Fast-acting plant-based medicinal compounds and nutritional supplements

Abstract

To provide fast-acting plant-based medicinal compounds and nutritional supplements formulated for oral delivery.SOLUTION: Plant-based medicinal compounds or nutritional supplements in various carrier combinations are provided. The carriers can include N-acylated fatty amino acids, penetration enhancers, and / or various other beneficial carriers. The plant-based composition / carrier combinations can create administration benefits.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 326,490, filed on April 22, 2016, and U.S. Provisional Patent Application No. 62 / 429,544, filed on December 2, 2016, the entire contents of each of which are incorporated herein by reference.

[0002] The present disclosure provides instant - acting plant - derived pharmaceutical compounds or nutritional supplements in various carrier combinations. Carriers can include N - acylated fatty amino acids, penetration enhancers, and / or various other beneficial carriers. The plant - derived composition / carrier combination can create an administration benefit after oral administration.

Background Art

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

[0004] However, now, it is increasingly recognized that many plants and plant extracts are extremely effective agents for the prevention and treatment of diseases. A single plant can carry many pharmaceutically active substances, and the extracts obtained therefrom can exert their activity in various physiological processes and increase the range of desirable therapeutic effects.

[0005] As an example, U.S. Patent Application Publication No. 2015 / 0050373 describes the use for treating metabolic disorders of plants derived from the Calophyllum genus. Calophyllum is a genus of angiosperm trees, approximately 180 - 200 species of tropical evergreens. 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 pharmaceutical uses of this plant have been reported in the literature. For example, a decoction of the bark of this plant is used for the treatment of internal bleeding. The oil extracted from the seeds of Calophyllum inophyllum is used to treat rheumatoid arthritis or joint diseases; itching; eczema; eruptions on the head; eye diseases; and kidney failure.

[0006] U.S. Patent Application Publication No. 2014 / 0193345 describes the use of 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 for the treatment of mucosal lesions.

[0007] U.S. Patent Application Publication No. 2010 / 0068297 describes the use of Punica granatum, Viburnum plicatum, Camellia sinensis, and species of the genus Acer (Acer spp.) as antibacterial agents.

[0008] Numerous medical uses have also been confirmed in cannabis plants. For example, delta-9-tetrahydrocannabinol (THC, also known as dronabinol), an extract of the cannabis plant, is formulated in sesame oil for oral delivery. THC exhibits complex effects on the central nervous system (CNS), including central sympathomimetic-like activity. THC has been shown to have a significant appetite-stimulating effect and is used in the treatment of AIDS-related anorexia. THC affects appetite, mood, cognition, memory, and perception. Additionally, this drug has anti-emetic properties and is 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 is described in Pharm. J. 259, 104, 1997 and Pharm. Sci. 3, 546, 1997. Nabilone, a synthetic cannabinoid, is an anti-emetic and anxiolytic 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 the treatment of AIDS when administered orally (J. Pain. Symptom Manage. 1995, 10, 89-97).

[0010] Another cannabinoid whose health benefits are well-documented in the literature is cannabidiol (CBD). In contrast to THC, CBD does not have 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 effects (Campos AC, et al. Pharmacol Res. 2016. 112:119-127).

[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.In March 2009; 11(1): 109-119); there is treatment for 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] For additional uses described in the literature for the asafoetida plant, there is treatment for hypothyroidism, acute gastritis, agoraphobia, stiffness, arthritis, Asperger's syndrome, atherosclerosis, autism, bipolar disorder, blood diseases, cachexia, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervical radiculopathy, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, influenza, fungal infections, digestive diseases, glaucoma, glioma, Graves' disease, hepatitis, herpes, hypertension, 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 poisoning, obesity, obsessive-compulsive disorder (OCD), pancreatitis, panic disorder, periodontal disease, phantom limb pain, poison 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 disorder (TMJ), tension headache, tinnitus, Tourette syndrome, traumatic memories, wasting syndrome, and withdrawal.

Prior Art Documents

Patent Documents

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Non-Patent Literature

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Summary of the Invention

Problems to be Solved by the Invention

[0015] Despite numerous benefits associated with plant-derived compounds and nutritional supplements, when administered in oral form, the onset of their action may be delayed, which can, in some cases, compromise their usefulness. For example, after oral administration, THC has an onset of action as fast as 15 minutes to 1.5 hours and a peak effect of 2 - 4 hours. The duration of action for the psychoactive effect is 4 - 6 hours, but the appetite-stimulating effect may persist for more than 24 hours after administration. THC is almost completely (90 - 95%) absorbed after a single oral dose. However, due to the combined effects of first-pass liver metabolism and poor water solubility (the water solubility of THC is 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 a delayed 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 an immediate - acting plant - derived pharmaceutical compound and a nutritional supplement (collectively, a plant - derived composition) formulated for oral delivery. By providing immediate - acting delivery, physiological benefits are observed earlier, increasing the usefulness of these compounds.

[0017] The disclosed immediate - acting plant - derived compositions can create various administration benefits when providing a therapeutically effective amount in various states. Representative administration benefits include increased absorption, increased bioavailability, faster onset of action, higher peak concentration, shorter time to peak concentration, shorter duration of action, increased subjective therapeutic effect, and increased objective therapeutic effect.

[0018] The immediate - acting property 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 acid in the oral formulation can be linear, branched, cyclic, bicyclic, or aromatic, for example, containing 1 to 50 carbon atoms. The fact that using N - acylated fatty amino acids with the plant - derived composition can provide an immediate - acting benefit was unexpected considering certain aspects of the plant - derived components further described 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 comprises 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, 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 species of the genus Acer, 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

Figure 1B

Figure 2-1

Figure 2-2

Figure 3-1

Figure 3-2

Figure 3-3

Figure 4-1

Figure 4-2

Figure 5A

Figure 5B

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Figure 6B

Figure 6C

Figure 6D

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Figure 6F

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Figure 8

DETAILED DESCRIPTION

[0021] Despite numerous benefits associated with plant-derived compounds and nutritional supplements, when administered in oral form, the onset of their action can be delayed, which in some cases can compromise their usefulness. For example, after oral administration, THC has an onset of action of at least 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, but the appetite-stimulating effect may persist for more than 24 hours after administration. THC is almost completely (90 - 95%) absorbed after a single oral dose. However, due to the combined effects of first-pass liver metabolism and poor water solubility (the water solubility of THC is 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 a delayed 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 immediate-release plant-derived pharmaceutical compounds and nutritional supplements (collectively, plant-derived compositions) formulated for oral delivery. By providing immediate-release delivery, physiological benefits are observed earlier, increasing the usefulness of these compounds.

[0023] The disclosed immediate - acting plant - derived compositions can create various dosing benefits in providing a therapeutically effective amount in various states. Representative dosing benefits include increased absorption, increased bioavailability, more rapid onset of action, higher peak concentrations, shorter time to peak concentration, shorter duration of action, increased subjective therapeutic effects, and increased objective therapeutic effects.

[0024] The immediate - acting nature of the plant - derived compositions 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 from 1 to 50 carbon atoms. That N - acylated fatty amino acids can be used with plant - derived compositions to obtain the benefit of immediate - acting nature was unexpected considering certain aspects of the plant - derived components further described 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] Figure 1A shows the demonstrated correlation between water solubility and the ability of SNAC to improve the absorption of molecules. For cromolyn, vitamin B12, atorvastatin, and ibandronate, the published results include the area under the curve (AUC) calculated from the change in plasma concentration over time. 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. Figure 1A shows the fold improvement derived from SNAC plotted against the water solubility of each of cromolyn, vitamin B12, atorvastatin, and ibandronate. The plotted data shows a marked fit to a logarithmic approximation curve (R 2 = 0.998), indicating a logarithmic relationship between the water solubility of each and the extent 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 absorption improved by SNAC, as evidenced by Cmax (maximum drug plasma concentration) and / or Tmax (time taken to reach the maximum drug plasma concentration). As shown in Figure 1B, these molecules each have a water solubility greater than 0.15 mg / ml, and thus this model accurately predicts that SNAC can improve their absorption. This result demonstrates that SNAC - based improvement in absorption is correlated with the water solubility of the molecule. Figure 1B further shows the water solubility of THC (0.0028 mg / ml) and the predicted effect of SNAC based on it against a logarithmic approximation curve. Based at least on the above, 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 present disclosure are described in more detail below.

[0029] The present disclosure provides an immediate-release plant-derived composition containing a vegetable matter and a carrier as an oral formulation. The plant-derived composition means a plant-derived pharmaceutical compound and a plant-derived nutritional supplement. The plant-derived pharmaceutical compound provides a therapeutically effective amount for treating diseases such as those described in the background art section of the present disclosure. The plant-derived nutritional supplement shows benefits associated with classical nutritional deficiencies; explains how the supplementation is intended to affect the structure or function of the human body; characterizes the identified mechanisms by which the supplement acts to maintain such structure or function; and / or describes the general health status associated with the consumption of the product. In certain embodiments, the nutritional supplement does not diagnose, mitigate, treat, cure, or prevent a particular disease or group of diseases.

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

[0031] In certain embodiments, the plant-derived composition includes phytochemicals derived from 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, 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 / or species of the genus Acer (Acer spp.) or extracts thereof.

[0032] In certain embodiments, the plant-derived composition includes phytochemicals derived from the Cannabis plant. The Cannabis plant means flowering plants including the species (or subspecies) Cannabis sativa, Cannabis ruderalis, and Cannabis indica.

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

[0034] The components of plant-derived compositions can be produced, for example, by grinding, decocting, pressing, and extracting starting plant products. The term "extract" can include all kinds of preparations containing some or all of the active ingredients found in the relevant plants. Extracts can be produced by cold maceration using various extraction solvents such as water, lipid solvents (e.g., olive oil), and alcoholic solvents (e.g., 70% ethanol). Cold maceration is usually applied to the softer parts of plants such as leaves and flowers, or when the desired active ingredient of the plant is heat-sensitive. Alternatively, the extract of the desired plant can be produced by hot extraction techniques using the aforementioned solvents, in which case the solvent is heated to a high temperature (the exact value of this temperature depends on the nature of the selected solvent) and maintained at that temperature throughout the extraction process. Hot extraction techniques are more commonly applied to the harder and more robust parts of plants such as bark, woody branches, and large roots. In some cases, sequential extractions can be carried out with more than one solvent and at different temperatures. Plant extracts can be used in concentrated form. Alternatively, the extract can 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, the crude ethanol extract of hemp plant material is passed through a column of activated carbon and evaporated by rotary evaporation. The resulting THC-enriched extract is subsequently 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 rotary evaporation twice.

[0036] U.S. 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 preset value and one or more low-purity fractions having a THC content lower than the preset value, where the preset value ranges from 95 to 99 wt% of the dry matter; d) subjecting the one or more high-purity fractions to thin-film evaporation again; and e) collecting a THC isolate containing at least 97% of THC of the dry matter, wherein in step b) and / or step d), the thin-film evaporation is performed by using wiped film evaporation. This method offers the advantage that a high-purity THC extract can be obtained in good yield without using health-risk solvents. The method further offers the advantage of being highly reproducible in producing a THC isolate with a specific cannabinoid profile. More specifically, in this method, a THC isolate is obtained that contains at least 97.0 - 99.5% THC and 0.4 - 2.0% other cannabinoids, such as at least 0.3% cannabinol and cannabidiol (percentages are all by weight of the dry matter).

[0037] Additional methods of producing plant extracts (including hot extraction, cold maceration, 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 component (e.g., plant extract) of the plant-derived composition can 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 fractional molecular weight (e.g., less than 10,000 Da) can be performed, for example, by membrane ultrafiltration before storage.

[0039] In certain embodiments, the plant-derived composition contains a carrier such as a modified amino acid, surfactant, detergent, azone, pyrrolidone, glycol, or bile salt. An amino acid is any carboxylic acid having at least one free amine group, including natural, non-natural, and synthetic amino acids. A polyamino acid is a peptide or two or more amino acids linked by a bond that can be formed by other groups that can bind, such as an ester, anhydride, or anhydride bond. A peptide is two or more amino acids linked by a peptide bond. Peptides can vary in length from dipeptides having two amino acids to polypeptides having hundreds of amino acids. See Chambers Biological Dictionary, editor Peter M. B. Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Di-peptides, tri-peptides, tetra-peptides, and penta-peptides can also be used.

[0040] Carriers that are modified amino acids include acylated fatty acid amino acids (FA-aa) or salts thereof, and are typically produced 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 typical N-acylated fatty amino acid salt is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC). Other names for SNAC are 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] [Chemical formula] The salts of SNAC can also be used as carriers.

[0043] Other forms of SNAC include those of the following formula:

[0044] [Chemical formula] In the formula, 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] Typical modified amino acids such as N-acylated FA-aa are provided as Compounds I - XXXV (see Figure 3). The 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 by methods within the skill of the art based on the present disclosure. For example, Compounds I-VII are derived from aminobutyric acid. Compounds VIII-X and XXXI-XXIV are derived from aminocaproic acid. Compounds XI-XXVI and XXXV are derived from aminocaprylic acid. For example, the modified amino acid compounds can be produced by reacting a single amino acid with a suitable modifying agent that reacts with the free amino moiety present in the amino acid to form an amide. Protecting groups can be used to avoid unwanted side reactions as is known to those skilled in the art.

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

[0048] Thereafter, a suitable amino acid modifying agent is added to the amino acid solution with stirring. The temperature of the mixture is generally maintained at a temperature in the range of 5°C to 70°C, preferably 10°C to 40°C, for a period in the range of 1 to 4 hours. The amount of amino acid modifying agent used is based on the moles of the total free NH2 in the amino acid. Generally, the amino acid modifying agent is used in an amount in the range of 0.5 to 2.5 molar equivalents, preferably 0.75 to 1.25 equivalents, per molar equivalent of the 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 the pH reaches 2 - 3. The mixture separates into a clear upper layer and a white or off - white precipitate when left to stand at room temperature. Discard the upper layer and collect the modified amino acid 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 materials are removed by filtration and the filtrate is dried in vacuo. The yield of the modified amino acid generally ranges from 30 - 60% and is usually 45%.

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

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

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

[0053] In certain embodiments, the formula

[0054]

Chemical formula

[0055]

Chemical formula

[0056]

Chemical formula

[0057] In certain embodiments, the modified amino acid also includes an amino acid in which its alpha - amino group is acylated with a fatty acid, which can be represented by the general formula A - X, where A is an alpha - amino acid residue and X is a fatty acid bonded 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" means 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 means 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 (Gln), aspartic acid (Asp), and glutamic acid.

[0058] In certain embodiments, the acylated FA-aa comprises an alpha amino acid residue of a nonpolar hydrophobic amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula A-X, wherein A is an amino acid residue of a nonpolar hydrophobic amino acid and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "nonpolar hydrophobic amino acid" as used herein means the category classification of amino acids used by those of ordinary skill in the art. In certain embodiments, the term "nonpolar hydrophobic amino acid" means 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 A-X, wherein 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 means the category classification of amino acids used by those of ordinary skill in the art. In certain embodiments, the term "polar uncharged amino acid" means 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 A-X, wherein A is an amino acid residue of a polar acidic amino acid and X is a fatty acid bonded to the alpha-amino group of A by acylation. In certain embodiments, the term "polar acidic amino acid" as used herein means the category classification of amino acids used by those skilled in the art. In certain embodiments, the term "polar acidic amino acid" means 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 not encoded by the genetic code. Modification of an amino acid by acylation can be readily performed using an acylating agent known in the art that reacts with the free alpha-amino group of the amino acid.

[0062] In certain embodiments, the alpha-amino acid or alpha-amino acid residue in the present invention is in the L-form unless otherwise stated.

[0063] In certain embodiments, the amino acid residue is in the free acid form and / or its salt such as its sodium (Na+) salt.

[0064] A representative embodiment of the acylated FA-aa can be represented by general formula I of a typical Fa-aa.

[0065]

Chemical formula

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

[0067] In certain embodiments, the acylated FA-aa is soluble at enteric 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 pH less than 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 an aqueous solution at a pH value of 1 unit above or below the pKa of FA-aa at 37°C. In certain embodiments, the solubility of the acylated FA-aa is determined in an aqueous solution at pH 8 at 37°C. In certain embodiments, the solubility of the acylated FA-aa is determined in an aqueous solution at a pH value of 1 unit above or below the pI of FA-aa at 37°C. In certain embodiments, the solubility of the acylated FA-aa is determined in an aqueous solution at a pH value of 1 unit above or below the pI of 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 group), 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 shown in Figure 4.

[0070] In certain embodiments, the acylated FA-aas are 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-decanoyl valinate, N-decanoyl-L-valine, sodium N-decanoyl isoleucinate, N-decanoyl-L-isoleucine, sodium N-decanoyl methioninate, N-decanoyl-L-methionine, sodium N-decanoyl prolinate, N-decanoyl-L-proline, sodium N-decanoyl threoninate, N-decanoyl-L-threonine, sodium N-decanoyl tryptophanate, N-decanoyl-L-tryptophan, sodium N-decanoyl sarcosinate, N-decanoyl-L-sarcosine, N-dodecanoyl asparaginat, N-dodecanoyl-L-asparagine, sodium N-dodecanoyl aspartate, N-dodecanoyl-L-aspartate, sodium N-dodecanoyl cysteinate, N-dodecanoyl-L-cysteine, sodium N-dodecanoyl glutaminat, N-dodecanoyl-L-glutamine, sodium N-dodecanoyl glycinate, N-dodecanoyl-L-glycine, sodium N-dodecanoyl serineate, N-dodecanoyl-L-serine,Sodium N-dodecanoyl threoninate, N-dodecanoyl-L-threonine, sodium N-dodecanoyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium N-decanoyl aspartate, N-decanoyl-L-asparagine, sodium N-decanoyl aspartic acid, N-decanoyl-L-aspartic acid, sodium N-decanoyl cysteinate, N-decanoyl-L-cysteine, sodium N-decanoyl glutaminate, N-decanoyl-L-glutamine, sodium N-decanoyl glycinate, N-decanoyl-L-glycine, sodium N-decanoyl serineate, N-decanoyl-L-serine, sodium N-decanoyl tyrosinate, N-decanoyl-L-tyrosine, sodium N-dodecanoyl aspartate, sodium N-dodecanoyl glutamate, N-dodecanoyl-L-glutamate, sodium N-decanoyl glutamate, N-decanoyl-L-glutamate, Amisoft HS-11 P (sodium stearoyl glutamate), Amisoft MS-11 (sodium myristoyl glutamate), Amisoft LS-11 (sodium dodecanoyl glutamate), Amisoft CS-11 (sodium cocooyl glutamate), sodium N-cocooyl glutamate, Amisoft HS-11 P, Amisoft HS-11 P (sodium N-stearoyl glutamate), (sodium N-myristoyl glutamate)), (sodium N-dodecanoyl glutamate), and one or more of Amisoft HS-11 P can be selected.

[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 mean an amino acid whose alpha-amino group is acylated with a fatty acid.

[0074] In certain embodiments, plant substances having low solubility, or very low solubility, are utilized. In certain embodiments, plant substances that are essentially water-insoluble are utilized. In certain embodiments, solubility in water is defined as low to zero, low solubility: 100 to 1000 parts of water required to dissolve 1 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, according to the United States Pharmacopeia (USP 32) in terms of the amount of water required to dissolve 1 part of solute. However, at basic pH, SNAC and other modified amino acids and the FA-aas described herein are water-soluble. Thus, the dosing benefits described herein would not be readily predictable. In certain embodiments, very low solubility can mean a solubility in water or aqueous solution of less than 1 mg / ml, less than 0.1 mg / ml, or less than 0.01 mg / ml.

[0075] In certain embodiments, N-acylated fatty amino acids act as absorption enhancers, thereby creating dosing benefits. An absorption enhancer means a compound that promotes absorption in the gastrointestinal tract. Absorption enhancers can improve drug absorption by improving the solubility of the drug in the gastrointestinal tract or enhancing membrane permeability as compared to formulations that do not contain an absorption enhancer. Additional examples of absorption enhancers include surfactants, detergents, azones, pyrrolidones, glycols, or bile salts.

[0076] In certain embodiments, the N-acylated fatty amino acid acts as a bioavailability enhancer. Bioavailability refers to the fraction of the active ingredient that is actually absorbed by the subject and reaches the bloodstream. In certain embodiments, the bioavailability enhancer will increase the fraction of the active ingredient in the bloodstream or cause the active ingredient in the bloodstream to be detected at an earlier time, as compared to a formulation that does not contain the bioavailability enhancer.

[0077] In certain embodiments, the additional dosing benefits produced by the absorption enhancer and / or bioavailability enhancer include a more rapid onset of action, a higher peak concentration, a shorter 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 otherwise similar except for not containing the absorption enhancer and / or bioavailability enhancer.

[0078] Embodiments that utilize an absorption enhancer and / or bioavailability enhancer (e.g., and in certain embodiments, N-acylated fatty amino acids) may be beneficial because many oral plant-derived compositions designed to address various physiological states are unsuitable because they are characterized by a delayed onset of action and low bioavailability. The delayed onset of action poses a difficult problem in clinical applications that require a rapid therapeutic effect (e.g., pain and migraine); the low bioavailability requires the patient to ingest a significantly higher dose than is required in another dosage form (e.g., smoking, vaping). The specific embodiments disclosed herein provide plant-derived composition oral formulations that have improved bioavailability and a shorter time to onset of therapeutic effect.

[0079] As described above, in certain embodiments, the N-acylated fatty amino acid acts as a subjective treatment facilitator. Subjective treatment facilitation means a marked reduction in symptoms recognized by the subject. In certain embodiments, the subjective treatment facilitator increases the reduction of symptoms or reduces the symptoms more rapidly compared to a formulation that does not include the subjective treatment facilitator.

[0080] In certain embodiments, the N-acylated fatty amino acid acts as an objective treatment facilitator. Objective treatment facilitation means a reduction in clinical measures such as nutrient deficiencies detected by a blood or saliva assay or a health test when administered by a physician. In certain embodiments, the objective treatment facilitator increases the reduction of objective clinical measures or brings about the reduction more rapidly compared to a formulation that does not include the objective treatment facilitator.

[0081] Certain embodiments include cannabis as well as an absorption enhancer and / or a bioavailability enhancer. These embodiments can enable more rapid absorption of cannabis and higher bioavailability compared to cannabis ingested by currently available oral dosage forms.

[0082] In certain embodiments, the carriers disclosed herein produce an administration benefit selected from increased absorption, increased bioavailability, more rapid onset of action, higher peak concentration, shorter 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, more rapid onset of action, higher peak concentration, shorter time to peak concentration, and shorter duration of action can more rapidly alleviate adverse conditions (e.g., pain reduction). "Mouthfeel" means aspects not related to the pleasant taste that a person feels when ingesting an oral dosage form (e.g., chewing or swallowing). Aspects of mouthfeel include whether the composition is hard and brittle, has a biting texture, is gritty, oily, creamy, watery, sticky, easily dissolves, astringent, effervescent, etc., as well as the size, shape, and form of the composition (tablet, powder, gel, etc.).

[0083] A plant-derived composition can be manufactured for administration to a subject by adding, mixing, suspending, dissolving, blending, granulating, tableting, encapsulating, or performing other dosage form-specific techniques on a plant-derived substance, a carrier that exhibits an administration benefit, and one or more excipients, followed by packaging. For clarity, the carrier contributes to exhibiting an administration benefit. Excipients are not necessarily required but can contribute to an administration benefit.

[0084] Certain embodiments include plant-derived compositions manufactured as oral formulations. Representative oral formulations include capsules, coated tablets, edibles, elixirs, emulsions, gels, gelcaps, granules, gums, juices, liquids, oils, pastes, pellets, pills, powders, rapidly dissolving tablets, sachets, semi-solids, sprays, solutions, suspensions, syrups, tablets, etc.

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

[0086] A binder is a substance used to cause adhesion of powder particles during granulation. Typical binders include acacia, compressible sugar, gelatin, sucrose and its derivatives, maltodextrin, cellulose polymers such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and methyl cellulose, acrylic polymers such as insoluble acrylate ammonium methacrylate copolymer, polyacrylate or polymethacrylic copolymer, povidone, copovidone, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, guar gum, and polyethylene glycol.

[0087] Coloring agents can be included in oral formulations to impart color to the formulation. Typical 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. Typical diluents include microcrystalline cellulose, sucrose, dicalcium phosphate, starch, lactose and polyols having less than 13 carbon atoms such as mannitol, xylitol, sorbitol, maltitol and pharmaceutically acceptable amino acids such as glycine.

[0089] Disintegrants can also be included in oral formulations to facilitate dissolution. Disintegrants, such as permeabilising and wicking agents, can draw water or saliva, which facilitates dissolution, into the oral formulation both internally and externally. Such disintegrants, permeabilising and / or wicking agents that can be used include starch, such as corn starch, potato starch, its pregelatinised 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, arabia, xanthan and tragacanth, silica having a high affinity for aqueous solvents, such as colloidal silica, precipitated silica, maltodextrin, beta-cyclodextrin, polymers, such as carbopol, and cellulosic agents, such as hydroxymethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Dissolution of the oral formulation can be facilitated by including components having a relatively small particle size for use.

[0090] Typical dispersing or suspending agents include acacia, alginates, dextran, tragacanth, gelatin, hydrogenated edible fats, methyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, sorbitol syrup, and synthetic and natural gums.

[0091] Typical emulsifying agents include acacia and lecithin.

[0092] A flavorant is a natural or artificial compound used to impart a pleasant aroma and often a fragrance to oral formulations. Representative flavorants include natural and synthetic flavor oils, flavor aromatics, extracts of plants, leaves, flowers, and fruits, 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, hinoki 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, coconut, blueberry, kiwi, strawberry, raspberry, cherry, plum, pineapple, and apricot. In certain embodiments, flavorants that can be used include natural berry extracts and natural mixed berry flavors, as well as citric and malic acids.

[0093] A glidant improves the flow of the powder blend during manufacture and minimizes oral formulation weight variation. Representative glidants include silicon dioxide, colloidal or fumed silica, magnesium stearate, calcium stearate, stearic acid, corn starch, and talc.

[0094] A lubricant is a substance used in oral formulations that reduces friction during compression of the composition. Representative 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] Typical sweeteners include aspartame, dextrose, fructose, isomerized sugar, maltodextrin, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, acesulfame potassium, sodium saccharin, stevia, sucralose, and sucrose.

[0097] Certain embodiments include ingestible compositions. An ingestible composition is one that does not readily 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 manufacturing ingestible compositions. In certain embodiments, the ingestible composition can have a shape that does not contain sharp edges and a smooth, uniform, and substantially bubble-free outer coating.

[0098] To manufacture an ingestible composition, each component may be combined as a dense admixture with a suitable carrier according to conventional compounding techniques. In certain embodiments of the ingestible composition, the surface of the composition may be coated with a polymeric film. Such film coating has several beneficial effects. First, by reducing the adhesion of the composition to the inner surface of the mouth, it increases the ability of the subject to swallow the composition. Second, the film can assist in masking the unpleasant taste of certain components. Third, the film coating can protect the composition from degradation in the atmosphere. Examples of polymeric films that can be used in manufacturing ingestible compositions include vinyl polymers such as polyvinylpyrrolidone, polyvinyl alcohol and acetate, cellulose derivatives such as methyl and ethyl cellulose, hydroxyethyl cellulose and hydroxylpropylmethyl cellulose, 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. The chewable composition has a pleasant taste and mouthfeel, is relatively soft, and upon chewing begins to break down and dissolve into smaller fragments rapidly, such that it can be swallowed substantially as a solution.

[0100] U.S. Patent No. 6,495,177 describes a method for producing a chewable composition having an improved mouthfeel. U.S. Patent No. 5,965,162 describes a kit and method for producing an edible unit that rapidly disintegrates 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 aroma and mouthfeel and promote relative softness and solubility in the mouth. The following considerations describe ingredients that may help achieve these properties.

[0102] Sugars such as granulated 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 oil and refined lard having a melting point in the range of 30° to 42°C), cocoa butter, margarine, butter, and shortening.

[0103] Alkyl polysiloxanes (polymers commercially available in various molecular weight ranges and various different substitution patterns) can also be used to enhance the texture, mouthfeel, or both of a chewable composition. "Enhancing the texture" means that the alkyl polysiloxane improves one or more of the firmness, brittleness, and chewiness of the chewable composition compared to the same formulation lacking the alkyl polysiloxane. "Enhancing the mouthfeel" means that the alkyl polysiloxane reduces the gritty texture of the chewable composition when liquefied in the mouth compared to the same formulation lacking the alkyl polysiloxane.

[0104] Alkyl polysiloxanes generally contain 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 can further contain silica gel. Alkyl polysiloxanes are generally viscous oils. Representative alkyl polysiloxanes that can be used in ingestible, chewable, or soluble compositions include monoalkyl or dialkyl polysiloxanes, where the alkyl groups are each independently selected from C1-C6-alkyl groups which may optionally be substituted by phenyl groups. A specific alkyl polysiloxane that can be used is dimethyl polysiloxane (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 a mixture of up to 90.5% by weight of (CH3)3-Si{OSi(CH3)2}CH3 with 4.0% - 7.0% by weight of SiO2.

[0105] To prevent stickiness that may occur in a chewable composition and to facilitate the conversion of the active ingredient into an emulsion or suspension upon ingestion, the composition may further contain an emulsifier, such as glycerin fatty acid ester, sorbitan monostearate, sucrose fatty acid ester, 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 formulation to be administered. In certain embodiments, if the level of the emulsifier is lower or higher than that, emulsification does not occur or the wax value increases.

[0106] Liquid formulations for oral administration can take the form of, for example, solutions, syrups or suspensions, or may exist as dry products for reconstitution with water or other suitable excipients before use.

[0107] In addition to the above, when manufacturing a swallowable, chewable and / or soluble composition or any other oral formulation described herein, any suitable fillers and additives may be utilized as long as they are compatible with the stated purposes.

[0108] Oral formulations also include food products. Food products mean any product that can be consumed as food or beverage. In some cases, food products are made into food ingredients by decocting plant extracts. Examples of edible food suitable for use include candies, candy bars, bread, brownies, cakes, cheeses, chocolates, cocoa, cookies, gummies, lollipops, mints, pastries, peanut butter, popcorn, protein bars, mochi, yogurt, etc. Strictly speaking, although not edible, gums can also be used. Examples of edible beverages include beer, juice, flavored milk, flavored water, liqueur, milk, punch, milkshake, soda, tea, and water. In certain embodiments, food products are created by combining the ingredients used to make the food products with plant extracts. Examples include butter and oils. Representative oils include coconut oil, grape seed oil, olive oil, palm oil, papaya seed oil, peanut oil, sesame oil, germinated wheat oil, wheat germ oil, or any combination thereof.

[0109] Oral formulations can be individually packaged or wrapped as composite units in one or more packages, cans, vials, blister packs, or bottles of any size. The dosage amount should be of a size that provides 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 of a plant-based substance (e.g., a plant part or extract).

[0111] 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 of a carrier.

[0112] 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 of an additive.

[0113] In certain embodiments, 10 g of the dry plant extract can be used for 150 ml of water. Thereby, effective concentrations of 1 - 99% (w / w) of the plant extract, 2 - 80% (w / w) of the plant extract, and 5 - 50% (w / w) of the plant extract can be obtained.

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

[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. Furthermore, the formulations can be manufactured to meet the standards of sterility, pyrogenicity, general safety, and purity required by the U.S. 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 an amount effective to provide a prophylactic treatment and / or a therapeutic treatment.

[0117] An "effective amount" is the amount of the plant-derived composition necessary to effect 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, can stimulate appetite in animal models, can reduce seizures (e.g., epileptic seizures) in animal models, can reverse bone loss in animal models, can reduce (constrict cranial blood vessels) migraines in animal models, can treat poisoning in animal models, can reduce anxiety in animal models, and / or can reduce the symptoms of asthma in animal models.

[0118] "Preventive treatment" includes a treatment that is administered to a subject who does not show signs or symptoms of a disease or nutritional deficiency or shows only initial signs or symptoms of a disease or nutritional deficiency, for the purpose of reducing, suppressing, or decreasing the risk of further developing the disease or nutritional deficiency. Thus, preventive treatment functions as a preventive measure against the onset of a disease or nutritional deficiency.

[0119] As an example of preventive treatment, the oral formulations disclosed herein can be administered to a subject at risk of developing migraine. An effective preventive treatment for migraine manifests when the number of migraines felt by the subject decreases by at least 10% or, in certain embodiments, 25% per month.

[0120] As another example of preventive treatment, the oral formulations disclosed herein can be administered to a subject at risk of having epileptic seizures. An effective preventive treatment for epileptic seizures manifests when the number of seizures per month decreases by at least 10% or, in certain embodiments, 25%.

[0121] As yet another example of preventive treatment, the oral formulations disclosed herein can be administered to a subject at risk of suffering from neuropathic pain. An effective preventive treatment for neuropathic pain manifests when the occurrence of neuropathic pain decreases by at least 10% or, in certain embodiments, 25% as measured by standard subjective or objective pain assessments.

[0122] As another example of preventive treatment, the oral formulations disclosed herein can be administered to a subject at risk of developing breakthrough pain. An effective preventive treatment for breakthrough pain manifests when the occurrence of breakthrough pain decreases by 10% or, in certain embodiments, 25% as measured by 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 25%, as measured by standard subjective or objective CINV assessments.

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

[0125] "Therapeutic treatment" includes treatments administered to a subject having a disease or nutritional deficiency and is administered to the subject for the purpose 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 subjects having migraine headaches. Effective therapeutic treatment of migraine headaches occurs when the severity of the headache is completely reduced or alleviated, as measured by standard subjective or objective headache assessments, and / or when the headache dissipates more rapidly.

[0127] Another example of therapeutic treatment includes administration of the oral formulations disclosed herein to subjects experiencing CINV. Therapeutic treatment of CINV occurs when vomiting is reduced or stopped (or stops more rapidly) or nausea is alleviated, as measured by standard subjective or objective CINV assessments.

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

[0129] Another example of a therapeutic treatment involves administering the oral formulations disclosed herein to a subject having anxiety. An effective therapeutic treatment for anxiety is evidenced when the severity of anxiety is completely and / or more rapidly reduced or alleviated as measured by standard subjective or objective anxiety assessments.

[0130] Another example of a therapeutic treatment involves administering the oral formulations disclosed herein to a subject having multiple sclerosis. An effective therapeutic treatment for multiple sclerosis is evidenced when the score in a standard walking test is improved by 10%, and in certain embodiments by 25%.

[0131] As an example of a therapeutic treatment for nutritional deficiencies, the oral formulations disclosed herein can be administered to a subject having scurvy due to vitamin C deficiency, anemia due to iron deficiency in the diet, and / or osteopenia due to calcium deficiency. An effective therapeutic treatment for these conditions is evidenced when these conditions are reduced or resolved due to nutritional supplementation with the oral formulations disclosed herein.

[0132] A therapeutic treatment can be distinguished from an effective amount based on the presence or absence of the research component in the administration. However, as will be understood by those skilled in the art, in human clinical trials, the effective amount, prophylactic treatment, and therapeutic treatment may overlap.

[0133] For administration, a therapeutically effective amount (also referred to herein as a dosage) can first be evaluated based on the results of in vitro assays and / or animal model tests. Such information can be used to more precisely determine a useful dosage in the intended subject.

[0134] The actual dosage administered to a particular subject can be determined by a subject, physician, veterinarian, 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] The useful dosage can be in the range of 0.1 to 5 μg / kg or 0.5 to 1 μg / kg. In other non-limiting examples, the dosage can include 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, 150 μg / kg, 200 μg / kg, 250 μg / kg, 350 μg / kg, 400 μg / kg, 450 μg / kg, 500 μg / kg, 550 μg / kg, 600 μg / kg, 650 μg / kg, 700 μg / kg, 750 μg / kg, 800 μg / kg, 850 μg / kg, 900 μg / kg, 950 μg / kg, 1000 μg / kg, 0.1 to 5 mg / kg or 0.5 to 1 mg / kg. In other non-limiting examples, the dosage can include 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, 100 mg / kg, 150 mg / kg, 200 mg / kg, 250 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, 500 mg / kg, 550 mg / kg, 600 mg / kg, 650 mg / kg, 700 mg / kg, 750 mg / kg, 800 mg / kg, 850 mg / kg, 900 mg / kg, 950 mg / kg, 1000 mg / kg or more.

[0136] A therapeutically effective amount can be achieved by administering a single or multiple dosages during the course of a treatment regimen (e.g., every 1 hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 9 hours, every 12 hours, every 18 hours, daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, weekly, 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 time window of 10 minutes, 1 hour, 3 hours, 10 hours, 15 hours, 24 hours, or 48 hours, or when the complementary active agent is within a clinically relevant therapeutic concentration range.

[0138] The following representative embodiments and examples are included to illustrate specific embodiments of the present disclosure. As will be recognized by those skilled in the art in light of the present disclosure, many changes can be made to the specific embodiments disclosed herein without departing from the spirit and scope of the present disclosure, and still obtain similar or comparable results.

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

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

[0141] 3. The plant-derived composition of Embodiment 1 or 2, which is derived from plant substances including 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, 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 / or Acer spp, or extracts thereof.

[0142] 4. The plant-derived composition of any one of Embodiments 1 to 3, wherein the plant substance is derived from cannabis.

[0143] 5. A plant-derived composition according to any one of Embodiments 1 to 4, wherein the plant substance is derived from Cannabis sativa, Cannabis ruderalis, or Cannabis indica.

[0144] 6. A plant-derived composition according to any one of Embodiments 1 to 5, comprising a cannabis extract.

[0145] 7. A plant-derived composition according to any one of Embodiments 1 to 6, comprising a cannabinoid.

[0146] 8. A plant-derived composition according to any one of Embodiments 1 to 7, comprising Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabinol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabidiorol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinolic acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA), and / or a mixture thereof.

[0147] 9. A plant-derived composition according to any one of Embodiments 1 to 8, comprising a flavonoid compound, a terpene, or a terpenoid.

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

[0149] 11. A plant-derived composition according to any one of Embodiments 1 to 10, wherein the N-acylated fatty amino acid contains monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, and N-(salicyloyl)-8-aminocaprylic acid.

[0150] 12. The N-acylated fatty amino acid or a salt thereof is

[0151]

Chemical Formula

[0152] 13. A plant-derived composition according to Embodiment 12, wherein the monovalent cation contains sodium or potassium.

[0153] 14. A plant-derived composition according to Embodiment 12, wherein the metal cation contains calcium or magnesium.

[0154] 15. A plant-derived composition according to Embodiment 12, wherein the organic cation contains ammonium or tetramethylammonium.

[0155] 16. A plant-derived composition according to Embodiment 12, wherein X is H.

[0156] 17. A plant-derived composition according to Embodiment 12, wherein X is a monovalent cation containing sodium or potassium.

[0157] 18. A plant-derived composition according to Embodiment 12, wherein X is a divalent metal cation containing calcium or magnesium.

[0158] 19. A plant-derived composition according to Embodiment 12, wherein X is an organic cation containing ammonium or tetramethylammonium.

[0159] 20. A plant-derived composition according to Embodiment 12, wherein Z is H.

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

[0161] 22. The plant-derived composition of Embodiment 12, wherein Z is a divalent cation containing 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 according to any one of Embodiments 1 to 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 to 200 mg.

[0168] 29. The administration benefit includes one or more of increased absorption of the measured components of the plant substance, increased bioavailability of the measured components of the plant substance, more rapid onset of action of the measured components of the plant substance, higher peak concentration of the measured components of the plant substance, shorter time to the peak concentration of the measured components of the plant substance, shorter duration of action, increased subjective therapeutic effect, increased objective therapeutic effect, improved taste, and improved mouthfeel, as compared to a control composition not containing the N-acylated fatty amino acid. The plant-derived composition of Embodiment 26.

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

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

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

[0172] 33. The plant-derived composition according to any one of Embodiments 1 to 32, comprising a therapeutically effective amount of a phytochemical.

[0173] 34. A therapeutically effective amount treats hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), stiffness, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, osteopenia, blood diseases, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervical radiculopathy, 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 diseases, 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 poisoning, obesity, obsessive-compulsive disorder (OCD), pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, tularemia 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, seizure, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headache, tinnitus, Tourette syndrome, traumatic memories, wasting syndrome, and withdrawal symptoms; the plant-derived composition of Embodiment 33.

[0174] 35. A plant-derived composition according to any one of Embodiments 1 to 34, comprising a vitamin or a mineral.

[0175] 36. A plant-derived composition according to any one of Embodiments 1 to 34, comprising a vitamin and a mineral.

[0176] 37. The plant-derived composition of Embodiment 35 or 36, wherein the vitamin is 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 mineral is selected from one or more of calcium, chromium, iodine, iron, magnesium, selenium or zinc.

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

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

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

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

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

[0183] 44. The oral preparation of any one of embodiments 39 to 43, wherein the oral preparation is flavored.

[0184] 45. A method for producing an oral preparation of cannabis having a faster onset of action, the method comprising adding an absorption enhancer to the oral preparation of cannabis, the oral preparation of cannabis having a faster onset of action than the oral preparation of cannabis that does not contain 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. The N-acylated fatty amino acid or a salt thereof is

[0187]

Chemical formula

[0188] 48. The method according to any one of embodiments 45 to 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 in need thereof a therapeutically effective amount of a composition according to any one of embodiments 1 to 39 or a formulation according to any one of embodiments 40 to 45.

[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 eradicating 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 a composition of any of embodiments 1-39 or an oral formulation of any of embodiments 40-45 to reduce or eradicate one or more symptoms of the disease or disorder, wherein the disease or disorder is hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), stiffness, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune disease, bacterial infection, bipolar disorder, osteopenia, blood disease, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervical brachial 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 disease, 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 disorder, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesion, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine poisoning, obesity, obsessive-compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, tularemia 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, seizure, sleep apnea, sleep disorder, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headache, tinnitus, Tourette syndrome, traumatic memory, wasting syndrome, or withdrawal syndrome.

Example

[0192] An oral cannabinoid dosage form that exhibits improved bioavailability and a shortened time to onset of action.

[0193] Considering the wealth of health conditions that may benefit from cannabis treatment, there is an important unmet need for products with immediate efficacy that exhibit improved bioavailability in oral form. Current oral cannabis products include edibles and traditional pharmaceutical dosage forms that suffer from low bioavailability and long times to onset of action. The present disclosure addresses the shortcomings of all currently available oral cannabis products in order to provide improved times to onset of action and improved bioavailability.

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

[0195] Suspension formulation. Mix cannabis with one or more N-acylated fatty amino acids in water, an aqueous / organic solvent mixture or an organic solvent mixture. The resulting blend can be stirred to suspend.

[0196] Solution formulation. Mix cannabis with one or more absorption promoters in an aqueous / organic solvent mixture. Stir the resulting blend vigorously for 1 hour. If dissolution is incomplete, a surfactant can be added and stirring can be continued to prepare the final formulation.

[0197] Suspension formulation. Mix cannabis with one or more absorption promoters in water, an aqueous / organic solvent mixture or an organic solvent mixture. The resulting blend can be stirred to suspend.

[0198] Gel cup composition. A suspension formulation or a solution formulation can be filled into a gel cup to contain up to 1 g of cannabis. The gel cup can be treated with an enteric coating or used without a coating.

[0199] Tablet / Capsule Composition. Solution and suspension formulations can be dried by evaporation, lyophilization, or spray drying. The resulting dried product can be mixed with tableting additives and compressed into tablets or caplets to contain 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 Composition. This study was designed to evaluate the utility of SNAC in enabling an immediate-release oral form of cannabis.

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

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

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

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

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

[0206]

Table 2

[0207] Results. The results shown below are the average scale values obtained from a total of 6 participants (also shown in Figures 5A and 5B).

[0208]

Table 3

[0209]

Table 4

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

[0211] Intensity: The average 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 average euphoria scale value after ingestion of the cannabis-only formulation (control) was 2.2, which occurred at the 2 hour 15 minute time point (see Figures 5A and 5B). Thus, ingestion of the cannabis / SNAC formulation resulted in a higher peak intensity of euphoria, which occurred on average 1 hour 45 minutes faster than when the cannabis-only formulation was ingested. The intensity of the observed discomfort was minimal in both the test and control, with an average scale value at the peak of 0.83 in both experiments.

[0212] Duration: The results indicate that the addition of the absorption enhancer does not shorten the action of cannabis.

[0213] In summary, addition of an absorption enhancer such as SNAC to an oral dosage formulation of cannabis results in a more rapid onset of action and a higher intensity of action at the peak activity level of cannabis. The absorption enhancer does not affect the duration of the action of cannabis.

[0214] [Example 3] Onset and duration of action of an oral low dose of SNAC in a cannabis / SNAC composition. This study was designed to evaluate the usefulness of SNAC at low doses in enabling an immediate oral form of cannabis.

[0215] Participant selection. Three study participants were recruited and administered the cannabis composition, and the onset, duration, and intensity of cannabis-induced euphoria and / or discomfort were recorded. The study participants participated in two separate studies: 1) use of a control substance containing a liquid cannabis extract dissolved in aqueous ethanol, and 2) use of a test substance containing a liquid cannabis extract dissolved in aqueous ethanol and SNAC.

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

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

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

[0219] In both the control experiment and the test experiment, each participant recorded the time of drug administration, the time of onset of euphoria and / or discomfort, and the observed levels of euphoria and / or discomfort at 15 - minute intervals for 5 hours after the administration of the cannabis dose. Euphoria and discomfort were reported using a scale value in the range of 1 - 5. Table 1 describes the levels of euphoria and discomfort for each scale value.

[0220] Results. The results, combined with the data of Example 2, are shown in FIG. 7 for all participants.

[0221] Onset: All three participants who ingested the cannabis / SNAC formulation (test) reported euphoria within 5 minutes, and the onset time was in the range of 2 - 5 minutes. In contrast, the first time point of euphoria reported by the participants after ingestion of the cannabis - only formulation (control) was 15 minutes after ingestion, and the onset time was in the range of 15 minutes to 1 hour 15 minutes. By 15 minutes after ingestion, the average 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 average reported euphoria scale value was 0.25.

[0222] Intensity: The average peak euphoria scale value after ingestion of the cannabis / SNAC formulation (test) was 3.4, which occurred 30 minutes after ingestion. In contrast, the highest average euphoria scale value after ingestion of the cannabis-only formulation (control) was 2.2, which occurred at the 2 hour 15 minute time point. Compared to Example 2 where the SNAC dose was 200 mg, the participants in Example 3 ingested 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. Similar to Example 2, ingestion of the cannabis / SNAC formulation showed a higher peak intensity of euphoria, which occurred on average 1 hour 45 minutes faster than when the cannabis-only formulation was ingested.

[0223] Duration: The results indicate that the addition of the absorption enhancer does not shorten the action of cannabis.

[0224] In summary, adding an absorption enhancer such as SNAC to an oral dosage formulation of cannabis results in a faster onset of action and a higher intensity of action at the peak activity level of cannabis. Note that the absorption enhancer does not affect the duration of the action of cannabis. The varying amounts of SNAC result in a clear dose-response relationship between the observed cannabis effect (euphoria) and the SNAC dose.

[0225] As will be understood by those skilled in the art, each embodiment disclosed herein can comprise, consist essentially of, or consist of its specific recited elements, steps, components, or constituents. Accordingly, the terms "include" or "including" are to be interpreted to mean "comprising, consisting of, or consisting essentially of." As used herein, the transitional term "comprising" means including, but not limited to, and can contain elements, steps, components, or constituents not specifically recited, even if present in a major amount. The transitional phrase "consisting of" excludes elements, steps, components, or constituents not specifically recited. The transitional phrase "consisting essentially of" limits the scope of an embodiment to the specifically recited elements, steps, components, or constituents and those that do not materially affect the embodiment. As used herein, a material effect would cause a statistically significant reduction in the administered benefit when evaluated 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 attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the reported number of significant digits and in reference to the usual rounding conventions. Further, when the term "about" is used in conjunction with a numerical value or range, it is intended to have the meaning that would be naturally understood by one of ordinary skill in the art, i.e., a value that is somewhat larger or somewhat smaller than the stated value or range, within ±20% of the stated value; within ±19% of the stated value; within ±18% of the stated value; within ±17% of the stated value; within ±16% of the stated value; within ±15% of the stated value; within ±14% of the stated value; within ±13% of the stated value; within ±12% of the stated value; within ±11% of the stated value; within ±10% of the stated value; within ±9% of the stated value; within ±8% of the stated value; within ±7% of the stated value; within ±6% of the stated value; within ±5% of the stated value; within ±4% of the stated value; within ±3% of the stated value; within ±2% of the stated value; or within ±1% of the stated value.

[0227] Although 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. Nevertheless, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in the respective testing measurements.

[0228] As used in the description of the present invention (especially in the following claims), the terms "a", "an", "the" and similar indicators are to be construed as including both the singular and the plural, unless otherwise indicated herein or clearly inconsistent from the context. The description of a range of values herein is merely intended as a shorthand for separately referring to each individual value falling within that range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were separately recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly inconsistent from the context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is merely intended to make the understanding of the present invention easier and is not intended to limit the scope of the present invention as claimed. No language in this specification should be construed as meaning any element essential to the practice of the invention that is 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 referred to and claimed individually, or in any combination with other members of that group or other elements found herein. One or more members of a group may be included in a group for convenience and / or patentability, or may be omitted. When such inclusion or omission occurs, the specification is considered to include the group as modified so as to meet the requirements for recitation of all Markush groups used in the appended claims.

[0230] Some embodiments of the present invention are described herein, including the best mode known to the inventor for carrying out the present invention. Of course, modifications to these described embodiments will be apparent to those skilled in the art upon reading the above description. The inventor expects those skilled in the art to use such modifications as appropriate, and the inventor also intends that the present invention be practiced otherwise than as specifically described herein. Accordingly, the present invention encompasses all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Further, any combination of all possible variations of the above elements is included in the present invention unless otherwise indicated herein or otherwise clearly contradicted from the context.

[0231] Also, numerous patents, publications, academic papers and other documents (reference materials) have been referred to throughout this specification. These reference materials are each incorporated herein by reference in their entirety for the teachings for which they are individually cited.

[0232] In conclusion, it should be understood that the embodiments of the present invention disclosed herein are illustrative of the principles of the present invention. Other modifications that can be used are within the scope of the present invention. Thus, by way of example and not limitation, another aspect of the present invention can also be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to what is precisely shown and described above.

[0233] The details shown herein are for the purpose of illustration only in describing the preferred embodiments of the present invention and are presented to show what is considered to be the most useful and readily understood description of the principles and conceptual aspects of the 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, and the description in conjunction with the drawings and / or examples will make it apparent to those skilled in the art how some forms of the present invention can be embodied in practice.

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

Claims

[Claim 1] (i) an extract of Vaccinium myrtillus or Curcuma longa having a water solubility of less than 0.1 mg / ml; and (ii) containing an N-acylated fatty amino acid or a salt thereof; An oral formulation comprising: N-acylated fatty amino acid or a salt thereof 【Chemistry 1】 wherein X and Z are independently hydrogen, a monovalent cation, a divalent metal cation, or an organic cation.

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