Fast acting plant-derived pharmaceutical compounds and nutritional supplements

Abstract

To provide fast-acting plant-based medicinal compounds and nutritional supplements.SOLUTION: The disclosure provides fast-acting plant-based medicinal compounds and nutritional supplements formulated for oral delivery. The fast-acting nature of the plant-based compositions can be created by blending oral formulations with one or more N-acylated fatty amino acids, absorption enhancers, and / or various other beneficial carriers such as surfactants, detergents, azones, pyrrolidones, glycols, and bile salts.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 326,490, filed April 22, 2016, and U.S. Provisional Patent Application No. 62 / 429,544, filed December 2, 2016, the entire contents of each of which are incorporated herein by reference.

[0002] The present disclosure provides fast-acting plant-derived pharmaceutical compounds or nutritional supplements in a variety of carrier combinations. The carriers can include N-acylated fatty amino acids, penetration enhancers, and / or a variety of other beneficial carriers. The plant-derived composition / carrier combinations can create administration benefits following oral administration. [Background technology]

[0003] Historically, the plant world has been the most important source of medicinal agents used for the treatment of human and animal diseases and as prophylactics in maintaining good health, but for at least the last 150 years, Western medicine has been dominated by synthetic chemical drugs.

[0004] However, it is now increasingly recognized that many plants and plant extracts are highly effective agents for the prevention and treatment of disease. A single plant can possess many pharmacologic active substances, and the extracts derived therefrom can exert their activity on a variety of physiological processes, enhancing the spectrum of desirable therapeutic effects.

[0005] As an example, US Patent Application Publication No. 2015 / 0050373 describes the use of plants from the Calophyllum genus to treat metabolic disorders. Calophyllum is a genus of tropical evergreen flowering plants with approximately 180-200 species. The Calophyllum genus includes four subcategories: Calophyllum brasiliense, Calophyllum caledonicurn, Calophyllum inophyllum, and Calophyllum soulattri. Calophyllum inophyllum is a medium to large evergreen tree with an average height of 25-65 feet. Various medicinal uses of this plant have been reported in the literature, for example, a decoction of the bark of this plant is used to treat internal bleeding. Oil extracted from the seeds of Calophyllum inophyllum is used to treat rheumatoid arthritis or joint diseases; itching; eczema; scalp breakouts; eye diseases; and kidney failure.

[0006] US Patent Application Publication No. 2014 / 0193345 describes the use of the plants Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis, Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia sinensis, and Krameria triandra to treat mucosal lesions.

[0007] US Patent Application Publication No. 2010 / 0068297 describes the use of the plants Punica granatum, Viburnum plicatum, Camellia sinensis, and Acer spp. as antimicrobial agents.

[0008] Numerous medical uses have also been identified for the cannabis plant. For example, delta-9-tetrahydrocannabinol (THC, also known as dronabinol), an extract of the cannabis plant, has been formulated in sesame oil for oral delivery. THC has multiple effects on the central nervous system (CNS), including central sympathomimetic activity. THC has been shown to have significant appetite-stimulating properties and has been used to treat AIDS-associated anorexia. THC has effects on appetite, mood, cognition, memory, and perception. The drug also has antiemetic properties and has been used to control nausea and vomiting associated with cancer chemotherapy. These effects appear to be dose-dependent.

[0009] The efficacy of THC in pain treatment has been described in Pharm. J. 259, 104, 1997 and Pharm. Sci. 3, 546, 1997. The synthetic cannabinoid nabilone is an antiemetic and anxiolytic agent and has also been reported to be useful in treating pain of various etiologies, such as multiple sclerosis (MS), peripheral neuropathy, and spinal cord injury (Lancet, 1995, 345, 579, Pharm. J. 259, 104, 1997; Baker & Pryce, Expert Opin Investig Drugs. 2003 Apr;12(4):561-7)). THC has also been reported to be useful in treating AIDS when administered orally (J. Pain. Symptom Manage. 1995, 10, 89-97).

[0010] Another cannabinoid whose health benefits are well documented is cannabidiol (CBD). In contrast to THC, CBD does not exert psychoactive effects. CBD has been reported to have antidepressant (Zanelati T, et al. Journal of Pharmacology. 2010. 159(1):122-8;), anxiolytic (Resstel BM, et al. Br J Pharmacol. 2009. 156(1):181-188), anti-inflammatory (Vuolo F, et al. Mediators of Inflammation. 2015. 538670), and neuroprotective (Campos AC, et al. Pharmacol Res. 2016. 112:119-127) properties.

[0011] Additional uses for the Asa plant include poisoning (De Vries, et al., Psychopharmacology (Berl). 2003 Jul;168(1-2):164-9); ADHD (O’Connell and Che, Harm Reduction Journal. 2007; 4:16); alcohol dependence (Basavarajappa & Hungund, See comment in PubMed Commons below Alcohol. 2005 Jan-Feb;40(1):15-24); Alzheimer's disease (Eubanks et al., Mol Pharm. 2006 Nov-Dec;3(6):773-7); amyotrophic lateral sclerosis (ALS) (Raman et al., Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Mar;5(1):33-9); anxiety (The British Journal of Psychiatry Feb 2001, 178 (2) 107-115); asthma (Tashkin et al., American Review of Respiratory Disease, 1975; 112, 377); autoimmune diseases (Lyman et al., J Neuroimmunol. 1989 Jun;23(1):73-81); bacterial infections (Nissen et al., Fitoterapia. 2010 Jul;81(5):413-9); osteopenia (Bab et al., Ann Med. 2009;41(8):560-7); brain injury / stroke (Shohami et al., Br J Pharmacol. 2011 Aug;163(7):1402-10); cancer (Guindon & Hohmann, Br J Pharmacol. 2011 Aug;163(7):1447-63); heart disease (Walsh et al., Br J Pharmacol. 2010 Jul;160(5):1234-42); Huntington's disease (Lastres-Becker et al., J Neurochem. 2003 Mar;84(5):1097-109); inflammation (AAPS J.2009 Mar; 11(1): 109-119); Parkinson's disease (Sieradzan et al., Neurology. 2001 Dec 11;57(11):2108-11); and psoriasis (Trends Pharmacol Sci. 2009 Aug; 30(8): 411-420).

[0012] Additional documented uses for the cannabis plant include: acquired hypothyroidism, acute gastritis, agoraphobia, rigidity, arthritis, Asperger's syndrome, atherosclerosis, autism, bipolar disorder, blood disorders, cachexia, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headaches, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, and seizures. Fever, fibromyalgia, flu, fungal infections, gastrointestinal disorders, glaucoma, glioma, Graves' disease, hepatitis, herpes, high blood pressure, lethargy, incontinence, infant mortality, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, migraine, motion sickness, MRSA, muscular dystrophy, nail-patella syndrome, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), pancreatitis, panic disorder, periodontal disease, phantom limb pain, poison ivy allergy These include the treatment of chronic ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles, sickle cell disease, seizures, sleep apnea, sleep disorders, stress, stuttering, temporomandibular joint disorders (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, and withdrawal. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] US Patent Application Publication No. 2015 / 0050373 [Patent Document 2] US Patent Application Publication No. 2014 / 0193345 [Patent Document 3] U.S. Patent Application Publication No. 2010 / 0068297

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[0015] Despite the numerous benefits associated with plant-derived compounds and nutritional supplements, when administered in oral form, their onset of action can be slow, which in some cases can impair their usefulness. For example, after oral administration, THC has the fastest onset of action of 15 minutes to 1.5 hours and a peak effect of 2-4 hours. The duration of action for psychoactive effects is 4-6 hours, while appetite stimulant effects can last for more than 24 hours after administration. THC is almost completely absorbed (90-95%) after a single oral dose. However, due to the combined effects of first-pass hepatic metabolism and poor water solubility (THC has an aqueous solubility of 2.8 mg / L), only 10-20% of the administered dose reaches the systemic circulation. Thus, oral consumption of cannabis is characterized by low bioavailability of cannabinoids and slow onset of action. Thus, as can be seen from this example, there is room for improvement in the oral administration of plant-derived compounds and nutritional supplements. [Means for solving the problem]

[0016] The present disclosure provides fast-acting, plant-derived pharmaceutical compounds and nutritional supplements (collectively, plant-derived compositions) formulated for oral delivery. By providing fast-acting delivery, physiological benefits are observed sooner, increasing the usefulness of these compounds.

[0017] The disclosed fast-acting plant-derived compositions can produce a variety of dosing benefits in providing therapeutically effective amounts in a variety of conditions, including increased absorption, increased bioavailability, faster onset of action, higher peak concentration, faster time to peak concentration, shorter duration of action, increased subjective therapeutic effect, and increased objective therapeutic effect.

[0018] The immediate effect of the plant-derived composition is created by including in the oral formulation one or more N-acylated fatty amino acids, absorption enhancers, and / or various other beneficial carriers such as surfactants, detergents, azones, pyrrolidones, glycols, and bile salts. In certain embodiments, the N-acylated fatty amino acids in the oral formulation can be linear, branched, cyclic, bicyclic, or aromatic, for example, containing 1-50 carbon atoms. The fact that N-acylated fatty amino acids can be used with plant-derived compositions to obtain immediate effect benefits was unexpected given certain aspects of the plant-derived ingredients described further herein. For example, the ability of N-acylated fatty amino acids to increase the absorption of a compound is proportional to the water solubility of the compound. Many plant-derived compounds are not water soluble and were not expected to be affected by the presence of N-acylated fatty amino acids.

[0019] In certain embodiments, the plant-derived composition is selected from the group consisting of Calophyllum brasiliense, Calophyllum caledonicurn, Calophyllum inophyllum, Calophyllum soulattri, Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis, Vaccinium myrtillus, Lemon balm, Melissa officinalis, and others. officinalis, Allium sativum, Camellia sinensis, Krameria triandra, Punica granatum, Viburnum plicatum, Nicotiana tabacum, Duboisia hopwoodii, Asclepias syriaca, Curcuma longa, Cannabis sativa, Cannabis indica, Cannabis ruderalis, and Acer spp., or extracts thereof. In certain embodiments, the plant-derived composition comprises a cannabis plant, or an extract thereof. [Brief description of the drawings]

[0020] [Figure 1A]Figures 1A and 1B show the demonstrated correlation between water solubility and the ability of SNAC to improve absorption of molecules. Figure 1A shows the multiple improvement from SNAC plotted for cromolyn, vitamin B12, atorvastatin, and ibandronate along with the aqueous solubility of each molecule. The plotted data show excellent fit to a logarithmic trendline (R2=0.998), demonstrating a logarithmic relationship between the aqueous solubility of each and the degree to which SNAC improves absorption. [Figure 1B] The aqueous solubilities of heparin, acyclovir, rhGH, PTH, MT-II, GLP-1, calcitonin, yy peptide, and THC are plotted according to the logarithmic trend line derived from FIG. 1A. [Figure 2-1] The structures of representative cannabinoids are shown below. [Figure 2-2] The structures of representative cannabinoids are shown below. [Figure 3-1] The modified amino acids of compounds I to XXXV are shown. [Figure 3-2] The modified amino acids of compounds I to XXXV are shown. [Figure 3-3] The modified amino acids of compounds I to XXXV are shown. [Figure 4-1] Representing fatty acid amino acids of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., a methyl group), and R3 is H; or a salt or free acid form thereof. [Figure 4-2] Representing fatty amino acids of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., a methyl group), and R3 is H; or a salt or free acid form thereof. [Figure 5A]Figure 1 shows the average results of a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 5B] FIG. 1 shows the average results of a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6A] FIG. 1 shows results for individual participants in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6B] FIG. 1 shows results for individual participants in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6C] FIG. 1 shows results for individual participants in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6D] FIG. 1 shows results for individual participants in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6E] FIG. 1 shows results for individual participants in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6F]FIG. 1 shows results for individual participants in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 7] Figure 1 shows a comparison of the potency, duration and onset of action of orally administered cannabis formulations with a high SNAC dose (200 mg, "High Dose"), a low SNAC dose (100 mg, "Low Dose") and no SNAC ("Control"). [Figure 8] 1 shows the potency, duration and onset of action of cannabis formulated with SNAC administered orally ("PO") compared to cannabis administered by inhalation ("INH"). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Despite the numerous benefits associated with plant-derived compounds and nutritional supplements, when administered in oral form, their onset of action can be slow, which in some cases can impair their usefulness. For example, after oral administration, THC has the fastest onset of action of 15 minutes to 1.5 hours and a peak effect of 2-4 hours. The duration of action for psychoactive effects is 4-6 hours, while appetite stimulant effects can last for more than 24 hours after administration. THC is almost completely absorbed (90-95%) after a single oral dose. However, due to the combined effects of first-pass hepatic metabolism and poor water solubility (THC has an aqueous solubility of 2.8 mg / L), only 10-20% of the administered dose reaches the systemic circulation. Thus, oral consumption of cannabis is characterized by low bioavailability of cannabinoids and slow onset of action. Thus, as can be seen from this example, there is room for improvement in the oral administration of plant-derived compounds and nutritional supplements.

[0022] The present disclosure provides fast-acting, plant-derived pharmaceutical compounds and nutritional supplements (collectively, plant-derived compositions) formulated for oral delivery. By providing fast-acting delivery, physiological benefits are observed sooner, increasing the usefulness of these compounds.

[0023] The disclosed fast-acting plant-derived compositions can produce a variety of dosing benefits in providing therapeutically effective amounts in a variety of conditions, including increased absorption, increased bioavailability, faster onset of action, higher peak concentration, faster time to peak concentration, shorter duration of action, increased subjective therapeutic effect, and increased objective therapeutic effect.

[0024] The immediate effect of the plant-derived composition is created by including in the oral formulation one or more N-acylated fatty amino acids, absorption enhancers, and / or various other beneficial carriers such as surfactants, detergents, azones, pyrrolidones, glycols, and bile salts. In certain embodiments, the N-acylated fatty amino acids in the oral formulation can be linear, branched, cyclic, bicyclic, or aromatic, for example, containing 1-50 carbon atoms. The fact that N-acylated fatty amino acids can be used with plant-derived compositions to obtain immediate effect benefits was unexpected given certain aspects of the plant-derived ingredients described further herein. For example, the ability of N-acylated fatty amino acids to increase the absorption of a compound is proportional to the water solubility of the compound. Many plant-derived compounds are not water soluble and were not expected to be affected by the presence of N-acylated fatty amino acids.

[0025] Molecules that have been shown to have improved absorption when administered with N-acylated fatty amino acids (e.g., SNAC) include water-soluble molecules such as cromolyn, vitamin B12, atorvastatin, ibandronate, heparin, acyclovir, recombinant human growth hormone (rhGH), parathyroid hormone 1-34 (PTH 1-34), α-melanotropin (MT-II), GLP-1, calcitonin, and peptide yy.

[0026] FIG. 1A shows the demonstrated correlation between aqueous solubility and the ability of SNAC to improve absorption of molecules. For cromolyn, vitamin B12, atorvastatin, and ibandronate, published results include the area under the curve (AUC) calculated from the time course of plasma concentrations. To quantify the effect of co-administration with SNAC, the fold improvement can be calculated by dividing the AUC for the molecule with SNAC by the AUC for the molecule without SNAC. FIG. 1A shows the fold improvement from SNAC plotted for cromolyn, vitamin B12, atorvastatin, and ibandronate along with the aqueous solubility of each molecule. The plotted data shows remarkable fit to a logarithmic trendline (R 2 = 0.998), showing the logarithmic relationship between the aqueous solubility of each and the degree to which SNAC improves its absorption.

[0027] Heparin, acyclovir, rhGH, PTH, MT-II, GLP-1, calcitonin, and yy peptide are other molecules that have been shown to have improved absorption with SNAC, as evidenced by Cmax (maximum drug plasma concentration) and / or Tmax (time taken to reach maximum drug plasma concentration). As shown in FIG. 1B, each of these molecules has an aqueous solubility greater than 0.15 mg / ml, and thus the model accurately predicts that SNAC can improve their absorption. The results demonstrate that the improvement in absorption based on SNAC correlates with the aqueous solubility of the molecule. FIG. 1B further shows the aqueous solubility of THC (0.0028 mg / ml) on the logarithmic fit curve and the predicted effect of SNAC thereon. Based at least on the foregoing, the results described herein are unexpected and would not have been reasonably expected by one of ordinary skill in the art.

[0028] Various aspects of the disclosure are described in more detail below.

[0029] The present disclosure provides a fast acting plant-derived composition comprising vegetable matter and a carrier as an oral formulation. By plant-derived composition is meant a plant-derived pharmaceutical compound and a plant-derived nutritional supplement. The plant-derived pharmaceutical compound is provided in a therapeutically effective amount to treat a disease, such as those described in the Background section of this disclosure. The plant-derived nutritional supplement demonstrates benefits associated with classic nutritional deficiencies; describes how the supplement is intended to affect the structure or function of the human body; characterizes the identified mechanism by which the supplement acts to maintain such structure or function; and / or describes the general health condition associated with consumption of the product. In certain embodiments, the nutritional supplement does not diagnose, mitigate, treat, cure, or prevent a specific disease or group of diseases.

[0030] The plant-derived composition includes botanical material. Botanical material is material produced by a plant, including the whole plant or plant parts (e.g., bark, wood, leaves, stems, roots, flowers, fruits, seeds, or parts thereof) and / or any exudates or extracts thereof. In certain embodiments, the plant-derived composition includes a botanical product. The botanical product can include plant material, algae, macroscopic fungi, and / or combinations thereof. In certain embodiments, the plant-derived composition includes a mixture of various types of botanical material. The plant-derived composition can also include materials derived from the botanical material, such as resins, oils, dried flowers, kief, tinctures, infusions, etc. In certain embodiments, the plant material has little or no water solubility. In certain embodiments, the plant-derived composition does not include synthetic, semi-synthetic, or chemically modified drugs.

[0031] In certain embodiments, the plant-derived composition includes any of the following: Calophyllum brasiliense, Calophyllum caledonicurn, Calophyllum inophyllum, Calophyllum soulattri, Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis, Vaccinium myrtillus, Melissa officinalis, Lemon balm, and the like. officinalis, garlic (Allium sativum), tea plant (Camellia sinensis), Krameria triandra, pomegranate (Punica granatum), bush clover (Viburnum plicatum), tobacco (Nicotiana tabacum), pichuri (Duboisia hopwoodii), milkweed (Asclepias syriaca), turmeric (Curcuma longa), hemp (Cannabis sativa), hemp (Cannabis indica), Cannabis ruderalis and / or maple species (Acer spp.) or extracts thereof.

[0032] In certain embodiments, the plant-derived composition comprises botanical material derived from a cannabis plant, which refers to a flowering plant including the species (or subspecies) Cannabis sativa, Cannabis ruderalis, and Cannabis indica.

[0033] Certain extracts of the cannabis plant contain cannabinoids. Cannabinoids are a group of cyclic molecules derived from the cannabis plant that activate cannabinoid receptors (i.e., CB1 and CB2) in cells. There are at least 85 different cannabinoids that can be isolated from cannabis. Many cannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), produced by the cannabis plant, have very low or no solubility in water. The most notable cannabinoids are THC and CBD. Additional examples include cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabidiol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarinic acid (THCVA). See, for example, FIG. 2. Extracts of the cannabis plant also include flavonoid compounds, terpenes, terpenoids, and synthetic, semi-synthetic, or highly purified versions of any such components.

[0034] The components of the plant-derived composition can be produced, for example, by grinding, decoction, pressing, and extraction of the starting plant product. The term "extract" can include all of the many types of preparations that contain some or all of the active ingredients found in the relevant plant. Extracts can be produced by cold infusion using a variety of different extraction solvents, including water, fatty solvents (e.g., olive oil), and alcoholic solvents (e.g., 70% ethanol). Cold infusion is typically applied to the softer parts of the plant, such as leaves and flowers, or when the desired active ingredients of the plant are heat-sensitive. Alternatively, the aforementioned solvents can be used to produce the extract of the desired plant by hot extraction techniques, where the solvent is heated to an elevated temperature (the exact value of which depends on the nature of the solvent chosen) and maintained at that temperature throughout the extraction process. Hot extraction techniques are more commonly applied to the harder, more robust parts of the plant, such as bark, woody branches, and larger roots. In some cases, sequential extractions can be performed with more than one solvent and at different temperatures. The plant extracts can be used in concentrated form. Alternatively, the extract may be diluted appropriately for its intended use.

[0035] WO 2004 / 026857 provides a method for producing a purified cannabis extract in which the cannabinoids are purified to at least 99 wt% THC (Δ9-tetrahydrocannabinol). In this method, a crude ethanol extract of cannabis plant material is passed through a column of activated charcoal and evaporated by rotary evaporation. The resulting THC-enriched extract is then passed through a column packed with Sephadex LH20 and eluted with chloroform / dichloromethane. The solvent used is removed by rotary evaporation. To further increase the purity of the THC-enriched extract, the extract is dissolved in methanol and then in pentane and subjected to two rotary evaporations.

[0036] US Patent Application Publication No. 2015 / 0126754 describes a method of a) preparing a crude solvent extract of cannabis plant material; b) subjecting the crude extract to thin film evaporation to obtain a purified extract; c) fractionating the purified extract by chromatography to produce one or more high purity fractions having a THC content higher than a pre-set value and one or more low purity fractions having a THC content lower than a pre-set value, the pre-set value being in the range of 95-99% by weight of the dry material; d) subjecting the one or more high purity fractions to another thin film evaporation; e) collecting a THC isolate containing at least 97% THC of the dry material; wherein in step b) and / or step d) the thin film evaporation is carried out by using wiped film evaporation. This method offers the advantage that a high purity THC extract is obtained in good yield without the use of solvents that pose health risks. The method further offers the advantage that it is highly reproducible in producing THC isolates with unique cannabinoid profiles. More particularly, the method produces a THC isolate containing at least 97.0-99.5% THC and 0.4-2.0% other cannabinoids, such as at least 0.3% cannabinol and cannabidiol (all percentages by weight of dry matter).

[0037] Additional methods of producing plant extracts, including hot extraction, cold infusion and other techniques, are described in publications such as “Medicinal plants: a field guide to the medicinal plants of the Land of Israel (in Hebrew), author: N. Krispil, Har Gilo, Israel, 1986” and “Making plant medicine, author: R. Cech, pub. by Horizon Herbs, 2000.”

[0038] In certain embodiments, the plant components (e.g., plant extracts) of the plant-derived composition may be sterilized, for example, by autoclaving, then allowed to cool and stored at an appropriate temperature (e.g., −20° C.). In certain embodiments, further purification to a molecular weight cutoff (e.g., less than 10,000 Da) may be performed, for example, by membrane ultrafiltration before storage.

[0039] In certain embodiments, the plant-derived composition includes a carrier such as a modified amino acid, a surfactant, a detergent, an azone, a pyrrolidone, a glycol, or a bile salt. An amino acid is any carboxylic acid having at least one free amine group, including natural, unnatural, and synthetic amino acids. A polyamino acid is a peptide or two or more amino acids joined by a bond formed by other groups capable of binding, such as an ester, anhydride, or anhydride bond. A peptide is two or more amino acids linked by peptide bonds. Peptides can vary in length from a dipeptide with two amino acids to a polypeptide with several hundred amino acids. See Chambers Biological Dictionary, editor Peter MB Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Di-peptides, tri-peptides, tetra-peptides, and pentapeptides can also be used.

[0040] Modified amino acid carriers include acylated fatty acid amino acids (FA-aa) or salts thereof, which are typically prepared by modifying an amino acid or its ester by acylation or sulfonation. Acylated fatty acid amino acids include N-acylated FA-aa or amino acids in which the alpha amino group is acylated with a fatty acid.

[0041] A representative N-acylated fatty amino acid salt is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC). Other names for SNAC include sodium-N-salicyloyl-8-aminocaprylate, monosodium 8-(N-salicyloylamino)octanoate, N-(salicyloyl)-8-aminooctanoic acid monosodium salt, monosodium N-{8-(2-hydroxybenzoyl)amino}octanoate, or sodium 8-[(2-hydroxybenzoyl)amino]octanoate. SNAC has the following structure:

[0042] [ka] Salts of SNAC can also be used as carriers.

[0043] Other forms of SNAC include:

[0044] [ka] where X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation. Examples of monovalent cations include sodium and potassium. Examples of divalent cations include calcium and magnesium. Examples of organic cations include ammonium and tetramethylammonium.

[0045] Representative modified amino acids, such as N-acylated FA-aa, are provided as compounds I to XXXV (see FIG. 3). Salts of these compounds and other N-acylated FA-aa can also be used as carriers.

[0046] Many of these compounds can be readily prepared from amino acids based on the present disclosure by methods within the skill of one of ordinary skill in the art. For example, compounds I-VII are derived from aminobutyric acid. Compounds VIII-X and XXXI-XXIIV are derived from aminocaproic acid. Compounds XI-XXVI and XXXV are derived from aminocaprylic acid. For example, the modified amino acid compounds can be prepared by reacting a single amino acid with an appropriate modifying agent that reacts with a free amino moiety present in the amino acid to form an amide. Protecting groups can be used to avoid unwanted side reactions as known to those of ordinary skill in the art.

[0047] The amino acid can be dissolved in an aqueous alkaline solution of a metal hydroxide, e.g., sodium or potassium hydroxide, and heated to a temperature ranging from 5°C to 70°C, preferably from 10°C to 40°C, for a period ranging from 1 hour to 4 hours, preferably 2.5 hours. The amount of alkali used per equivalent of NH2 group of the amino acid is generally in the range of 1.25 to 3 mmol, preferably 1.5 to 2.25 mmol per equivalent of NH2. The pH of the solution is generally in the range of 8 to 13, preferably 10 to 12.

[0048] A suitable amino acid modifying agent is then added to the amino acid solution with stirring. The temperature of the mixture is generally maintained at a temperature ranging from 5°C to 70°C, preferably from 10°C to 40°C, for a period ranging from 1 to 4 hours. The amount of amino acid modifying agent used relative to the amount of amino acid is based on the total moles of free NH2 in the amino acid. Generally, the amino acid modifying agent is used in an amount ranging from 0.5 to 2.5 molar equivalents, preferably 0.75 to 1.25 equivalents per molar equivalent of total NH2 groups in the amino acid.

[0049] The reaction is quenched by adjusting the pH of the mixture with a suitable acid, such as concentrated hydrochloric acid, until a pH of 2-3 is reached. The mixture is allowed to stand at room temperature and separates to form a clear upper layer and a white or off-white precipitate. The upper layer is discarded and the modified amino acid is collected from the lower layer by filtration or decantation. The crude modified amino acid is then dissolved in water at a pH in the range of 9-13, preferably 11-13. Insoluble material is removed by filtration and the filtrate is dried in vacuum. The yield of modified amino acid is generally in the range of 30-60%, usually 45%.

[0050] If desired, modified amino acids may be prepared using amino acid esters such as, for example, benzyl, methyl, or ethyl esters of the amino acid compounds. The amino acid esters dissolved in a suitable organic solvent such as dimethylformamide, pyridine, or tetrahydrofuran may be reacted with a suitable amino acid modifying agent at a temperature ranging from 5° C. to 70° C., preferably at 25° C., for a period ranging from 7 to 24 hours. The amount of amino acid modifying agent used for the amino acid ester is the same as described above for the amino acid. The reaction may be carried out with or without a base such as, for example, triethylamine or diisopropylethylamine.

[0051] The reaction solvent is then removed under negative pressure and the ester functionality is removed by hydrolyzing the modified amino acid ester with a suitable alkaline solution, such as 1N sodium hydroxide, at a temperature in the range of 50°C to 80°C, preferably 70°C, for a period of time sufficient to hydrolyze the ester group and form a modified amino acid having a free carboxyl group. The hydrolysis mixture is then cooled to room temperature and acidified, for example with 25% aqueous hydrochloric acid, to a pH in the range of 2 to 2.5. The modified amino acid precipitates from the solution and is recovered by conventional means such as filtration or decantation. Benzyl esters can be removed by hydrogenation with a transition metal catalyst in an organic solvent.

[0052] The modified amino acids may be purified by recrystallization or fractionation on solid column supports. Suitable recrystallization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation can be performed on suitable solid column supports such as alumina using methanol / n-propanol mixtures as the mobile phase; on reverse phase column supports using trifluoroacetic acid / acetonitrile mixtures as the mobile phase; and by ion exchange chromatography using water as the mobile phase. When ion exchange chromatography is performed, a sodium chloride gradient of 0-500 mM is preferably used.

[0053] In certain embodiments, the formula

[0054] [ka] (Wherein, Y is

[0055] [ka] or SO2; R 1 is C3~C 24 Alkylene, C2-C 20 Alkenylene, C2-C 20 is aromatic, such as alkynylene, cycloalkylene, or arylene; R 2 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; R 3 is C1-C7 alkyl, C3-C 10 cycloalkyl, aryl, thienyl, pyrrolo, or pyridyl; R 3 is optionally one or more of a C1-C5 alkyl group, a C2-C4 alkenyl group, F, Cl, OH, OR 1 , SO2, COOH, COOR 1 or replaced by SO3H) The modified amino acid having the formula

[0056] [ka] The lactam having the formula R 3 -YX(where, Y, R 1 , R 2 , and R 3 where X is a leaving group. Lactams of the above formula can be prepared, for example, by the method described in Olah et al., Synthesis, 537-538 (1979).

[0057] In certain embodiments, modified amino acids also include amino acids whose alpha amino group is acylated with a fatty acid, which can be represented by the general formula AX, where A is an alpha-amino acid residue and X is a fatty acid attached to the alpha-amino group of A by acylation. Amino acids include cationic and non-cationic amino acids. In certain embodiments, the term "non-cationic amino acid" refers to an amino acid selected from the group consisting of non-polar hydrophobic amino acids, polar uncharged amino acids, and polar acidic amino acids. In certain embodiments, the term "non-cationic amino acid" as used herein refers to an amino acid selected from the group consisting of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tryptophan (Trp), methionine (Met), proline (Pro), sarcosine, glycine (Gly), serine (Ser), threonine (Thr), cysteine ​​(Cys), tyrosine (Tyr), asparagine (Asn), and glutamine (Gin), aspartic acid (Asp), and glutamic acid.

[0058] In certain embodiments, the acylated FA-aa comprises an alpha amino acid residue of a non-polar hydrophobic amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a non-polar hydrophobic amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "non-polar hydrophobic amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "non-polar hydrophobic amino acid" refers to an amino acid selected from the group consisting of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tryptophan (Trp), methionine (Met), proline (Pro), and sarcosine.

[0059] In certain embodiments, the acylated FA-aa comprises an amino acid residue of a polar uncharged amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a polar uncharged amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "polar uncharged amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "polar uncharged amino acid" refers to an amino acid selected from the group consisting of glycine (Gly), serine (Ser), threonine (Thr), cysteine ​​(Cys), tyrosine (Tyr), asparagine (Asn), and glutamine (Gln).

[0060] In certain embodiments, the acylated FA-aa comprises an amino acid residue of a polar acidic amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a polar acidic amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "polar acidic amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "polar acidic amino acid" refers to an amino acid selected from the group consisting of aspartic acid (Asp) and glutamic acid (Glu).

[0061] In certain embodiments, the amino acid residue of the acylated FA-aa comprises an amino acid residue of an amino acid that is not encoded by the genetic code. Modification of an amino acid by acylation can be readily accomplished using acylating agents known in the art to react with the free alpha-amino group of an amino acid.

[0062] In certain embodiments, an alpha-amino acid or alpha-amino acid residue referred to herein is in the L-configuration, unless otherwise stated.

[0063] In certain embodiments, the amino acid residues are in the free acid form and / or a salt thereof, such as the sodium (Na+) salt thereof.

[0064] Representative embodiments of acylated FA-aa can be represented by general Fa-aa formula I:

[0065] [ka] wherein R1 is an alkyl or aryl group containing 5 to 19 carbon atoms; R2 is H (i.e., hydrogen), CH3 (i.e., a methyl group), or is covalently bonded to R4 via a (CH2)3 group; R3 is H or absent; R4 is an amino acid side chain or is covalently bonded to R2 via a (CH2)3 group; or a salt thereof.

[0066] FA-aa can be acylated with a fatty acid comprising a substituted or unsubstituted alkyl group of 5-19 carbon atoms. In certain embodiments, the alkyl group comprises 5-17 carbon atoms. In certain embodiments, the alkyl group comprises 5-15 carbon atoms. In certain embodiments, the alkyl group comprises 5-13 carbon atoms. In certain embodiments, the alkyl group comprises 6 carbon atoms.

[0067] In certain embodiments, the acylated FA-aa is soluble at intestinal pH values, particularly in the range of pH 5.5 to 8.0, such as in the range of pH 6.5 to 7.0 In certain embodiments, the acylated FA-aa is soluble at a pH below 9.0.

[0068] In certain embodiments, the acylated FA-aa has a solubility of at least 5 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 10 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 20 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 30 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 40 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 50 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 60 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 70 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 80 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 90 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 100 mg / mL. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH values ​​one unit above and below the pKa of the FA-aa at 37° C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH 8 at 37° C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH values ​​one unit above and below the pI of the FA-aa at 37° C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solutions at pH values ​​one unit above and below the pI of the FA-aa at 37° C., where the FA-aa has two or more ionizable groups with opposite charges. In certain embodiments, the solubility of the FA-aa is determined at 37° C. in aqueous 50 mM sodium phosphate buffer, pH 8.0.

[0069] In certain embodiments, the acylated FA-aa is selected from the group consisting of formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., methyl), and R3 is H, or a salt or free acid form thereof. Formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r) are depicted in FIG. 4.

[0070] In certain embodiments, the acylated FA-aa is selected from the group consisting of sodium N-dodecanoyl alaninate, N-dodecanoyl-L-alanine, sodium N-dodecanoyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium N-dodecanoyl leucinate, N-dodecanoyl-L-leucine, sodium N-dodecanoyl methioninate, N-dodecanoyl-L-methionine, sodium N-dodecanoyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium N-dodecanoyl prolinate, N-dodecanoyl- L-Proline, Sodium N-Dodecanoyl Tryptophanate, N-Dodecanoyl-L-Tryptophan, Sodium N-Dodecanoyl Valinate, N-Dodecanoyl-L-Valine, Sodium N-Dodecanoyl Sarcosinate, N-Dodecanoyl-L-Sarcosine, Sodium N-Oleoyl Sarcosinate, Sodium N-Decyl Leucine, Sodium N-Decanoyl Alaninate, N-Decanoyl-L-Alanine, Sodium N-Decanoyl Leucinate, N-Decanoyl-L-Leucine, Sodium N-Decanoyl Phenylalaninate , N-decanoyl-L-phenylalanine, Sodium N-decanoylvalinate, N-decanoyl-L-valine, Sodium N-decanoylisoleucinate, N-decanoyl-L-isoleucine, Sodium N-decanoylmethioninate, N-decanoyl-L-methionine, Sodium N-decanoylprolinate, N-decanoyl-L-proline, Sodium N-decanoylthreoninate, N-decanoyl-L-threonine, Sodium N-decanoyltryptophanate, N-decanoyl-L-tryptophan, Sodium N-decanoyl N-dodecanoyl sarcosinate, N-decanoyl-L-sarcosine, N-dodecanoyl asparaginate, N-dodecanoyl-L-asparagine, sodium N-dodecanoyl aspartate, N-dodecanoyl-L-aspartic acid, sodium N-dodecanoyl cysteinate, N-dodecanoyl-L-cysteine, sodium N-dodecanoyl glutamate, N-dodecanoyl-L-glutamine, sodium N-dodecanoyl glycinate, N-dodecanoyl-L-glycine, sodium N-dodecanoyl serinate, N-dodecanoyl-L-serine,Sodium N-dodecanoylthreoninate, N-dodecanoyl-L-threonine, Sodium N-dodecanoyltyrosinate, N-dodecanoyl-L-tyrosine, Sodium N-decanoylasparaginate, N-decanoyl-L-asparagine, Sodium N-decanoylaspartic acid, N-decanoyl-L-aspartic acid, Sodium N-decanoylcysteinate, N-decanoyl-L-cysteine, Sodium N-decanoylglutamate, N-decanoyl N-decanoyl-L-glutamine, Sodium N-decanoylglycinate, N-decanoyl-L-glycine, Sodium N-decanoylserinate, N-decanoyl-L-serine, Sodium N-decanoyltyrosinate, N-decanoyl-L-tyrosine, Sodium N-dodecanoylasparaginate, Sodium N-dodecanoylglutamate, N-dodecanoyl-L-glutamic acid, Sodium N-decanoylglutamate, N-decanoyl-L-glutamic acid, Amisoft The hydroxypropyl ester may be selected from one or more of HS-11 P (sodium stearoyl glutamate), Amisoft MS-11 (sodium myristoyl glutamate), Amisoft LS-11 (sodium dodecanoyl glutamate), Amisoft CS-11 (sodium cocoyl glutamate), sodium N-cocoyl glutamate, Amisoft HS-11 P, Amisoft HS-11 P (sodium N-stearoyl glutamate), (sodium N-myristoyl glutamate), (sodium N-dodecanoyl glutamate), and Amisoft HS-11 P.

[0071] The following acylated FA-aa are commercially available:

[0072] [Table 1]

[0073] In certain embodiments, the terms "fatty acid N-acylated amino acid," "fatty acid acylated amino acid," or "acylated amino acid" are used interchangeably herein and refer to an amino acid whose alpha-amino group is acylated with a fatty acid.

[0074] Certain embodiments utilize plant materials with low or very low solubility. Certain embodiments utilize plant materials that are essentially water insoluble. In certain embodiments, solubility in water is defined according to the amount of water required to dissolve one part of solute according to the United States Pharmacopoeia (USP 32) as follows: low to zero; low solubility: 100 to 1000 parts of water required to dissolve one part of solute; very low solubility: 1000 to 10 000 parts of water required; essentially water insoluble: more than 10 000 parts of water required. However, at basic pH, SNAC and other modified amino acids and FA-aas described herein are water soluble. Thus, the administration benefits described herein would not be reasonably predictable. In certain embodiments, very low solubility can mean a solubility in water or aqueous solutions of less than 1 mg / ml, less than 0.1 mg / ml, or less than 0.01 mg / ml.

[0075] In certain embodiments, the N-acylated fatty amino acid acts as an absorption enhancer, thereby producing a dosing benefit. An absorption enhancer refers to a compound that enhances absorption in the gastrointestinal tract. An absorption enhancer can improve drug absorption by improving the solubility of the drug in the gastrointestinal tract or by increasing membrane permeation, compared to a formulation that does not contain an absorption enhancer. Additional examples of absorption enhancers include surfactants, detergents, azones, pyrrolidones, glycols, or bile salts.

[0076] In certain embodiments, N-acylated fatty amino acids act as bioavailability enhancers.Bioavailability refers to the fraction of active ingredient that is actually absorbed by a subject and reaches the bloodstream.In certain embodiments, bioavailability enhancers increase the fraction of active ingredient in the bloodstream or allow earlier detection of active ingredient in the bloodstream compared to a formulation that does not contain bioavailability enhancers.

[0077] In certain embodiments, the additional dosing benefit provided by the absorption enhancer and / or bioavailability enhancer includes a faster onset of action, a higher peak concentration, a faster time to peak concentration, a shorter duration of action, an increased subjective therapeutic effect, and / or an increased objective therapeutic effect, as compared to a control plant-derived composition or oral formulation that is similar in all respects except that it does not contain the absorption enhancer and / or bioavailability enhancer.

[0078] Embodiments utilizing absorption enhancers and / or bioavailability enhancers (e.g., and in certain embodiments, N-acylated fatty amino acids) can be beneficial because many oral plant-derived compositions designed to address various physiological conditions are inadequate because they are characterized by delayed onset of action and low bioavailability. Delayed onset of action presents a challenge in clinical indications requiring rapid therapeutic effect (e.g., pain and migraine); low bioavailability requires patients to ingest significantly higher doses than would be required with alternative forms of administration (e.g., smoking, vaping). Certain embodiments disclosed herein provide oral plant-derived composition formulations with improved bioavailability and shorter time to onset of therapeutic effect.

[0079] As mentioned above, in certain embodiments, the N-acylated fatty amino acid acts as a subjective therapeutic enhancer. Subjective therapeutic enhancer refers to a noticeable reduction in symptoms as recognized by the subject. In certain embodiments, the subjective therapeutic enhancer enhances or reduces symptoms more rapidly compared to a formulation that does not include the subjective therapeutic enhancer.

[0080] In certain embodiments, the N-acylated fatty amino acid acts as an objective therapeutic enhancer. Objective therapeutic enhancement means that when administered by a physician, it reduces clinical measures such as nutritional deficiencies detected by blood or saliva assays or health tests. In certain embodiments, the objective therapeutic enhancer increases or provides a more rapid reduction in objective clinical measures compared to a formulation that does not include the objective therapeutic enhancer.

[0081] Certain embodiments include cannabis and an absorption enhancer and / or bioavailability enhancer. These embodiments may allow for more rapid absorption and greater bioavailability of cannabis compared to cannabis ingested via currently available oral dosage forms.

[0082] In certain embodiments, the carriers disclosed herein produce an administration benefit selected from increased absorption, increased bioavailability, faster onset of action, higher peak concentration, faster time to peak concentration, shorter duration of action, increased subjective therapeutic effect, increased objective therapeutic effect, improved taste, and improved mouthfeel. Administration benefits associated with increased absorption, increased bioavailability, faster onset of action, higher peak concentration, faster time to peak concentration, and shorter duration of action can more quickly alleviate adverse conditions (e.g., reduced pain). "Mouthfeel" refers to the non-taste-related aspects of the pleasantness felt by a person when ingesting (e.g., chewing or swallowing) an oral dosage form. Aspects of mouthfeel include the hardness and friability of the composition, whether the composition is chewy, gritty, oily, creamy, watery, sticky, easily dissolving, astringent, effervescent, etc., as well as the size, shape, and form of the composition (tablet, powder, gel, etc.).

[0083] The plant-derived composition can be prepared for administration to a subject by adding the plant material, a carrier that provides an administration benefit, and one or more excipients, mixing, suspending, dissolving, blending, granulating, tableting, encapsulating, or performing other dosage form specific procedures, and then packaging. For clarity, the carrier contributes to provide an administration benefit. The excipients can, but do not necessarily, contribute to an administration benefit.

[0084] Certain embodiments include the plant-derived compositions prepared as oral formulations. Exemplary oral formulations include capsules, coated tablets, edibles, elixirs, emulsions, gels, gel caps, granules, gums, juices, liquids, oils, pastes, pellets, pills, powders, fast dissolving tablets, sachets, semi-solids, sprays, solutions, suspensions, syrups, tablets, and the like.

[0085] Representative types of excipients include binders, buffers, chelating agents, coating agents, colorants, complexing agents, diluents (i.e., fillers), disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, release agents, surfactants, stabilizers, solubilizers, sweeteners, thickeners, wetting agents, and vehicles.

[0086] Binders are substances used to cause adhesion of powder particles during granulation. Representative binders include acacia, compressible sugars, gelatin, sucrose and its derivatives, maltodextrin, cellulose polymers such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and methyl cellulose, acrylic polymers such as insoluble acrylate ammonio methacrylate copolymers, polyacrylate or polymethacrylic copolymers, povidone, copovidone, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, guar gum, and polyethylene glycol.

[0087] Coloring agents can be included in the oral dosage form to impart color to the formulation. Representative coloring agents include grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, and paprika. Additional coloring agents include FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, FD&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide.

[0088] Diluents can enhance granulation of oral formulations. Exemplary diluents include microcrystalline cellulose, sucrose, dicalcium phosphate, starch, lactose, and polyols with less than 13 carbon atoms, such as mannitol, xylitol, sorbitol, maltitol, and pharma- ceutically acceptable amino acids, such as glycine.

[0089] Disintegrants may also be included in the oral formulation to facilitate dissolution. Disintegrants, such as permeabilising and wicking agents, may draw water or saliva into the oral formulation, facilitating dissolution from the inside as well as the outside of the oral formulation. Such disintegrants, permeation enhancers and / or wicking agents that can be used include starches such as corn starch, potato starch, pregelatinized and modified starches, cellulosic agents such as Ac-di-sol, montmorillonite clay, cross-linked PVP, sweeteners, bentonite, microcrystalline cellulose, croscarmellose sodium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, arabic, xanthan and tragacanth, silicas with high affinity for aqueous solvents such as colloidal silica, precipitated silica, maltodextrin, beta-cyclodextrin, polymers such as carbopol, and cellulosic agents such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Dissolution of oral formulations can be facilitated by including ingredients with relatively small particle size.

[0090] Representative dispersing or suspending agents include acacia, alginate, dextran, fragcanth, gelatin, hydrogenated edible fats, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, sorbitol syrup, and synthetic natural gums.

[0091] Exemplary emulsifying agents include acacia and lecithin.

[0092] Flavorants are natural or artificial compounds used to impart a pleasant flavor and often an aroma to oral preparations. Representative flavorants include natural and synthetic flavor oils, flavoring aromatics, plant, leaf, flower, and fruit extracts, and combinations thereof. Such flavorants include anise oil, cinnamon oil, vanilla, vanillin, cocoa, chocolate, natural chocolate flavor, menthol, grape, peppermint oil, wintergreen oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, cassia oil; citrus oils such as lemon, orange, lime, and grapefruit oil; and fruit essences such as apple, pear, peach, berry, wineberry, date, blueberry, kiwi, strawberry, raspberry, cherry, plum, pineapple, and apricot. In certain embodiments, flavoring agents that can be used include natural berry extracts and natural mixed berry flavors, as well as citric and malic acid.

[0093] Glidants improve the flow of powder blends during manufacturing and minimize oral dosage form weight change.Typical glidants include silicon dioxide, colloidal or fumed silica, magnesium stearate, calcium stearate, stearic acid, corn starch, and talc.

[0094] Lubricants are substances used in oral formulations that reduce friction during compression of the composition. Exemplary lubricants include stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, mineral and vegetable oils, benzoic acid, poly(ethylene glycol), glyceryl behenate, stearyl fumarate, and sodium lauryl sulfate.

[0095] Representative preservatives include methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and sorbic acid.

[0096] Representative sweeteners include aspartame, dextrose, fructose, isomerized sugar, maltodextrin, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, acesulfame potassium, sodium saccharin, stevia, sucralose, and sucrose.

[0097] Certain embodiments include swallowable compositions. Swallowable compositions are those that do not easily dissolve when placed in the mouth and can be swallowed whole without chewing or discomfort. U.S. Patent Nos. 5,215,754 and 4,374,082 describe methods for making swallowable compositions. In certain embodiments, the swallowable composition may have a shape that does not contain sharp edges and a smooth, uniform, and substantially bubble-free outer coating.

[0098] To prepare a swallowable composition, each component may be combined into an intimate mixture with a suitable carrier according to conventional compounding techniques. In certain embodiments of the swallowable composition, the surface of the composition may be coated with a polymeric film. Such film coatings have several beneficial effects. First, they reduce the adhesion of the composition to the inner surface of the mouth, thereby increasing the subject's ability to swallow the composition. Second, the film may help mask the unpleasant taste of certain ingredients. Third, the film coating may protect the composition from atmospheric degradation. Polymeric films that can be used in preparing swallowable compositions include vinyl polymers such as polyvinylpyrrolidone, polyvinyl alcohol and acetate, cellulose derivatives such as methyl and ethyl cellulose, hydroxyethyl cellulose and hydroxylpropyl methylcellulose, acrylates and methacrylates, copolymers such as vinyl-maleic and styrene-maleic types, and natural gums and resins such as zein, gelatin, shellac and acacia.

[0099] In certain embodiments, the oral formulation may include a chewable composition that has a pleasant taste and mouthfeel, is relatively soft, and quickly breaks into smaller pieces and begins to dissolve after being chewed, resulting in a composition that can be swallowed substantially as a solution.

[0100] U.S. Patent No. 6,495,177 describes a method for producing chewable compositions with improved mouthfeel.U.S. Patent No. 5,965,162 describes a kit and method for producing edible units that disintegrate rapidly in the mouth, especially when chewed.

[0101] To create a chewable composition, certain ingredients should be included to achieve the attributes described above. For example, a chewable composition should include ingredients that create a pleasant flavor and mouthfeel, and promote relative softness and dissolution in the mouth. The following discussion describes ingredients that may help achieve these characteristics.

[0102] Sugars such as white sugar, corn syrup, sorbitol (solution), maltitol (syrup), oligosaccharides, isomaltooligosaccharides, sucrose, fructose, lactose, glucose, lycasin, xylitol, lactitol, erythritol, mannitol, isomaltose, dextrose, polydextrose, dextrin, compressible cellulose, compressible honey, compressible molasses and mixtures thereof may be added to improve mouthfeel and palatability. Fondants or gums such as gelatin, agar, gum arabic, guar gum, and carrageenan may be added to improve the chewiness of the composition. Fatty materials that can be used include vegetable oils (e.g., coconut oil, hydrogenated palm oil, hydrogenated corn germ oil, hydrogenated castor oil, cottonseed oil, olive oil, peanut oil, palm olein oil, and palm stearin oil), animal oils (e.g., refined oils and refined lard having a melting point in the range of 30°-42° C.), cocoa butter, margarine, butter, and shortening.

[0103] Alkylpolysiloxanes (polymers available commercially in a variety of molecular weight ranges and with a variety of different substitution patterns) can also be used to enhance the texture, mouthfeel, or both of the chewable composition. By "enhancing texture" it is meant that the alkylpolysiloxane improves one or more of the firmness, brittleness, and chewiness of the chewable composition compared to the same formulation lacking the alkylpolysiloxane. By "enhancing mouthfeel" it is meant that the alkylpolysiloxane reduces the gritty texture of the chewable composition when liquefied in the mouth compared to the same formulation lacking the alkylpolysiloxane.

[0104] Alkylpolysiloxanes generally comprise a polymer backbone containing silicon and oxygen, with one or more alkyl groups pendant from the silicon atoms of the backbone. Depending on their grade, they may further comprise silica gel. Alkylpolysiloxanes are generally viscous oils. Representative alkylpolysiloxanes that can be used in swallowable, chewable or dissolvable compositions include monoalkyl or dialkylpolysiloxanes, where the alkyl groups are each independently selected from C1-C6-alkyl groups, optionally substituted with phenyl groups. A particular alkylpolysiloxane that can be used is dimethylpolysiloxane (commonly referred to as simethicone). More specifically, a granular simethicone formulation designated as simethicone GS can be used. Simethicone GS is a formulation containing 30% simethicone USP. Simethicone USP contains up to 90.5% by weight of (CH3)3-Si{OSi(CH3)2}CH3 mixed with 4.0% to 7.0% by weight of SiO2.

[0105] To prevent stickiness that may occur in chewable compositions and to facilitate conversion of the active ingredients into an emulsion or suspension upon ingestion, the composition may further comprise an emulsifier, such as glycerol fatty acid esters, sorbitan monostearate, sucrose fatty acid esters, lecithin, and mixtures thereof. In certain embodiments, one or more of such emulsifiers may be present in an amount of 0.01% to 5.0% by weight of the administered formulation. In certain embodiments, lower or higher levels of emulsifiers may result in no emulsification or increased waxiness.

[0106] Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.

[0107] In addition to the above, in preparing the swallowable, chewable and / or dissolvable compositions or any other oral formulation described herein, any suitable fillers and additives may be utilized so long as they are compatible with the described purpose.

[0108] Oral formulations also include edibles. By edibles is meant any product that can be consumed as food or drink. In some cases, edibles are made into foodstuffs by infusion of plant extracts. Examples of edible foods suitable for use include candy, candy bars, bread, brownies, cakes, cheese, chocolate, cocoa, cookies, gummies, lollipops, mints, pastries, peanut butter, popcorn, protein bars, mochi, yogurt, etc. Although not strictly edible, gum can also be used. Examples of edible beverages include beer, juice, flavored milk, flavored water, liquor, milk, punch, milkshakes, soda, tea, and water. In certain embodiments, edibles are made by combining the plant extract with ingredients used to make the edible. Examples include butter and oil. Representative oils include coconut oil, grapeseed oil, olive oil, palm oil, papaya seed oil, peanut oil, sesame oil, germinated wheat oil, wheat germ oil, or any combination thereof.

[0109] The oral formulations can be individually wrapped or packaged as a multiple unit in one or more packages, cans, vials, blister packs, or bottles of any size. The dosages are sized to provide a therapeutically effective amount.

[0110] In certain embodiments, the oral formulation comprises at least 0.1% w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; at least 95% w / v or w / w of the oral formulation; or at least 99% w / v or w / w of the oral formulation.

[0111] In certain embodiments, the oral formulation comprises a carrier that is at least 0.1% w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; at least 95% w / v or w / w of the oral formulation; or at least 99% w / v or w / w of the oral formulation.

[0112] In certain embodiments, the oral formulation comprises an additive in at least 0.1% w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; at least 95% w / v or w / w of the oral formulation; or at least 99% w / v or w / w of the oral formulation.

[0113] In certain embodiments, 10 g of dried plant extract can be used per 150 ml of water, resulting in effective concentrations of 1-99% (w / w) plant extract, 2-80% (w / w) plant extract, and 5-50% (w / w) plant extract.

[0114] Additives are commercially available from companies such as Aldrich Chemical Co., FMC Corp, Bayer, BASF, Alexi Fres, Witco, Mallinckrodt, Rhodia, , ISP, and others.

[0115] Additional information can be found in WADE & WALLER, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (2nd ed. 1994) and Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. Additionally, formulations can be manufactured to meet sterility, pyrogenicity, general safety, and purity standards required by the US FDA and / or other relevant foreign regulatory agencies.

[0116] The plant-derived compositions disclosed herein can be used to treat subjects (humans, veterinary animals (dogs, cats, reptiles, birds, etc.), livestock (horses, cows, goats, pigs, chickens, etc.), and research animals (monkeys, rats, mice, fish, etc.)). Treating a subject includes providing a therapeutically effective amount. A therapeutically effective amount includes those that provide an effective amount, prophylactic treatment, and / or therapeutic treatment.

[0117] An "effective amount" is the amount of the plant-derived composition required to produce a desired physiological change in a subject. Effective amounts are often administered for testing purposes. Representative effective amounts disclosed herein can reduce pain perception (neuropathic pain, acute pain, visceral pain) in animal models, stimulate appetite in animal models, reduce seizures (e.g., epileptic seizures) in animal models, reverse bone loss in animal models, reduce migraine headaches (constrict cranial blood vessels) in animal models, treat addiction in animal models, reduce anxiety in animal models, and / or reduce asthma symptoms in animal models.

[0118] "Prophylactic treatment" includes treatment administered to a subject who does not exhibit signs or symptoms of a disease or nutritional deficiency, or who exhibits only early signs or symptoms of a disease or nutritional deficiency, for the purpose of minimizing, inhibiting, or reducing the risk of further developing the disease or nutritional deficiency. Thus, prophylactic treatment serves as a preventative measure against the onset of the disease or nutritional deficiency.

[0119] As an example of preventative treatment, the oral formulations disclosed herein can be administered to a subject at risk of developing a migraine headache. Effective preventative treatment of migraine headaches is indicated when the number of migraines experienced by the subject per month is reduced by at least 10%, or in certain embodiments, by 25%.

[0120] As another example of preventive treatment, the oral formulations disclosed herein can be administered to subjects at risk of having epileptic seizures. Effective preventive treatment of epileptic seizures occurs when the number of seizures per month is reduced by at least 10%, or in certain embodiments, by 25%.

[0121] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of suffering from neuropathic pain. Effective prophylactic treatment of neuropathic pain occurs when the incidence of neuropathic pain is reduced by at least 10%, or in certain embodiments, 25%, as measured by standard subjective or objective pain assessments.

[0122] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of developing breakthrough pain. Effective prophylactic treatment of breakthrough pain is indicated when the occurrence of breakthrough pain is reduced by 10%, and in certain embodiments, by 25%, according to standard subjective or objective pain assessments.

[0123] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of developing chemotherapy-induced nausea and vomiting (CINV). Effective prophylactic treatment of CINV occurs when CINV is reduced by 10%, and in certain embodiments, by 25%, as measured by standard subjective or objective CINV assessments.

[0124] As an example of preventative treatment of nutritional deficiencies, the oral formulations disclosed herein can be administered to subjects at risk of developing rickets due to vitamin C deficiency, anemia due to lack of iron in the diet, and / or bone loss due to calcium deficiency. Effective preventative treatment of these conditions occurs when these conditions are avoided or delayed due to nutritional supplementation with the oral formulations disclosed herein.

[0125] "Therapeutic treatment" includes treatment administered to a subject having a disease or nutritional deficiency, which is administered to the subject with the intent of curing or reducing the severity of the disease or nutritional deficiency.

[0126] As an example of therapeutic treatment, the oral formulations disclosed herein can be administered to a subject suffering from migraine headaches. Effective therapeutic treatment of migraine headaches is manifested when the severity of the headache is completely reduced or alleviated, as measured by standard subjective or objective headache assessments, and / or the headache resolves more quickly.

[0127] Another example of therapeutic treatment includes administration of an oral formulation disclosed herein to a subject experiencing CINV. Therapeutic treatment of CINV is manifested when vomiting is reduced or ceases (or ceases more quickly) or nausea is alleviated, as measured by standard subjective or objective CINV assessments.

[0128] Another example of a therapeutic treatment involves administration of the disclosed oral formulations to a subject with osteoporosis. Effective therapeutic treatment of osteoporosis occurs when bone density increases by 10%, and in certain embodiments, by 25%.

[0129] Another example of therapeutic treatment involves administration of an oral formulation disclosed herein to a subject with anxiety. Effective therapeutic treatment of anxiety is manifested when there is a complete and / or more rapid reduction or alleviation of the severity of anxiety as measured by standard subjective or objective anxiety assessments.

[0130] Another example of a therapeutic treatment comprises administering an oral formulation disclosed herein to a subject with multiple sclerosis. Effective therapeutic treatment of multiple sclerosis is manifested by a 10%, and in certain embodiments, a 25% improvement in score on a standard walking test.

[0131] As an example of therapeutic treatment of nutritional deficiencies, the oral formulations disclosed herein can be administered to subjects with rickets due to vitamin C deficiency, anemia due to iron deficiency in the diet, and / or bone loss due to calcium deficiency. Effective therapeutic treatment of these conditions occurs when these conditions are reduced or resolved due to nutritional supplementation with the oral formulations disclosed herein.

[0132] Therapeutic treatments can be distinguished from effective amounts based on the presence or absence of the study component upon administration, however, as will be appreciated by those of skill in the art, there may be overlap in effective amounts, prophylactic treatments and therapeutic treatments in human clinical trials.

[0133] For administration, a therapeutically effective amount (also referred to herein as a dosage) can be estimated initially based on the results of in vitro assays and / or animal model studies. Such information can be used to more accurately determine useful dosages in intended subjects.

[0134] The actual dosage administered to a particular subject can be determined by the subject, a physician, veterinarian or researcher, taking into account parameters such as physical, physiological and psychological factors, including the subject's target, weight, condition, previous or concurrent therapeutic interventions, and / or idiopathic diseases.

[0135] Useful dosages can range from 0.1 to 5 μg / kg or 0.5 to 1 μg / kg. In other non-limiting examples, dosages are 1 μg / kg, 5 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg, 100 μg / kg, 15 0μg / kg, 200μg / kg, 250μg / kg, 350μg / kg, 400μg / kg, 450μg / kg, 500μg / kg, 550μg / kg, 600μg / kg, 650μg / kg, 700μ g / kg, 750μg / kg, 800μg / kg, 850μg / kg, 900μg / kg, 950μg / kg, 1000μg / kg, 0.1-5mg / kg or 0.5-1mg / kg. In other non-limiting examples, the dosage is 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 1 The dose may include 00mg / kg, 150mg / kg, 200mg / kg, 250mg / kg, 350mg / kg, 400mg / kg, 450mg / kg, 500mg / kg, 550mg / kg, 600mg / kg, 650mg / kg, 700mg / kg, 750mg / kg, 800mg / kg, 850mg / kg, 900mg / kg, 950mg / kg, 1000mg / kg or more.

[0136] A therapeutically effective amount can be achieved by administration of single or multiple doses over the course of a treatment regimen (e.g., every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 9 hours, every 12 hours, every 18 hours, every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, or once a month).

[0137] One or more active agents can be administered simultaneously or within a selected time window, such as within a 10 minute, 1 hour, 3 hour, 10 hour, 15 hour, 24 hour, or 48 hour time window, or when the complementary active agents are within a clinically relevant therapeutic window.

[0138] The following representative embodiments and examples are included to demonstrate specific embodiments of the present disclosure. As one of ordinary skill in the art will recognize in light of this disclosure, many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0139] Representative Embodiments 1. A plant-derived composition comprising a plant material and an N-acylated fatty amino acid or a salt thereof.

[0140] 2. The plant-derived composition of embodiment 1, comprising a botanical product.

[0141] 3. Plant substances are Santa Maria (Calophyllum brasiliense), Calophyllum caledonicurn, Calophyllum inophyllum, Hypericum (Calophyllum soulattri), Cat's claw (Uncaria tomentosa), Thymus vulgaris, Chamomile (Matricaria recutita), Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheria procumbens, Tea plant (Camellia sinensis), Vaccinium myrtillus, Lemon balm (Melissa officinalis), Garlic (Allium 3. The plant-derived composition of embodiment 1 or 2, wherein the composition is derived from a plant selected from the group consisting of Camellia sativum, Camellia sinensis, Krameria triandra, Punica granatum, Viburnum plicatum, Nicotiana tabacum, Duboisia hopwoodii, Asclepias syriaca, Curcuma longa, Cannabis sativa, Cannabis indica, Cannabis ruderalis and / or Acer spp, or extracts thereof.

[0142] 4. The plant-derived composition of any of embodiments 1-3, wherein the botanical material is derived from cannabis.

[0143] 5. The plant-derived composition of any of embodiments 1-4, wherein the botanical material is derived from Cannabis sativa, Cannabis ruderalis, or Cannabis indica.

[0144] 6. The plant-derived composition of any of embodiments 1-5, comprising a cannabis extract.

[0145] 7. The plant-derived composition of any of embodiments 1-6, comprising a cannabinoid.

[0146] 8. The plant-derived composition of any of embodiments 1-7, comprising Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabidiol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA), and / or mixtures thereof.

[0147] 9. The plant-derived composition of any of embodiments 1-8, comprising a flavonoid compound, a terpene, or a terpenoid.

[0148] 10. The plant-derived composition of any of embodiments 1-9, wherein the N-acylated fatty amino acid comprises one or more of compounds I-XXXV (Figure 3), or compounds a-r (Figure 4).

[0149] 11. The plant-derived composition of any of embodiments 1-10, wherein the N-acylated fatty amino acids include monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, and N-(salicyloyl)-8-aminocaprylic acid.

[0150] 12. N-acylated fatty amino acids or their salts

[0151] [ka] 12. The plant-derived composition of any of embodiments 1-11, comprising: wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

[0152] 13. The plant-derived composition of embodiment 12, wherein the monovalent cation comprises sodium or potassium.

[0153] 14. The plant-derived composition of embodiment 12, wherein the metal cation comprises calcium or magnesium.

[0154] 15. The plant-derived composition of embodiment 12, wherein the organic cation comprises ammonium or tetramethylammonium.

[0155] 16. The plant-derived composition of embodiment 12, wherein X is H.

[0156] 17. The plant-derived composition of embodiment 12, wherein X is a monovalent cation comprising sodium or potassium.

[0157] 18. The plant-derived composition of embodiment 12, wherein X is a divalent metal cation comprising calcium or magnesium.

[0158] 19. The plant-derived composition of embodiment 12, wherein X is an organic cation comprising ammonium or tetramethylammonium.

[0159] 20. The plant-derived composition of embodiment 12, wherein Z is H.

[0160] 21. The plant-derived composition of embodiment 12, wherein Z is a monovalent cation comprising sodium or potassium.

[0161] 22. The plant-derived composition of embodiment 12, wherein Z is a divalent cation comprising calcium or magnesium.

[0162] 23. The plant-derived composition of embodiment 12, wherein X is H and Z is H.

[0163] 24. The plant-derived composition of embodiment 12, wherein X is H and Z is sodium.

[0164] 25. The plant-derived composition of embodiment 12, wherein X is sodium and Z is sodium.

[0165] 26. The plant-derived composition of any of embodiments 1-25, wherein the N-acylated fatty amino acid provides an administration benefit.

[0166] 27. The plant-derived composition of embodiment 26, wherein the administration benefit is a dose-dependent administration benefit.

[0167] 28. The plant-derived composition of embodiment 27, wherein the dose-dependent administration benefit is at a dose of 100-200 mg.

[0168] 29. The plant-derived composition of embodiment 26, wherein the administration benefits include one or more of: increased absorption of the measured component of the botanical substance, increased bioavailability of the measured component of the botanical substance, faster onset of action of the measured component of the botanical substance, higher peak concentration of the measured component of the botanical substance, faster time to peak concentration of the measured component of the botanical substance, shorter duration of action, increased subjective therapeutic effect, increased objective therapeutic effect, improved taste, and improved mouthfeel, compared to a control composition not containing an N-acylated fatty amino acid.

[0169] 30. The plant-derived composition of any of embodiments 1-29, wherein the plant-derived composition is a pharmaceutical composition.

[0170] 31. The plant-derived composition of any of embodiments 1-30, wherein the plant-derived composition is a nutritional supplement.

[0171] 32. The plant-derived composition of any of embodiments 1-31, comprising a surfactant, detergent, azone, pyrrolidone, glycol, or bile salt.

[0172] 33. The plant-derived composition of any of embodiments 1-32, comprising a therapeutically effective amount of botanical material.

[0173] 34. A therapeutically effective amount of the compound may be administered to treat acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infections, gastrointestinal disorders, glaucoma, glioma, Graves' disease, heart disease. Hepatitis, herpes, Huntington's disease, hypertension, lethargy, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, ivy The plant-derived composition of embodiment 33 for treating symptoms of allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles, sickle cell disease, stroke, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, and withdrawal.

[0174] 35. The plant-derived composition of any of embodiments 1-34, comprising a vitamin or mineral.

[0175] 36. The plant-derived composition of any of embodiments 1-34, comprising vitamins and minerals.

[0176] 37. The plant-derived composition of embodiment 35 or 36, wherein the vitamins are selected from one or more of vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, or vitamin K.

[0177] 38. The plant-derived composition of embodiment 35 or 36, wherein the minerals are selected from one or more of calcium, chromium, iodine, iron, magnesium, selenium or zinc.

[0178] 39. An oral formulation comprising the plant-derived composition of any of embodiments 1-38.

[0179] 40. The oral formulation of embodiment 39, wherein the oral formulation can be swallowed or chewed.

[0180] 41. The oral formulation of embodiment 39 or 40, wherein the oral formulation is a liquid or a solid.

[0181] 42. The oral formulation of any of embodiments 39-41, wherein the oral formulation is a solution, suspension, or spray.

[0182] 43. The oral formulation of any of embodiments 39-41, wherein the oral formulation is a tablet, capsule or sachet.

[0183] 44. The oral dosage form of any of embodiments 39-43, wherein the oral dosage form is flavored.

[0184] 45. A method of producing an oral formulation of cannabis having a faster onset of action, the method comprising adding an absorption enhancer to an oral formulation of cannabis, wherein the oral formulation of cannabis has a faster onset of action than an oral formulation of cannabis that does not include the absorption enhancer.

[0185] 46. ​​The method of embodiment 45, wherein the absorption enhancer is an N-acylated fatty amino acid or a salt thereof.

[0186] 47. N-acylated fatty amino acids or their salts

[0187] [ka] 47. The method of embodiment 45 or 46, comprising: wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

[0188] 48. The method of any of embodiments 45-47, wherein the N-acylated fatty amino acid is selected from monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, and N-(salicyloyl)-8-aminocaprylic acid.

[0189] 49. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition of any of embodiments 1-39 or the formulation of any of embodiments 40-45, thereby treating the subject in need thereof.

[0190] 50. The method of embodiment 50, wherein the therapeutically effective amount provides an effective amount, prophylactic treatment, and / or therapeutic treatment.

[0191] 51. A method for reducing or eliminating one or more symptoms of a disease or disorder in a human subject, the method comprising delivering to the subject a therapeutically effective amount of the composition of any of embodiments 1-39 or the oral formulation of any of embodiments 40-45, thereby reducing or eliminating one or more symptoms of the disease or disorder, the disease or disorder being selected from the group consisting of acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and / or rheumatoid arthritis. LS), rigidity, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headaches, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infections, digestive disorders, glaucoma, glioma, Graves' disease, heart disease Hepatitis, herpes, Huntington's disease, hypertension, lethargy, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral vascular disease, peripheral neuropathy, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles, sickle cell disease, seizures, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, or withdrawal syndrome. EXAMPLES

[0192] An oral cannabinoid dosage form exhibiting improved bioavailability and reduced time to onset of action.

[0193] Given the wealth of health conditions that may benefit from cannabis treatment, there is a significant unmet need for fast-acting products that exhibit improved bioavailability in oral formats. Current oral cannabis products include edibles and traditional pharmaceutical dosage forms that suffer from low bioavailability and long onset of action. The present disclosure addresses the shortcomings of all currently available oral cannabis products to provide improved time to action and improved bioavailability.

[0194] [Example 1] Representative formulations. Solution formulations. Cannabis and one or more N-acylated fatty amino acids are mixed in an aqueous / organic solvent mixture. The resulting blend is stirred vigorously for 1 hour. If dissolution is incomplete, a surfactant can be added and stirring continued to prepare the final formulation.

[0195] Suspension formulations. Cannabis and one or more N-acylated fatty amino acids are mixed in water, an aqueous / organic solvent mixture, or an organic solvent mixture. The resulting blend can be stirred to form a suspension.

[0196] Solution formulations. Cannabis and one or more absorption enhancers are mixed in an aqueous / organic solvent mixture. The resulting blend is stirred vigorously for 1 hour. If dissolution is incomplete, a surfactant can be added and stirring continued to prepare the final formulation.

[0197] Suspension formulations. Cannabis and one or more absorption enhancers are mixed in water, an aqueous / organic solvent mixture, or an organic solvent mixture. The resulting blend can be stirred to form a suspension.

[0198] Gel Cup Compositions. The suspension or solution formulation can be filled into the gel cup to contain up to 1 g of cannabis. The gel cup can be treated with an enteric coating or used uncoated.

[0199] Tablet / Capsule Compositions. Solution and suspension formulations can be dried by evaporation, freeze drying, or spray drying. The resulting dried product can be mixed with tableting excipients and compressed into tablets or caplets containing up to 1 g of cannabis. Alternatively, the dried product can be filled into capsules.

[0200] Example 2: Onset and duration of action of orally administered cannabis / SNAC compositions. This study was designed to evaluate the utility of SNAC in providing a fast-acting oral form of cannabis.

[0201] Participant Selection. Six study participants were recruited to ingest the cannabis composition and record the onset, duration, and intensity of cannabis-induced euphoria and / or dysphoria. Study participants participated in two separate studies: 1) use of a control substance comprising a liquid cannabis extract dissolved in aqueous ethanol, and 2) use of a test substance comprising a liquid cannabis extract dissolved in aqueous ethanol and SNAC.

[0202] Formulation. The cannabis concentrate selected was commercially available and given to participants as a solution in ethanol. The concentrate contained 8 mg of THC per dose. This was selected because it contains a high percentage of THC and shows a notable effect on the "euphoria" reported by users. Aqueous ethanol was used as the solvent since it effectively dissolves the cannabis extract as well as SNAC.

[0203] Methods: In a control experiment, each participant mixed cannabis concentrate with 15 ml (one tablespoon) of aqueous ethanol and immediately swallowed the mixture.

[0204] In the test experiment, each participant mixed the cannabis concentrate with a premixed solution of aqueous ethanol and 200 mg of SNAC and immediately swallowed the dissolved mixture.

[0205] In the control and test experiments, each participant recorded the time of dosing, the time of onset of euphoria and / or dysphoria, and the observed levels of euphoria and / or dysphoria at 15-minute intervals for 5 hours after administration of the cannabis drug dose. Euphoria and dysphoria were reported using a scale ranging from 1 to 10. Table 1 lists the euphoria and dysphoria levels for each scale value.

[0206] [Table 2]

[0207] Results. The results shown below are the average scale values ​​obtained across all six participants (also shown in Figures 5A and 5B).

[0208] [Table 3]

[0209] [Table 4]

[0210] Onset: All six participants reported euphoria within 5 minutes of ingestion of the cannabis / SNAC formulation (test), with onset times ranging from 2 to 5 minutes. In contrast, the first time point of euphoria reported by participants after ingestion of the cannabis-only formulation (control) was 15 minutes after ingestion, with onset times ranging from 15 minutes to 1 hour and 15 minutes (see Figures 6A-6F for individual participant results). By 15 minutes after ingestion, the mean reported euphoria scale value was 3.8 for the cannabis / SNAC formulation (test). In contrast, 15 minutes after ingestion of the cannabis-only formulation (control), the mean reported euphoria scale value was 0.17 (see Figures 5A and 5B for means at each time point).

[0211] Intensity: The mean peak euphoria scale value after ingestion of the cannabis / SNAC formulation (test) was 4.7, which occurred 30 minutes after ingestion. In contrast, the highest mean euphoria scale value after ingestion of the cannabis-only formulation (control) was 2.2, which occurred at 2 hours and 15 minutes (see Figures 5A and 5B). Thus, ingestion of the cannabis / SNAC formulation led to a higher peak intensity of euphoria, which occurred on average 1 hour and 45 minutes earlier than when the cannabis-only formulation was ingested. The observed intensity of dysphoria was minimal in both test and control, with a mean peak scale value of 0.83 in both experiments.

[0212] Duration: The results show that the addition of an absorption enhancer does not shorten the effect of cannabis.

[0213] In summary, the addition of an absorption enhancer such as SNAC to an oral cannabis dosage formulation exhibits a more rapid onset of action and a higher intensity of action at the peak activity level of cannabis, without affecting the duration of action of cannabis.

[0214] Example 3: Onset and duration of action of orally administered low SNAC dose cannabis / SNAC composition. This study was designed to evaluate the usefulness of low dose SNAC in enabling a fast-acting oral form of cannabis.

[0215] Participant Selection. Three study participants were recruited to ingest the cannabis composition and were recorded for the onset, duration, and intensity of cannabis-induced euphoria and / or dysphoria. Study participants participated in two separate studies: 1) use of a control substance comprising a liquid cannabis extract dissolved in aqueous ethanol, and 2) use of a test substance comprising a liquid cannabis extract dissolved in aqueous ethanol and SNAC.

[0216] Formulation. The cannabis concentrate selected was commercially available and given to participants as a solution in ethanol. The concentrate contained 8 mg of THC per dose. This was selected because it contains a high percentage of THC and shows a pronounced effect on the "euphoria" reported by users. Aqueous ethanol was used as the solvent since it effectively dissolves the cannabis extract as well as SNAC.

[0217] Methods: In a control experiment, each participant mixed cannabis concentrate with 15 ml (one tablespoon) of aqueous ethanol and immediately swallowed the mixture.

[0218] In the test experiment, each participant mixed the cannabis concentrate with a premixed solution of aqueous ethanol and 100 mg of SNAC and immediately swallowed the dissolved mixture.

[0219] In both the control and test experiments, each participant recorded the time of dose administration, the time of onset of euphoria and / or dysphoria, and the observed levels of euphoria and / or dysphoria at 15-minute intervals for 5 hours after administration of the cannabis dose. Euphoria and dysphoria were reported using a scale ranging from 1 to 5. Table 1 lists the levels of euphoria and dysphoria for each scale value.

[0220] Results. Results are shown in Figure 7 for all participants, along with the data from Example 2.

[0221] Onset: All three participants reported euphoria within 5 minutes of ingesting the cannabis / SNAC formulation (test), with onset times ranging from 2 to 5 minutes. In contrast, the first time point of euphoria reported by participants after ingestion of the cannabis-only formulation (control) was 15 minutes after ingestion, with onset times ranging from 15 minutes to 1 hour and 15 minutes. By 15 minutes after ingestion, the mean reported euphoria scale value was 3.0 for the cannabis / SNAC formulation (test). In contrast, 15 minutes after ingestion of the cannabis-only formulation (control), the mean reported euphoria scale value was 0.25.

[0222] Intensity: The mean peak euphoria scale score after ingestion of the cannabis / SNAC formulation (test) was 3.4, which occurred 30 minutes after ingestion. In contrast, the highest mean euphoria scale score after ingestion of the cannabis-only formulation (control) was 2.2, which occurred at 2 hours and 15 minutes. Compared to Example 2, where the SNAC dose was 200 mg, participants in Example 3 received only 100 mg of SNAC in combination with the same amount of cannabis used in Example 2. This reduced amount of SNAC resulted in a reduced cannabis effect, showing a clear dose-response relationship between the observed cannabis effect (euphoria) and the SNAC dose. As in Example 2, ingestion of the cannabis / SNAC formulation showed a higher peak intensity of euphoria, which occurred an average of 1 hour and 45 minutes earlier than when the cannabis-only formulation was ingested.

[0223] Duration: The results show that the addition of an absorption enhancer does not shorten the effect of cannabis.

[0224] In summary, the addition of an absorption enhancer such as SNAC to an oral cannabis dosage formulation shows a faster onset of action and a higher intensity of action at the peak activity level of cannabis. Furthermore, the absorption enhancer does not affect the duration of action of cannabis. Varying amounts of SNAC produce a clear dose-response relationship between the observed cannabis effect (euphoria) and the SNAC dose.

[0225] As will be appreciated by those skilled in the art, each embodiment disclosed herein can comprise, consist essentially of, or consist of its specific stated elements, steps, ingredients, or components. Thus, the terms "include" or "including" should be understood to mean "comprise, consist, or consist essentially of." As used herein, the transitional term "comprise" means to include, but is not limited to, and may contain, even in major amounts, elements, steps, ingredients, or components not specifically recited. The transitional phrase "consisting of" excludes elements, steps, ingredients, or components not specifically recited. The transitional phrase "consisting essentially of" limits the scope of the embodiment to the elements, steps, ingredients, or components specifically recited and those that do not substantially affect the embodiment. As used herein, a significant effect would result in a statistically significant reduction in the administration benefit as assessed by the experimental protocols disclosed herein.

[0226] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and without any intention of limiting the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by using ordinary rounding techniques. Where further clarity is needed, the term "about" when used in conjunction with a stated numerical value or range shall have the meaning that one of ordinary skill in the art would expect, i.e., a value that is somewhat greater or somewhat less than the stated value or range, a value within ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11% of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value.

[0227] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible, however, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0228] The terms "a," "an," "the," and similar modifiers used in describing the present invention (particularly in the claims that follow) are to be understood to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended as a shorthand alternative to individually referring to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if set forth individually. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") recited herein is intended merely to facilitate a better understanding of the invention, and is not intended to impose limitations on the scope of the invention as recited in the claims. No language in the specification should be construed to refer to any element essential to the practice of the invention, even if not recited in the claims.

[0229] Groups of alternative elements or embodiments of the invention disclosed herein should not be considered as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is understood that one or more members of a group may be included in or omitted from a group for convenience and / or patentability. When such inclusion or omission occurs, the specification is considered to include the group as modified to meet the recitation requirements of all Markush groups used in the appended claims.

[0230] Certain embodiments of the present invention have been described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of skill in the art upon reading the foregoing description. The inventors expect that such variations will be utilized by those of skill in the art, and the inventors intend that the invention be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of any possible variations of the elements described above is encompassed by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0231] Additionally, numerous patents, publications, journal articles and other documents ("references") are referenced throughout this specification. Each of these references is individually incorporated herein by reference for the teachings contained therein.

[0232] In closing, it should be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be used are within the scope of the invention. Thus, by way of example, and not of limitation, other aspects of the invention may be utilized in accordance with the teachings herein. Thus, the present invention is not limited to what has been precisely shown and described above.

[0233] The details shown in this specification are for the purpose of illustrating the preferred embodiments of the present invention only, by way of example, and are provided to illustrate what is believed to be the most useful and easily understood explanation of the principles and conceptual aspects of various embodiments of the present invention. In this regard, it is not intended to show the structural details of the present invention in more detail than is necessary for a fundamental understanding of the present invention, but rather, the description, taken together with the drawings and / or examples, will make clear to those skilled in the art how several forms of the present invention can be embodied in practice.

[0234] The definitions and explanations used in this disclosure are meant and intended to control in future constructions unless clearly and unambiguously modified in the following examples, or when application of the meaning would render any construction meaningless or essentially meaningless. If construction of the term renders it meaningless or essentially meaningless, the definition should be derived from a dictionary known to those skilled in the art, such as Webster's Dictionary, 3rd Edition, or the Oxford Dictionary of Biochemistry and Molecular Biology (Ed. Anthony Smith, Oxford University Press, Oxford, 2004).

Claims

1. (i) a cannabinoid having a solubility in water or an aqueous solution of less than 0.1 mg / ml; and (ii) An N-acylated fatty amino acid or a salt thereof, comprising the following formula: 【Chemistry 1】 wherein X and Z are independently hydrogen, a monovalent cation, a divalent metal cation, or an organic cation.

1. An oral formulation for reducing or eliminating one or more symptoms of a disease or disorder, comprising: The disease or disorder is selected from the group consisting of acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune disease, bacterial infection, bipolar disorder, bone loss, blood disease, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorder, eczema, epilepsy, fever, fibromyalgia, flu, fungal infection, digestive disorder, glaucoma, glioma, Graves' disease, and heart disease. Hepatitis, herpes, Huntington's disease, hypertension, lethargy, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral Oral formulations for the treatment of neurological disorders, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles), sickle cell disease, seizures, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorders (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, or withdrawal symptoms.

2. (i) a cannabinoid having a solubility in water or an aqueous solution of less than 0.1 mg / ml; and (ii) An N-acylated fatty amino acid or a salt thereof, comprising the following formula: 【Chemistry 2】 wherein X and Z are independently hydrogen, a monovalent cation, a divalent metal cation, or an organic cation. An oral formulation comprising: The cannabinoids are selected from the group consisting of Calophyllum brasiliensis, Calophyllum caledonicurn, Calophyllum inophyllum, Hypericum soulattri, Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendula officinalis, Usnea barbata, and the like. barbata), Ligusticum porteri-osha, Gaultheria procumbens, Camellia sinensis, Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia sinensis, Krameria triandra, Pomegranate, Viburnum plicatum, Nicotiana tabacum, tabacum, Duboisia hopwoodii, Asclepias syriaca, Curcuma longa, Cannabis sativa, Cannabis indica, Cannabis ruderalis, and / or Acer spp., or extracts thereof.

3. 3. The oral formulation of claim 1 or 2, comprising 100 to 200 mg of N-[8-(2-hydroxybenzoyl)amino]caprylate.

4. 3. The oral formulation of claim 1 or 2, wherein the cannabinoid is derived from cannabis.

5. 3. The oral formulation of claim 1 or 2, wherein the cannabinoid is derived from Cannabis sativa, Cannabis ruderalis, or Cannabis indica.

6. 3. An oral formulation according to claim 1 or 2 comprising a cannabis extract.

7. The oral formulation of claim 1, wherein the cannabinoid comprises Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiol acid (CBDA), cannabinol propyl variant (CBNV), cannabiditriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA), or a mixture thereof.

8. The oral formulation of claim 1 or 2, further comprising a flavonoid compound, a terpene, or a terpenoid.

9. X is selected from hydrogen, sodium, potassium or ammonium as monovalent cations, calcium or magnesium as divalent metal cations, or tetramethylammonium as organic cation; or Z is selected from hydrogen, sodium or potassium as monovalent cations, or calcium or magnesium as divalent metal cations; or 3. The oral formulation of claim 1 or 2, wherein X is hydrogen and Z is hydrogen, X is hydrogen and Z is sodium, or X is sodium and Z is sodium.

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