charge control agents, pH control agents, modulators of the physiological function of epithelial adhesion structures, such as nitric oxide (NO) stimulators, chitosan or chitosan derivatives, vasodilators, selective transport enhancers, delivery vehicles, delivery carriers, delivery supports, or delivery complex-forming species that effectively mix, associate with, contain, encapsulate, or bind exendin(s) to stabilize the active agent and promote mucosal transport, low-molecular-weight hydrophilic permeation enhancers, emulsifiers, mucolytic or mucus-cleaving agents (e.g., mucoadhesives and mucosal transport enhancers), membrane permeation enhancers, such as (i) alcohols, (ii) ethanol, and (iii) ethanol. (iii) NO donor compounds, (iv) long-chain amphipathic molecules, (v) hydrophobic small molecule permeation enhancers, (vi) sodium or salicylic acid derivatives, (vii) glycerol esters of acetoacetic acid, (viii) cyclodextrin derivatives or β-cyclodextrin derivatives, (ix) medium-chain fatty acids, (x) chelating agents, (xi) amino acids or salts thereof, (xii) N-acetylamino acids or salts thereof, (xiii) fatty acid synthesis inhibitors, (xiv) cholesterol synthesis inhibitors; or (xv) any combination of the membrane permeation enhancers described in (i) to (xv) above.

[0053] Examples of mucoadhesives or mucosal transport enhancers suitable as enhancers include Carbopol 934 + HPC, maize + Carbopol 907, HPC (hydroxypropyl cellulose), CMC or Na-CMC (carboxymethyl cellulose), HPMC (hydroxypropyl methyl cellulose), HEMA (hydroxyethyl methacrylate), Carbopol 907 crosslinked with sucrose, polyacrylic acid (PAA), chitosan, lectin, polymethacrylate derivatives, hyaluronic acid, P(AA-co-PEG) monomethyl ether monomethacrylate, PAA-PVP (polyacrylic acid-polyvinylpyrrolidone), PVP-PEG (polyethylene glycol), methylcellulose, pullulan, N-trimethylchitosan, PDMAEMA (poly(dimethylaminoethyl methacrylate)), HEC (hydroxyethyl cellulose), Carbomer 940, Carbomer 971, polyethylene glycol, methylcellulose ... Examples of suitable mucosal transport enhancers include oxide, dextrin, poly(methyl vinyl ether / maleic anhydride), polycarbophil (acrylic acid cross-linked with divinyl glycol), PVP (polyvinylpyrrolidone), agar, tragacanth, sodium alginate, karaya gum, MEC (methyl ethyl cellulose), HPC (hydroxypropyl cellulose), lectin, AB block copolymer of oligo(methyl methacrylate) and PAA, polymers containing thiol groups, spheromer, thiomer, sodium alginate, Carbopol 974P (carbomer), EC (ethyl cellulose), dextran, guar gum, pectin, starch, gelatin, casein, acrylic acid polymers, polymers of acrylic acid esters, acrylic acid copolymers, vinyl polymers, vinyl copolymers, polymers of vinyl alcohol, alkoxy polymers, polyethylene oxide polymers, and polyethers. In one embodiment, the exendin is combined with one, two, three, four, or more of the above mucosal transport enhancers.

[0054] The formulations of the present invention may contain an amount of antifoaming agent to achieve the desired antifoaming effect. Commonly used antifoaming agents include insoluble oils, polydimethylsiloxane and other silicones, certain alcohols, stearic acid esters, and glycols. Antifoaming agents are used to prevent foam formation or are added to destroy existing foam.

[0055] The formulations of the present invention may contain one or more flavorings selected from the group consisting of essential oils, essences, extracts, powders, acids, palm, coffee, chocolate, vanilla, grapefruit, orange, lime, menthol, licorice, caramel flavoring, honey flavoring, peanut, walnut, cashew nut, hazelnut, almond, pineapple, strawberry, raspberry, apple, pear, peach, apricot, blackberry, cherry, pineapple, plum essence, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg, cinnamon, menthol, peppermint, wintergreen, spearmint, eucalyptus, mint, and any combination thereof. The formulations of the present invention may further contain flue-cured tobacco, burley tobacco, Orient tobacco, dark-cured burley tobacco, flue-cured Virginia tobacco, and dark-cured Kentucky tobacco.

[0056] The formulations of the present invention may contain sweeteners such as bulk sweeteners, sugar sweeteners, sugar substitutes, artificial sweeteners, high-intensity sweeteners, and combinations thereof. Suitable bulk sweeteners include both sugar and non-sugar sweeteners. The content of the bulk sweetener may be about 5 to about 95% by weight of the total oral formulation of the present invention. In some cases, the content of the sweetener may be about 20 to about 80% by weight, for example, 30 to 70% by weight or 30 to 60% by weight of the total oral formulation of the present invention. However, the content of the sweetener may be selected so as to achieve the desired sweetness effect. Useful carbohydrate sweeteners include sugar-containing ingredients commonly known in the art, such as, but not limited to, sucrose, dextrose, maltose, dextrin, trehalose, D-tagatose, dry invert sugar, fructose, levulose, galactose, corn syrup solids, etc., which may be used alone or in combination. Sugar substitutes include, but are not limited to, sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, isomalt, erythritol, lactitol, etc.

[0057] The formulations of the present invention advantageously provide a method for effectively administering pharmaceutical agents, such as analgesics, cannabinoids, terpenes, and / or hallucinogens, or mixtures thereof, which can overcome one or more problems associated with oral formulations of such agents, such as low permeability, rapid degradation, rapid clearance, and chemical instability in the gastrointestinal (GI) tract. The formulations of the present invention incorporate an absorption enhancer, such as an enzymatic absorption enhancer, a non-enzymatic absorption enhancer, or a combination thereof, to improve the solubility of the pharmaceutical agent, thereby improving absorption of the pharmaceutical agent by the oral mucosa when the formulation of the present invention dissolves in the oral cavity and the pharmaceutical agent is released from the formulation of the present invention, thereby increasing the bioavailability of the pharmaceutical agent. Furthermore, the formulations of the present invention assist in masking the unpleasant taste of selected pharmaceutical agents.

[0058] Furthermore, the formulations of the present invention provide a means for enhancing or improving the efficacy of one or more pharmaceutical agents by administering them simultaneously. This is particularly useful when used with analgesics, with the aim of improving the efficacy of combining multiple agents to treat pain using different mechanisms of action. Furthermore, this may result in reduced dosage, which is important for analgesics such as opioids to prevent opioid dependency.

[0059] The embodiments of the present invention will be described with reference to the following specific examples, but the present invention is not limited to these examples. [Example]

[0060] Example 1 This example illustrates the preparation of a dissolvable, orally administrable formulation according to one embodiment of the present invention. The following ingredients were mixed in boiling water maintained at 90-100°C with high speed stirring (e.g., 2000 rpm) to form a polymer-based gel: [Table 1]

[0061] Once a clear solution was obtained, the following additional ingredients were added slowly with high speed stirring at elevated temperature (70-90°C): [Table 2]

[0062] High-speed stirring at elevated temperature was continued for 30 minutes. The resulting mixture was checked for lumps and any lumps were broken up with a stirrer to obtain a homogeneous solution or slurry. The resulting mixture was cooled to room temperature with high-speed stirring. The cooled solution was spread evenly on a belt equipped with a heater and doctor blade to cast a film of uniform thickness. This film was found to be soluble in the oral cavity.

[0063] Example 2 Another orally administrable formulation of the present invention is shown below: First, the polymer material was mixed with water as described above to form a polymer-based gel. 5g pectin / gelatin mixture Pullulan 50g 650g water 9g glycerin

[0064] Once a clear solution was obtained, the following ingredients, including the pharmaceutical agent, were added and stirred with heating to obtain a homogeneous solution or slurry. Colored (red) solution 0.8g 5g corn oil 1g peppermint oil Peppermint flavoring 1.5g Lecithin 0.5g SLS 1g Brij 30 0.5g Lipase 0.5g 0.04g psilocybin Sweetener (stevia or xylitol) 3g Bile acid 0.1g

[0065] The resulting solution is then cooled to form a soluble film in the oral cavity, which may be prepared for storage or formulated into a dosage form.

[0066] Example 3 This example illustrates the preparation of a dissolvable, orally administrable formulation according to one embodiment of the present invention. The following polymer base ingredients (in the following weight percentages relative to the total polymer base) are mixed in boiling water maintained at 90-100°C with high speed stirring (e.g., 2000 rpm) to form a polymer base gel: Pullulan and polysaccharide polymers that may be added: 50-80% by weight Non-polysaccharide hydrophilic polymer 1-10% by weight Glycerin 10-40% by weight

[0067] Once a clear solution is obtained, add the pharmaceutical ingredients containing the following main ingredients (in the following weight percentages based on the total pharmaceutical ingredient), along with flavoring, sweetening, and coloring agents as desired, and stir with heat to obtain a homogeneous solution or slurry. Lipase absorption enhancer 0.1-0.5% by weight Bile acids 0.1~5% by weight Other non-enzymatic absorption enhancers 5 to 25% by weight Psilocybin 0.1-1% by weight

[0068] The use of the above-described formulations containing psilocybin in combination with a second pharmaceutical agent (e.g., an analgesic) at a reduced dose, e.g., 1 / 4 to 1 / 2 of the usual dose, to prepare multimodal formulations as described above minimizes adverse side effects, including, but not limited to, dependence and addiction. Such formulations are particularly useful for reducing the dose of opioid analgesics, such as hydromorphone, oxycodone, codeine, morphine, and fentanyl. Opioid doses vary depending on the opioid. For example, hydromorphone is typically administered at a dose of 2 to 4 mg four to five times daily. The multimodal formulations of the present invention can reduce this dose to 0.5 to 2 mg two to three times daily or less, resulting in a synergistic effect in which the opioid analgesic is still effective at a significantly reduced dose.

[0069] Example 4 A multimodal formulation was prepared based on Example 3. This formulation contained hydroxypropyl methylcellulose as a non-polysaccharide polymer and alkali metal alkyl sulfate and polyoxyethylene ether as non-enzymatic absorption enhancers. The pharmaceutical ingredients included 25 mg of diclofenac, 20 mg of psilocybin, and 20 mg of morphine or 4 mg of hydromorphone. This formulation was shown to exhibit sufficient solubility and absorption in the oral cavity.

[0070] Example 5 The multimodal formulation of Example 4 was modified to incorporate cannabinoids. The pharmaceutical ingredients included 25 mg diclofenac, 10 mg psilocybin, 20 mg CBD, and 2 mg hydromorphone. This formulation was shown to exhibit sufficient solubility and absorption in the oral cavity.

[0071] In view of the description herein, various aspects of the present invention include, but are not limited to, the following. i) An orally administrable formulation that dissolves in the oral cavity, comprising a hydrophilic polymer base and a pharmaceutical component, the pharmaceutical component comprising one or more medicinal agents and an absorption enhancer. ii) The formulation described in i) above, wherein the hydrophilic polymer base comprises one or more hydrophilic elastomeric polymers selected from the group consisting of polyethylene glycol, polyacrylamide, polyacrylic acid, acrylic acid, polyacrylic acid copolymers, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethylcellulose, glycolide, polylactide, methyl methacrylate copolymers, carboxyvinyl polymers; polysaccharides such as pullulan, amylose, high amylose starch, hydroxypropylated high amylose starch, alginate, carrageenan, pectin, dextrin, dextran, chitin, chitosan, levan, elsinan, scleroglucan, and alternan; and combinations thereof. iii) The formulation of ii) above, wherein the hydrophilic polymer base further comprises a second film-forming agent selected from xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, carrageenan gum, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and mixtures thereof. iv) The formulation described in i) above, wherein the absorption enhancer is an enzyme selected from the group consisting of pancreatic lipase (PL), pancreatic lipase-related protein 1 or pancreatic lipase-related protein 2 (PLRP1 / PLRP2), hepatic lipase, endothelial lipase, lipoprotein lipase, lysosomal lipase, gastric lipase, and lingual lipase. v) The formulation described in i) above, wherein the absorption enhancer comprises a combination of an enzymatic absorption enhancer and a non-enzymatic absorption enhancer. vi) The formulation according to v) above, wherein the non-enzymatic absorption enhancer is a bile acid or a salt thereof. vii) The formulation according to vi) above, wherein the bile acid or its salt is selected from the group consisting of cholic acid, deoxycholic acid, glycocholic acid, chenodeoxycholic acid, taurocholic acid, glycodeoxycholic acid and taurodeoxycholic acid, and salts thereof and mixtures thereof. viii) The formulation according to v) above, wherein the non-enzymatic absorption enhancer is selected from the group consisting of polyoxyethylene ethers, polyoxyethylene esters, polyoxyethylene alcohols, alkali metal alkyl sulfates, lecithin, hyaluronic acid, pharmaceutically acceptable hyaluronates, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, oleic acid, linoleic acid, linolenic acid, monoolein, monooleic acid esters, monolauric acid esters, borage oil, evening primrose oil, chamomile extract, cucumber extract, menthol, trihydroxyoxocoloylglycine, lysine, polylysine, triolein, polidocanol alkyl ether, and mixtures thereof. ix) The formulation according to i) above, containing the pharmaceutical agent in an amount ranging from 0.1 to 40% by weight. x) The formulation described in i) above, wherein the pharmaceutical agent is a hallucinogenic compound selected from the group consisting of tryptamine, phenethylamine, ketamine, ibotenic acid, muscimol, salvinorin A, lysergamide, mescaline, ibogaine, and mixtures thereof. xi) The formulation of i) above, wherein the pharmaceutical agent is selected from the group consisting of DMT (N,N-dimethyltryptamine), 5-hydroxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, LSD (lysergic acid diethylamide), mescaline (3,4,5-trimethoxyphenethylamine), PCP (phenylcyclohexylpiperidine), 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin), [3-[2-(methylamino)ethyl]-1H-indol-4-yl]dihydrogen phosphate (baeocystin), 4-hydroxy-N,N-dimethyltryptamine (psilocin), amphetamine, 3,4-methylenedioxyamphetamine (MDA), methylenedioxyethylamphetamine (MDEA), MDMA (3,4-methylenedioxymethamphetamine), and mixtures thereof. xii) A formulation as described in i) above, wherein the pharmaceutical agent is one or more hallucinogenic compounds in the form of an extract from a fungus or mixture of fungi of the genus Broccoli, Broccoli, Broccoli, Broccoli, Broccoli or Broccoli genus. xiii) A formulation as described in i) above, wherein the pharmaceutical agent is in the form of an extract from a cactus. xiv) The pharmaceutical agent is cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidivaric acid (CBDVA), cannabinovarin (CBNV), cannabigerovarin (CBGV), cannabichromene (CBC), naphthoylindole; phenylacetylindole; benzoylindole; cyclohexylphenol; HU-210, 3-dimethylneptyl-11-carboxylic acid congener 8, delta-9-tetrahydrocannabinol (THC or or dronabinol), delta-8-tetrahydrocannabinol (D8-THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarinic acid (THCVA), nabilone, rimonabant (SR141716), JWH-018, JWH-073, CP-55940, dimethylheptylpyran, HU-210, HU-331, SR144528, WIN55,212-2, JWH-133, levonantradol, AM-2201, and combinations thereof. xv) The formulation described in xiv) above, wherein the cannabinoid is CBD, THC or a mixture thereof. xvi) The formulation described in i) above, wherein the pharmaceutical agent is psilocybin and the enzyme-based absorption enhancer comprises lingual lipase and sodium deoxycholate. xvii) The formulation described in i) above, wherein the hydrophilic polymer base comprises a film-forming agent selected from pullulan, hydroxypropyl methylcellulose, alginate, and combinations thereof, and a plasticizer comprising glycerin. xviii) The formulation described in i) above, wherein the pharmaceutical agent is psilocybin, the absorption enhancer comprises lingual lipase and sodium deoxycholate, and the hydrophilic polymer base comprises a film-forming agent selected from pullulan, hydroxypropyl methylcellulose, alginate, and combinations thereof, and a plasticizer comprising glycerin. xix) The formulation described in i) above, wherein the pharmaceutical ingredient comprises one or more additional pharmaceutical agents selected from cannabinoids, terpenes and hallucinogens, and an analgesic compound. xx) The formulation according to i) above, comprising a hydrophilic polymer in an amount ranging from 10 to 60% by weight based on the total formulation, a pharmaceutical ingredient in an amount ranging from 0.1 to 40% by weight based on the total formulation, and an enzyme absorption enhancer in an amount ranging from 25 to 170 U per liter of the formulation.

Claims

1. An orally administrable formulation that dissolves in the oral cavity, comprising a hydrophilic polymer base and a pharmaceutical component, the pharmaceutical component comprising one or more medicinal agents and an absorption enhancer.

2. 2. The formulation of claim 1, wherein the hydrophilic polymer base comprises one or more hydrophilic elastomeric polymers selected from the group consisting of polyethylene glycol, polyacrylamide, polyacrylic acid, acrylic acid, polyacrylic acid copolymers, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethylcellulose, glycolide, polylactide, methyl methacrylate copolymers, carboxyvinyl polymers; polysaccharides such as pullulan, amylose, high amylose starch, hydroxypropylated high amylose starch, alginate, carrageenan, pectin, dextrin, dextran, chitin, chitosan, levan, elsinan, scleroglucan, and alternan; and combinations thereof.

3. 3. The formulation of claim 1 or 2, wherein the hydrophilic polymer base comprises a polysaccharide selected from the group consisting of pullulan, amylose, high amylose starch, hydroxypropylated high amylose starch, alginate, carrageenan, pectin, dextrin, dextran, chitin, chitosan, levan, elsinan, scleroglucan, and alternan, and combinations thereof.

4. 4. The formulation of any one of claims 1 to 3, wherein the hydrophilic polymer base further comprises a second film-forming agent selected from xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, carrageenan gum, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and mixtures thereof.

5. 5. The formulation of claim 1, wherein the absorption enhancer is an enzyme selected from the group consisting of pancreatic lipase (PL), pancreatic lipase-related protein 1 or pancreatic lipase-related protein 2 (PLRP1 / PLRP2), hepatic lipase, endothelial lipase, lipoprotein lipase, lysosomal lipase, gastric lipase, and lingual lipase.

6. The formulation according to any one of claims 1 to 4, wherein the absorption enhancer comprises a combination of an enzymatic absorption enhancer and a non-enzymatic absorption enhancer.

7. The formulation of claim 6, wherein the non-enzymatic absorption enhancer is a bile acid or a salt thereof.

8. 8. The formulation of claim 7, wherein the bile acid or salt thereof is selected from the group consisting of cholic acid, deoxycholic acid, glycocholic acid, chenodeoxycholic acid, taurocholic acid, glycodeoxycholic acid and taurodeoxycholic acid, and salts thereof and mixtures thereof.

9. 7. The formulation of claim 6, wherein the non-enzymatic absorption enhancer is selected from the group consisting of bile acids, polyoxyethylene ethers, polyoxyethylene esters, polyoxyethylene alcohols, alkali metal alkyl sulfates, lecithin, hyaluronic acid, pharmaceutically acceptable hyaluronates, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, oleic acid, linoleic acid, linolenic acid, monoolein, monooleate esters, monolaurate esters, borage oil, evening primrose oil, chamomile extract, cucumber extract, menthol, trihydroxyoxocoloylglycine, lysine, polylysine, triolein, polidocanol alkyl ether, and mixtures thereof.

10. 10. The formulation of any one of claims 1 to 9, wherein the pharmaceutical agent is selected from the group consisting of anti-inflammatory agents, opioid analgesics, hallucinogens, cannabinoids and terpenes.

11. The formulation of any one of claims 1 to 10, wherein the pharmaceutical component comprises two or more pharmaceutical agents.

12. 12. The formulation of claim 11, wherein the pharmaceutical ingredient comprises a multimodal combination of pharmaceutical agents selected from the group consisting of anti-inflammatory agents, opioid analgesics, hallucinogens, cannabinoids and terpenes.

13. 12. The formulation of claim 11, wherein the multimodal combination reduces the dosage of at least one of the two or more pharmaceutical agents compared to the dosage of the at least one pharmaceutical agent when used alone.

14. The formulation of any one of claims 11 to 13, comprising psilocybin.

15. 14. A formulation according to any one of claims 11 to 13, comprising a cannabinoid selected from CBD, THC and mixtures thereof.

16. The formulation of any one of claims 11 to 13, comprising an opioid analgesic.

17. 5. The formulation of any one of claims 1 to 4, wherein the pharmaceutical agent is psilocybin and the enzyme-based absorption enhancer comprises lingual lipase and sodium deoxycholate.

18. 18. The formulation of any one of claims 1 to 17, wherein the hydrophilic polymer base comprises a film-forming agent selected from pullulan, hydroxypropyl methylcellulose, alginate, and combinations thereof, and a plasticizer comprising glycerin.

19. 10. The formulation of claim 1, wherein the pharmaceutical agent is psilocybin, the absorption enhancer comprises lingual lipase and sodium deoxycholate, and the hydrophilic polymer base comprises a film-forming agent selected from pullulan, hydroxypropyl methylcellulose, alginate, and combinations thereof, and a plasticizer comprising glycerin.

20. The formulation of any one of claims 1 to 19, wherein the hydrophilic polymer base comprises about 50 to 80% by weight of pullulan and optionally an additional polysaccharide polymer, based on the total weight of the hydrophilic polymer base, and about 10 to 40% by weight of glycerin, based on the total weight of the hydrophilic polymer base; and the pharmaceutical ingredient comprises about 0.1 to 0.5% by weight of a lipase-based absorption enhancer, based on the total weight of the pharmaceutical ingredient, about 0.1 to 5% by weight of a bile acid, based on the total weight of the pharmaceutical ingredient, and about 0.1 to 1% by weight of psilocybin, based on the total weight of the pharmaceutical ingredient.

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