Herbal compositions with improved bioavailability

Abstract

To provide an herbal composition formulated for oral delivery and having improved bioavailability.SOLUTION: Herbal compositions in combination with various carriers are described. The carriers can include N-acylated fatty amino acids, penetration enhancers, and / or a variety of other beneficial carriers. The herbal composition / carrier combination may produce administration benefits.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Ser. No. 62 / 568,678, filed Oct. 5, 2017, which is incorporated herein by reference in its entirety as if fully set forth herein.

[0002] The present disclosure provides herbal compositions with improved bioavailability in combination with various carriers, which may include N-acylated fatty amino acids, penetration enhancers, and / or various other beneficial carriers. The herbal composition / carrier combination can produce administration benefits after oral administration. [Background technology]

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

[0004] However, it is now increasingly recognized that many plant-derived compositions are highly effective agents for the prevention and treatment of diseases. A single plant can possess many pharmaceutically active substances, and the extracts obtained therefrom can exert their activity in a variety of physiological processes, increasing the range of desirable therapeutic effects. In general, pharmaceutically active agents found in plants fall into four major classes: alkaloids, glycosides, polyphenols, and terpenes.

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

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

[0007] US Patent Application Publication No. 2010 / 0068297 describes the use of the plants pomegranate (Punica granatum), bush clover (Viburnum plicatum), tea plant (Camellia sinensis), and maple species (Acer spp.) as antimicrobial agents.

[0008] US Patent No. 5,401,777 describes the use of turmeric (Curcuma longa) to treat chronic inflammatory bowel disease, chronic hepatitis, chronic bronchial asthma and psoriasis.

[0009] Butterweck, V., CNS Drugs. 2003;17(8):539-62, reviews studies demonstrating the antidepressant effects of the plant Hypericum perforatum, also known as St. John's wort. Hypericum perforatum may also be useful for treating menopause, inflammation, infection, pain, anxiety, and insomnia.

[0010] U.S. Patent Application No. 2008 / 0254135 describes the use of Polygonum cuspidatum and grape skin extracts as dietary supplements to provide antioxidants and promote general health and wellness. Antioxidants may help prevent cancer by preventing free radical-induced DNA damage.

[0011] While plants and plant extracts have been used to promote health throughout human history, researchers are now beginning to identify some active components in specific plants that are responsible for the health benefits. For example, curcumin, the active component of turmeric, has been shown to have anti-inflammatory and anti-cancer properties. Another example, hypericin, is the active component of St. John's wort, or Hypericum perforatum. Another example, resveratrol, is an active component present in Polygonum cuspidatum (i.e., Japanese knotweed) and the peel of many fruits, including grapes, blueberries, raspberries, and mulberries. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] US Patent Application Publication No. 2015 / 0050373 [Patent Document 2] US Patent Application Publication No. 2014 / 0193345 [Patent Document 3] US Patent Application Publication No. 2010 / 0068297 [Patent Document 4] U.S. Patent No. 5,401,777 [Patent Document 5] U.S. Patent Application No. 2008 / 0254135 [Non-patent literature]

[0013] [Non-Patent Document 1] Butterweck, V. CNS Drugs. 2003;17(8):539~62 Summary of the Invention [Problem to be solved by the invention]

[0014] Although many plants and plant extracts are associated with numerous health benefits, these active ingredients have low bioavailability when taken orally, which may impair their usefulness in some cases.For example, curcumin, hypericin, and resveratrol are plant active ingredients with low oral bioavailability.Therefore, as can be seen from these examples, there is room for improvement in the oral administration of herbal compositions. [Means for solving the problem]

[0015] (Summary of the Invention) The present disclosure provides herbal compositions formulated for oral delivery with improved bioavailability, thereby enhancing physiological benefits and increasing the usefulness of these compounds.

[0016] The disclosed herbal compositions can produce a variety of dosing benefits in providing a therapeutically effective amount in a variety of conditions, including increased absorption, increased bioavailability, faster onset of action, higher peak concentration, faster time to peak concentration, increased subjective therapeutic effect, and increased objective therapeutic effect.

[0017] Improved bioavailability of herbal compositions can be created by including 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 the oral formulation. In certain embodiments, the N-acylated fatty amino acids in the oral formulation can be linear, branched, cyclic, bicyclic, or aromatic, containing, for example, 1 to 50 carbon atoms. The bioavailability benefits of using N-acylated fatty amino acids with herbal compositions were unexpected given certain aspects of the herbal compositions described further herein. For example, the ability of N-acylated fatty amino acids to increase the absorption of a compound is proportional to the compound's water solubility. Many herbal compounds present in herbal compositions are not water soluble, and the presence of N-acylated fatty amino acids was not expected to affect this.

[0018] In certain embodiments, the herbal composition comprises Santa Maria (Calophyllum brasiliense), Calophyllum caledonicurn, Calophyllum inophyllum, St. John's wort (Calophyllum soulattri), Cat's claw (Uncaria tomentosa), Thyme (Thymus vulgaris), Chamomile (Matricaria recutita), Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Wintergreen (Gaultheria procumbens), Tea plant (Camellia sinensis), Vaccinium myrtillus, Lemon balm (Melissa officinalis), Garlic (Allium sativum), sativum, Tea plant (Camellia sinensis), Krameria triandra, Pomegranate (Punica granatum), Wild ragwort (Viburnum plicatum), Tobacco (Nicotiana tabacum), Pichuri (Duboisia hopwoodii), Giant milkweed (Asclepias syriaca), Turmeric (Curcuma longa), Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina serpentina), Vinca spp., Citrus spp.), Rheum rhabarbarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., Mentha spp., Cannabis sativa, Cannabis indica, Cannabis ruderalis, and / or Acer spp., or extracts and / or active ingredients thereof.

[0019] In certain embodiments, the barb composition comprises an active ingredient of the plant, such as capsaicin, reserpine, vinblastine, hesperidin, naringin, rutin, quercitrin, curcumin, hypericin, resveratrol, catechin, eugenol, limonene, or linalool. [Brief explanation of the drawings]

[0020] [Figure 1A] This figure shows a demonstrated correlation between water solubility and the ability of N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) to improve the absorption of molecules. Figure 1A shows the multiple improvement from SNAC plotted against cromolyn, vitamin B12, atorvastatin, and ibandronate, along with the aqueous solubility of each molecule. The plotted data showed excellent fit to a logarithmic trendline (R2 = 0.998), demonstrating a logarithmic relationship between the aqueous solubility of each molecule and the degree to which SNAC improves absorption. As the water solubility of a molecule increases, so does the ability of SNAC to promote absorption. As the water solubility of a molecule increases, so does the ability of SNAC to improve bioavailability. [Figure 1B]Figure 1B shows the demonstrated correlation between water solubility and the ability of N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) to improve absorption of molecules. The aqueous solubilities of heparin, acyclovir, rhGH, PTH, MT-II, GLP-1, calcitonin, yy peptide, THC, and resveratrol are plotted according to the logarithmic trendline derived from Figure 1A. [Figure 2-1] The active ingredients of the herbal composition are shown. [Figure 2-2] The active ingredients of the herbal composition are shown. [Figure 3-1] The modified amino acids of compounds I to XXXV are shown. [Figure 3-2] The modified amino acids of compounds I to XXXV are shown. [Figure 3-3] The modified amino acids of compounds I to XXXV are shown. [Figure 4-1]

[0023] Represents a fatty acid amino acid of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., a methyl group), and R3 is H; or a salt or free acid form thereof. [Figure 4-2]

[0023] Represents a fatty acid amino acid of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., a methyl group), and R3 is H; or a salt or free acid form thereof. [Figure 5A] , Average results from a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 5B]Figure 1 shows the mean results of a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6A] Figure 1 shows results for each individual participant in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6B] Figure 1 shows results for each individual participant in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6C] Figure 1 shows results for each individual participant in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6D] Figure 1 shows results for each individual participant in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6E] Figure 1 shows results for each individual participant in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 6F] Figure 1 shows results for each individual participant in a study comparing the onset and duration of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC, "test") and cannabis (no SNAC, "control") formulations. [Figure 7]Figure 1 shows a comparison of the potency, duration and onset of action of cannabis formulations administered orally at a high SNAC dose (200 mg, "High Dose"), a low SNAC dose (100 mg, "Low Dose") and no SNAC ("Control"). [Figure 8] Figure 1 shows the potency, duration and onset of action of cannabis formulated with SNAC administered orally ("PO") compared to cannabis administered by inhalation ("INH"). [Figure 9] Figure 1 shows the Cmax (ng / ml) and AUC (hr*ng / mL) values ​​of THC and CBD after a single oral administration to rats. [Figure 10] 1 shows graphs of Cmax (ng / ml) and AUC (hr*ng / mL) of THC and CBD after a single oral dose to rats. [Figure 11] Figure 1 shows the intensity, duration and onset of action of orally administered cannabis / N-[8-(2-hydroxybenzoyl)amino]caprylic acid (NAC, "test") and cannabis (no NAC, "control") formulations. DETAILED DESCRIPTION OF THE INVENTION

[0021] Despite the numerous health benefits associated with many plants and plant extracts, these active ingredients have low bioavailability when taken orally, which can impair their usefulness in some cases. For example, curcumin, hypericin, and resveratrol are plant active ingredients with low oral bioavailability. Therefore, as can be seen from these examples, there is room for improvement in the oral administration of herbal compositions. The present disclosure provides herbal extract compositions with improved bioavailability. By providing improved bioavailability, the usefulness of these herbal compositions can be increased.

[0022] The disclosed herbal compositions with improved bioavailability can produce various dosing benefits in providing a therapeutically effective amount in various conditions, including increased absorption, increased bioavailability, faster onset of action, higher peak concentration, faster time to peak concentration, increased subjective therapeutic effect, and increased objective therapeutic effect.

[0023] Improved bioavailability of herbal compositions can be achieved by including 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 the oral formulation. In certain embodiments, the N-acylated fatty amino acids in the oral formulation can be linear, branched, cyclic, bicyclic, or aromatic, containing, for example, 1 to 50 carbon atoms. The ability of N-acylated fatty amino acids to provide immediate benefits when used with herbal compositions was unexpected, given the specific aspects of the plant-derived ingredients described further herein. For example, the ability of N-acylated fatty amino acids to increase the absorption of a compound is proportional to the compound's water solubility. Many plant-derived compounds are not water soluble, and the presence of N-acylated fatty amino acids was not expected to affect this.

[0024] 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.

[0025] Figure 1A shows the demonstrated correlation between aqueous solubility and SNAC's ability to improve the absorption of molecules. For cromolyn, vitamin B12, atorvastatin, and ibandronate, published results include the area under the curve (AUC) calculated from the time course of plasma concentrations. To quantify the effect of co-administration with SNAC, the fold improvement can be calculated by dividing the AUC for the molecule with SNAC by the AUC for the molecule without SNAC. Figure 1A shows the fold improvement from SNAC plotted for cromolyn, vitamin B12, atorvastatin, and ibandronate, along with the aqueous solubility of each molecule. The plotted data show remarkable fit to a logarithmic trendline (R 2 =0.998), showing a logarithmic relationship between the aqueous solubility of each and the degree to which SNAC improves its absorption.

[0026] Heparin, acyclovir, rhGH, PTH, MT-II, GLP-1, calcitonin, and yy peptide are other molecules shown to have improved absorption with SNAC, as evidenced by Cmax (maximum drug plasma concentration) and / or Tmax (time to reach maximum drug plasma concentration). As shown in Figure 1B, each of these molecules has an aqueous solubility greater than 0.15 mg / ml, and therefore, the model accurately predicts that SNAC can improve their absorption. This result demonstrates that SNAC-based absorption improvement correlates with the aqueous solubility of the molecule. Figure 1B also shows the predicted effect of SNAC on the logarithmic fit curves of the aqueous solubilities of two botanical active ingredients, THC (0.0028 mg / ml) and resveratrol (0.03 mg / ml). Based at least on the foregoing, the results described herein are unexpected and would not have been reasonably expected by one of ordinary skill in the art.

[0027] Various aspects of the disclosure are described in more detail below.

[0028] The present disclosure provides herbal compositions with improved bioavailability, comprising vegetable matter and a carrier, for oral formulations. Herbal compositions can include botanical medicines and plant-derived nutritional supplements. Herbal compositions, such as botanical medicines, provide therapeutically effective amounts to treat conditions such as those described in the Background section. Nutritional supplements demonstrate benefits associated with classic nutritional deficiencies; describe how the supplement is intended to affect the structure or function of the human body; characterize the identified mechanism by which the supplement acts to maintain such structure or function; and / or describe general health conditions associated with consumption of the product. In certain embodiments, nutritional supplements do not diagnose, mitigate, treat, cure, or prevent a specific disease or group of diseases.

[0029] Herbal compositions include botanical materials. Botanical materials are substances produced by plants, including whole plants or plant parts (e.g., bark, wood, leaves, stems, roots, flowers, fruits, seeds, or parts thereof) and / or their exudates or extracts. In certain embodiments, herbal compositions include botanical products. Botanical products can include plant material, algae, macroscopic fungi, and / or combinations thereof. In certain embodiments, herbal compositions include mixtures of various types of botanical materials. Herbal compositions can also include substances derived from botanical materials, such as resins, oils (e.g., essential oils), dried flowers, spices, kief, tinctures, infusions, etc. In certain embodiments, the botanical materials have little or no water solubility. In certain embodiments, the herbal compositions do not include synthetic, semi-synthetic, or chemically modified drugs.

[0030] In certain embodiments, the herbal composition includes Santa Maria (Calophyllum brasiliense), Calophyllum caledonicurn, Calophyllum inophyllum, St. John's Wort (Calophyllum soulattri), Cat's Claw (Uncaria tomentosa), Thyme (Thymus vulgaris), Chamomile (Matricaria recutita), Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Wintergreen (Gaultheria procumbens), Tea plant (Camellia sinensis), Vaccinium myrtillus, Lemon balm (Melissa officinalis, garlic (Allium sativum), Krameria triandra, pomegranate (Punica granatum), bush clover (Viburnum plicatum), tobacco (Nicotiana tabacum), Pichuri (Duboisia hopwoodii), giant milkweed (Asclepias syriaca), turmeric (Curcuma longa), Hypericum perforatum, Polygonum cuspidatum, Vitis species, tea plant, Theobroma cacao, Capsicum species, Rauwolfia vomitoria, Rauwolfia serpentina, Vinca species, Citrus species, Rheum labarbarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula species, Mentha species, Cannabis sativa sativa, Cannabis indica, Cannabis ruderalis and / or Acer spp. or extracts thereof.

[0031] In certain embodiments, the herbal composition includes botanical material derived from turmeric, Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Camellia sinensis, Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina, Vinca spp., Citrus spp., Rheum lavalvarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., Mentha spp., or extracts thereof.

[0032] In certain embodiments, the herbal composition comprises active ingredients of the plant, such as polyphenols, alkaloids, glycosides, or terpenes.

[0033] In certain embodiments, the herbal composition comprises polyphenols with low water solubility. Examples of plant-derived polyphenols with low water solubility include curcumin, hypericin, resveratrol, and catechin.

[0034] In certain embodiments, the herbal composition comprises curcumin. Curcumin is a phenolic compound with low aqueous solubility (<0.1 mg / ml) that is responsible for the yellow color of turmeric, a spice derived from turmeric. Curcumin has been shown to have anti-inflammatory and anti-cancer effects and may be useful in the treatment of chronic inflammatory bowel disease, chronic hepatitis, chronic bronchial asthma, and psoriasis. See, e.g., Figure 2 for the chemical structure of curcumin.

[0035] In certain embodiments, the herbal composition includes hypericin. Hypericin is a water-insoluble naphthodianthrone and is the primary active ingredient of Hypericum perforatum, or St. John's wort. Hypericin is used as an antidepressant and can be used in photodynamic cancer therapy, as it preferentially accumulates in cancer tissue and induces photosensitivity. See, for example, Figure 2 for the chemical structure of hypericin.

[0036] In certain embodiments, the herbal composition contains resveratrol. Resveratrol is a polyphenol with very low aqueous solubility (0.03 mg / ml) and is the primary active ingredient in Polygonum cuspidatum, grapes (i.e., plants of the genus Vitis, also known as Vitis species), blueberries, raspberries, and mulberries. Resveratrol is a potent antioxidant and has anti-inflammatory effects. See, for example, Figure 2 for the chemical structure of resveratrol.

[0037] In certain embodiments, the herbal composition contains catechin. Catechin is a polyphenol with low aqueous solubility and includes four isomers: (-)-epicatechin, (+)-epicatechin, (-)-catechin, and (+)-catechin. Catechin is found in many plants, and dietary sources of catechin include tea (Camellia sinensis), cocoa (Theobroma cacao), acai, apple, and pear. Catechin is a potent antioxidant and has anti-inflammatory effects. See, for example, Figure 2 for the chemical structure of catechin.

[0038] In certain embodiments, the herbal composition comprises plant-derived alkaloids with low water solubility. Examples of plant-derived alkaloids with low water solubility include capsaicin, reserpine, and vinblastine.

[0039] In certain embodiments, the herbal composition comprises capsaicin. Capsaicin is an alkaloid with low aqueous solubility that can be used as an analgesic and to treat neuralgia. Capsaicin is found in the fruits of plants in the Capsicum genus, such as Capsicum annuum, Capsicum chinense, Capsicum baccatum, and Capsicum pubescens. See, for example, Figure 2 for the chemical structure of capsaicin.

[0040] In certain embodiments, the herbal composition contains reserpine. Reserpine is an indole alkaloid with low aqueous solubility and is found in the dried roots of plants in the Rauwolfia genus, such as Rauwolfia vomitoria and Rauwolfia serpentina. Reserpine-containing extracts have been used for centuries in India to treat insanity, fever, and snakebites. Reserpine is also used to treat high blood pressure. See, for example, Figure 2 for the chemical structure of reserpine.

[0041] In certain embodiments, the herbal composition contains vinblastine. Vinblastine is an alkaloid with low aqueous solubility and is produced by plants of the vinca genus, such as Vinca rosea. Vinblastine can block cell differentiation by disrupting microtubule formation and is used as a chemotherapeutic agent to treat various cancers. See, for example, Figure 2 for the chemical structure of vinblastine.

[0042] In certain embodiments, the herbal composition comprises glycosides with low aqueous solubility. Examples of plant-derived glycosides with low aqueous solubility include hesperidin, naringin, rutin, and quercitrin.

[0043] In certain embodiments, the herbal composition includes hesperidin. Hesperidin is a glycoside with low aqueous solubility. Hesperidin is found in the fruits of citrus trees, such as Citrus aurantium, Citrus sinensis, Citrus limon, and Citrus aurantifolia. Hesperidin is an antioxidant, anti-inflammatory, may help prevent cancer, and is used to treat vascular conditions such as hemorrhoids, varicose veins, and poor circulation. See, for example, Figure 2 for the chemical structure of hesperidin.

[0044] In certain embodiments, the herbal composition contains naringin. Naringin is a glycoside with low aqueous solubility found in the fruits of citrus plants, such as Citrus sinensis, Citrus aurantium, Citrus reticulata, Citrus clementina, and Citrus bergamia. Naringin is an antioxidant, anti-inflammatory, and can improve glucose regulation. See, for example, Figure 2 for the chemical structure of naringin.

[0045] In certain embodiments, the herbal composition includes rutin. Rutin is a glycoside with low aqueous solubility and is found in buckwheat (Fagopyrum tataricum), rheum species (e.g., Rheum labarum or Rhubarb), and asparagus. Rutin is a potent antioxidant. See, for example, Figure 2 for the chemical structure of rutin.

[0046] In certain embodiments, the herbal composition comprises quercitrin. Quercitrin is a glycoside with low aqueous solubility formed by the flavonoid quercetin and the deoxysugar rhamnose. Quercitrin has strong antioxidant properties and is found in a wide variety of plants, such as buckwheat (Fagopyrum tataricum) and St. John's wort (Hypericum perforatum). See, for example, Figure 2 for the chemical structure of quercitrin.

[0047] In certain embodiments, the herbal composition comprises terpenes. Terpenes are organic molecules that contain chains of isoprene subunits and are typically insoluble in water. Examples of plant-derived terpenes with low water solubility include eugenol, limonene, and linalool.

[0048] In certain embodiments, the herbal composition comprises eugenol. Eugenol is a terpene with low water solubility and has anti-inflammatory effects. Eugenol is found in clove (Syzygium aromaticum) oil, cinnamon, nutmeg, cannabis, and bay leaf. See, for example, Figure 2 for the chemical structure of eugenol.

[0049] In certain embodiments, the herbal composition includes limonene. Limonene is a terpene with low water solubility and forms two isomers. The D-isomer of limonene has a strong orange odor and can be found in large amounts in citrus fruits, while the L-isomer has a pine odor and is common in oil extracted from mint (Mentha spp.). Limonene is used for weight loss, cancer prevention, treatment of bronchitis, and cholesterol level control. See, for example, Figure 2 for the chemical structure of limonene.

[0050] In certain embodiments, the herbal composition comprises linalool.Linalool is a terpene with low water solubility, and forms two enantiomers known as licareol and coriandrol.Linalool is produced in large quantities by lavender (Lavandula spp.), and is also produced by many other plants, such as birch, mint, citrus fruits, and cinnamon.Linalool has sedative, anti-inflammatory, and anxiolytic properties.See, for example, Figure 2 for the chemical structure of linalool.

[0051] The ingredients of herbal compositions can be produced, for example, by crushing, decoction, pressing, and extraction of the starting plant product. The term "extract" encompasses many types of preparations containing some or all of the active ingredients found in the relevant plant. Extracts can be produced by the cold infusion method using a variety of different extraction solvents, including water, fatty solvents (e.g., olive oil), and alcoholic solvents (e.g., 70% ethanol). Cold infusion is typically applied to softer parts of plants, such as leaves and flowers, or when the desired active ingredients of the plant are heat-sensitive. Alternatively, extracts of the desired plant can be produced using the aforementioned solvents by hot extraction techniques, in which the solvent is heated to an elevated temperature (the exact temperature depends on the nature of the solvent selected) and maintained at that temperature throughout the extraction process. Hot extraction techniques are more commonly applied to harder, more robust parts of plants, such as bark, woody branches, and larger roots. In some cases, sequential extractions can be performed with more than one solvent and at different temperatures. Plant extracts may also be used in concentrated form. Alternatively, the extract may be diluted appropriately for its intended use.

[0052] Additional methods for producing plant extracts, including hot extraction, cold infusion, and other techniques, are described in publications such as "Medicinal plants: a field guide to the medicinal plants of the Land of Israel (in Hebrew), author: N. Krispil, Har Gilo, Israel, 1986" and "Making plant medicine, author: R. Cech, pub. by Horizon Herbs, 2000."

[0053] In certain embodiments, the botanical components (e.g., plant extracts) of the herbal composition may be sterilized, for example, by autoclaving, allowed to cool, and stored at an appropriate temperature (e.g., −20° C.). In certain embodiments, further purification to a molecular weight cutoff (e.g., less than 10,000 Da) may be achieved, for example, by membrane ultrafiltration before storage.

[0054] In certain embodiments, the herbal composition includes 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, unnatural, and synthetic amino acids. A polyamino acid is a peptide or two or more amino acids joined by a bond formed by other groups capable of bonding, such as an ester, anhydride, or anhydride bond. A peptide is two or more amino acids linked by peptide bonds. Peptides can vary in length from dipeptides with two amino acids to polypeptides with several hundred amino acids. See Chambers Biological Dictionary, editor Peter M.B. Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Di-, tri-, tetra-, and pentapeptides can also be used.

[0055] Modified amino acid carriers include acylated fatty acid amino acids (FA-aa) or salts thereof, typically prepared by modifying an amino acid or its ester by acylation or sulfonation. Acylated fatty acid amino acids include N-acylated FA-aa or amino acids in which the alpha amino group is acylated with a fatty acid.

[0056] A representative N-acylated fatty amino acid salt is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC). Other names for SNAC include sodium N-salicyloyl-8-aminocaprylate, monosodium 8-(N-salicyloylamino)octanoate, N-(salicyloyl)-8-aminooctanoic acid monosodium salt, monosodium N-{8-(2-hydroxybenzoyl)amino}octanoate, or sodium 8-[(2-hydroxybenzoyl)amino]octanoate. SNAC has the following structure:

[0057] [ka] Salts of SNAC can also be used as carriers.

[0058] In certain embodiments, the carrier comprises the formula:

[0059] [ka] In certain embodiments, the carrier includes N-[8-(2-hydroxybenzoyl)amino]caprylic acid (NAC).

[0060] Other forms of carriers include those of the formula:

[0061] [ka] wherein 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.

[0062] Representative modified amino acids, such as N-acylated FA-aa, are provided as compounds I to XXXV (see Figure 3). Salts of these compounds and other N-acylated FA-aa can also be used as carriers.

[0063] Many of these compounds can be readily prepared from amino acids based on the present disclosure by methods within the skill of one in the art. For example, compounds I-VII are derived from aminobutyric acid. Compounds VIII-X and XXXI-XXIIV are derived from aminocaproic acid. Compounds XI-XXVI and XXXV are derived from aminocaprylic acid. For example, the above modified amino acid compounds can be prepared by reacting a single amino acid with an appropriate modifying agent that reacts with the free amino moiety present in the amino acid to form an amide. Protecting groups may be used to avoid unwanted side reactions, as known to those skilled in the art.

[0064] The amino acid can be dissolved in an alkaline aqueous solution of a metal hydroxide, e.g., sodium or potassium hydroxide, and heated at a temperature ranging from 5°C to 70°C, and in certain embodiments, from 10°C to 40°C, for a period ranging from 1 hour to 4 hours, and in certain embodiments, 2.5 hours. The amount of alkali used per equivalent of NH2 group of the amino acid is generally in the range of 1.25 to 3 mmoles per equivalent of NH2, and in certain embodiments, in the range of 1.5 to 2.25 mmoles. The pH of the solution is generally in the range of 8 to 13, and in certain embodiments, in the range of 10 to 12.

[0065] An appropriate amino acid modifying agent is then added to the amino acid solution with stirring. The temperature of the mixture is generally maintained at a temperature ranging from 5°C to 70°C, and in certain embodiments, from 10°C to 40°C, for a period ranging from 1 to 4 hours. The amount of amino acid modifying agent used relative to the amount of amino acid is based on the total moles of free NH2 in the amino acid. Generally, the amino acid modifying agent is used in an amount ranging from 0.5 to 2.5 molar equivalents, and in certain embodiments, from 0.75 to 1.25 equivalents, per molar equivalent of total NH2 groups in the amino acid.

[0066] 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 is allowed to stand at room temperature and separates to form a clear upper layer and a white or off-white precipitate. The upper layer is discarded, and the modified amino acid is collected from the lower layer by filtration or decantation. The crude modified amino acid is then dissolved in water at a pH ranging from 9-13, and in certain embodiments, from 11-13. Insoluble material is removed by filtration, and the filtrate is dried under vacuum. The yield of the modified amino acid is generally in the range of 30-60%, usually 45%.

[0067] If desired, modified amino acids may be prepared using amino acid esters, such as benzyl, methyl, or ethyl esters of the 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 modifying agent at a temperature ranging from 5°C to 70°C, and in certain embodiments, at 25°C, for a period ranging from 7 to 24 hours. The amount of amino acid modifying agent 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, for example, triethylamine or diisopropylethylamine.

[0068] The reaction solvent is then removed under negative pressure, and the ester functionality is removed by hydrolyzing the modified amino acid ester with a suitable alkaline solution, e.g., 1N sodium hydroxide, at a temperature ranging from 50°C to 80°C, and in certain embodiments, at 70°C, for a period of time sufficient to hydrolyze the ester group and form a modified amino acid having a free carboxyl group. The hydrolysis mixture is then cooled to room temperature and acidified, e.g., with 25% aqueous hydrochloric acid, to a pH ranging from 2 to 2.5. The modified amino acid precipitates from the solution and is recovered by conventional means, such as filtration or decantation. Benzyl esters can be removed by hydrogenation using a transition metal catalyst in an organic solvent.

[0069] 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 performed on a suitable solid column support, such as alumina, using a methanol / n-propanol mixture as the mobile phase; on a reverse-phase column support, using a trifluoroacetic acid / acetonitrile mixture as the mobile phase; and by ion exchange chromatography, using water as the mobile phase. When performing ion exchange chromatography, a 0-500 mM sodium chloride gradient is used in certain embodiments.

[0070] In certain embodiments, the formula

[0071] [ka] (Wherein, Y is

[0072] [ka] or SO2; R 1 is C3~C 24 Alkylene, C2-C 20 Alkenylene, C2-C 20 aromatic, such as alkynylene, cycloalkylene, or arylene; R 2 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; R 3 is C1-C7 alkyl, C3-C 10 cycloalkyl, aryl, thienyl, pyrrolo, or pyridyl; R 3 optionally one or more C1-C5 alkyl groups, C2-C4 alkenyl groups, F, Cl, OH, OR 1 , SO2, COOH, COOR 1 or replaced by SO3H) The modified amino acid having the formula

[0073] [ka] and a lactam having the formula R 3 -YX(where, Y, R 1 , R 2 , and R 3 where X is a leaving group. The lactam of the above formula can be prepared, for example, by the method described in Olah et al., Synthesis, 537-538 (1979).

[0074] In certain embodiments, modified amino acids also include amino acids whose alpha-amino group is acylated with a fatty acid, which can be represented by the general formula AX, where A is an alpha-amino acid residue and X is a fatty acid attached to the alpha-amino group of A by acylation. Amino acids include cationic and non-cationic amino acids. In certain embodiments, the term "non-cationic amino acid" refers to an amino acid selected from the group consisting of non-polar hydrophobic amino acids, polar uncharged amino acids, and polar acidic amino acids. In certain embodiments, the term "non-cationic amino acid" as used herein refers to an amino acid selected from the group including 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), glutamine (Gln), aspartic acid (Asp), and glutamic acid (Glu).

[0075] In certain embodiments, the acylated FA-aa comprises an alpha amino acid residue of a non-polar, hydrophobic amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a non-polar, hydrophobic amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "non-polar, hydrophobic amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "non-polar, hydrophobic amino acid" refers to an amino acid selected from the group including Ala, Val, Leu, Ile, Phe, Trp, Met, Pro, and sarcosine.

[0076] In certain embodiments, the acylated FA-aa comprises an amino acid residue of a polar, uncharged amino acid. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is an amino acid residue of a polar, uncharged amino acid, and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "polar, uncharged amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "polar, uncharged amino acid" refers to an amino acid selected from the group including Gly, Ser, Thr, Cys, Tyr, Asn, and Gln.

[0077] In certain embodiments, the acylated FA-aa comprises a polar, acidic amino acid residue. In certain embodiments, the acylated FA-aa is represented by the general formula AX, where A is a polar, acidic amino acid residue and X is a fatty acid attached to the alpha-amino group of A by acylation. In certain embodiments, the term "polar, acidic amino acid" as used herein refers to a categorization of amino acids used by those skilled in the art. In certain embodiments, the term "polar, acidic amino acid" refers to an amino acid selected from the group including Asp and Glu.

[0078] In certain embodiments, the amino acid residue of the acylated FA-aa comprises an amino acid residue of an amino acid that is not encoded by the genetic code. Modification of an amino acid by acylation can be readily accomplished using acylating agents known in the art to react with the free alpha-amino group of an amino acid.

[0079] In certain embodiments, an alpha-amino acid or alpha-amino acid residue according to the present invention is in the L-configuration unless otherwise stated.

[0080] In certain embodiments, the amino acid residues are in the free acid form and / or a salt thereof, such as the sodium (Na+) salt thereof.

[0081] Representative embodiments of acylated FA-aa can be represented by general Fa-aa formula I:

[0082] [ka] wherein R1 is an alkyl or aryl group containing 5 to 19 carbon atoms; R2 is H, CH3, or is covalently bonded to R4 via a (CH2)3 group; R3 is H or absent; R4 is an amino acid side chain or is covalently bonded to R2 via a (CH2)3 group; or a salt thereof.

[0083] FA-aa can be acylated with a fatty acid containing a substituted or unsubstituted alkyl group containing 5 to 19 carbon atoms. In certain embodiments, the alkyl group contains 5 to 17 carbon atoms. In certain embodiments, the alkyl group contains 5 to 15 carbon atoms. In certain embodiments, the alkyl group contains 5 to 13 carbon atoms. In certain embodiments, the alkyl group contains 6 carbon atoms.

[0084] In certain embodiments, the acylated FA-aa is soluble at intestinal pH values, particularly in the range of pH 5.5 to 8.0, such as in the range of pH 6.5 to 7.0, hi certain embodiments, the acylated FA-aa is soluble at a pH below 9.0.

[0085] In certain embodiments, the acylated FA-aa has a solubility of at least 5 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 10 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 20 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 30 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 40 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 50 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 60 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 70 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 80 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 90 mg / mL. In certain embodiments, the acylated FA-aa has a solubility of at least 100 mg / mL. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solution at pH values ​​one unit above and one unit below the pKa of the FA-aa at 37°C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solution at pH 8 at 37°C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solution at pH values ​​one unit above and one unit below the pI of the FA-aa at 37°C. In certain embodiments, the solubility of the acylated FA-aa is determined in aqueous solution at pH values ​​one unit above and one unit above the pI of the FA-aa at 37°C, wherein the FA-aa comprises two or more ionizable groups with opposite charges. In certain embodiments, the solubility of the FA-aa is determined in aqueous 50 mM sodium phosphate buffer, pH 8.0, at 37°C.

[0086] In certain embodiments, the acylated FA-aa is selected from the group consisting of formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl group containing 5 to 19 carbon atoms, R2 is H (i.e., hydrogen) or CH3 (i.e., methyl), and R3 is H, or a salt or free acid form thereof. Formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and (r) are shown in Figure 4.

[0087] In certain embodiments, the acylated FA-aa is selected from the group consisting of sodium N-dodecanoyl alaninate, N-dodecanoyl-L-alanine, sodium N-dodecanoyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium N-dodecanoyl leucinate, N-dodecanoyl-L-leucine, sodium N-dodecanoyl methioninate, N-dodecanoyl-L-methionine, sodium N-dodecanoyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium N-dodecanoyl prolinate, N-dodecanoyl- L-Proline, Sodium N-Dodecanoyltryptophanate, N-Dodecanoyl-L-tryptophan, Sodium N-Dodecanoylvalinate, N-Dodecanoyl-L-valine, Sodium N-Dodecanoylsarcosinate, N-Dodecanoyl-L-sarcosine, Sodium N-Oleoylsarcosinate, Sodium N-Decylleucine, Sodium N-Decanoylalaninate, N-Decanoyl-L-alanine, Sodium N-Decanoylleucinate, N-Decanoyl-L-leucine, Sodium N-Decanoylphenylalaninate , N-Decanoyl-L-phenylalanine, Sodium N-Decanoylvalinate, N-Decanoyl-L-valine, Sodium N-Decanoylisoleucinate, N-Decanoyl-L-isoleucine, Sodium N-Decanoylmethioninate, N-Decanoyl-L-methionine, Sodium N-Decanoylprolinate, N-Decanoyl-L-proline, Sodium N-Decanoylthreoninate, N-Decanoyl-L-threonine, Sodium N-Decanoyltryptophanate, N-Decanoyl-L-tryptophan, Sodium N-Decano N-decanoyl sarcosinate, N-decanoyl-L-sarcosine, N-dodecanoyl asparaginate, N-dodecanoyl-L-asparagine, sodium N-dodecanoyl aspartate, N-dodecanoyl-L-aspartate, sodium N-dodecanoyl cysteinate, N-dodecanoyl-L-cysteine, sodium N-dodecanoyl glutaminate, N-dodecanoyl-L-glutamine, sodium N-dodecanoyl glycinate, N-dodecanoyl-L-glycine, sodium N-dodecanoyl serinate, N-dodecanoyl-L-serine,Sodium N-dodecanoylthreoninate, N-dodecanoyl-L-threonine, Sodium N-dodecanoyltyrosinate, N-dodecanoyl-L-tyrosine, Sodium N-decanoylasparaginate, N-decanoyl-L-asparagine, Sodium N-decanoylaspartic acid, N-decanoyl-L-aspartic acid, Sodium N-decanoylcysteinate, N-decanoyl-L-cysteine, Sodium N-decanoylglutaminate, N-decanoyl N-L-Glutamine, Sodium N-Decanoylglycinate, N-Decanoyl-L-Glycine, Sodium N-Decanoylserinate, N-Decanoyl-L-Serine, Sodium N-Decanoyltyrosinate, N-Decanoyl-L-Tyrosine, Sodium N-Dodecanoylasparaginate, Sodium N-Dodecanoylglutamate, N-Dodecanoyl-L-Glutamic Acid, Sodium N-Decanoylglutamate, N-Decanoyl-L-Glutamic Acid, Amisoft The surfactant may be selected from one or more of HS-11 P (sodium stearoyl glutamate), Amisoft MS-11 (sodium myristoyl glutamate), Amisoft LS-11 (sodium dodecanoyl glutamate), Amisoft CS-11 (sodium cocoyl glutamate), sodium N-cocoyl glutamate, Amisoft HS-11 P, Amisoft HS-11 P (sodium N-stearoyl glutamate), (sodium N-myristoyl glutamate), (sodium N-dodecanoyl glutamate), and Amisoft HS-11 P.

[0088] The following acylated FA-aa are commercially available:

[0089] [Table 1]

[0090] In certain embodiments, the terms "fatty acid N-acylated amino acid," "fatty acid acylated amino acid," or "acylated amino acid" are used interchangeably herein and refer to an amino acid whose alpha-amino group is acylated with a fatty acid.

[0091] Certain embodiments utilize botanical materials with low or very low solubility. Certain embodiments utilize botanical materials that are essentially water-insoluble. In certain embodiments, water solubility is defined by the United States Pharmacopoeia (USP 32) as follows: low to zero; low solubility: 100-1000 parts water required to dissolve 1 part solute; very low solubility: 1000-10,000 parts water required; and essentially water-insoluble: more than 10,000 parts water required. However, at basic pH, SNAC and other modified amino acids and FA-aa described herein are water-soluble. Therefore, the administration benefits described herein would not be reasonably predictable. In certain embodiments, low water solubility can refer to a solubility in water or aqueous solutions of less than 1 mg / ml, less than 0.1 mg / ml, or less than 0.01 mg / ml.

[0092] In certain embodiments, the N-acylated fatty amino acid acts as an absorption enhancer, thereby producing a beneficial effect on administration. An absorption enhancer refers to 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 by promoting membrane permeation, compared to a formulation that does not contain an absorption enhancer. Additional examples of absorption enhancers include surfactants, detergents, azones, pyrrolidones, glycols, or bile salts.

[0093] 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 a subject and reaches the bloodstream. In certain embodiments, the bioavailability enhancer increases the fraction of the active ingredient in the bloodstream or allows the active ingredient to be detected earlier in the bloodstream compared to a formulation that does not contain the bioavailability enhancer.

[0094] In certain embodiments, the additional administration benefit produced by the absorption enhancer and / or bioavailability enhancer includes a faster onset of action, a higher peak concentration, a faster time to peak concentration, an increased subjective therapeutic effect, and / or an increased objective therapeutic effect compared to a control herbal composition or oral formulation that is similar in all respects except that it does not contain the absorption enhancer and / or bioavailability enhancer.

[0095] Embodiments utilizing absorption enhancers and / or bioavailability enhancers (e.g., in certain embodiments, N-acylated fatty amino acids) can be beneficial because many orally administered herbal compositions designed to address various physiological conditions are inadequate because they are characterized by low bioavailability. Delayed onset of action poses challenges in clinical indications requiring rapid therapeutic effect (e.g., pain and migraine); low bioavailability requires patients to ingest significantly higher dosages than would otherwise be required with other dosage forms. Certain embodiments disclosed herein provide oral formulations of herbal compositions with improved bioavailability and shorter time to onset of therapeutic effect.

[0096] In certain embodiments, the herbal composition comprises a botanical, which refers to a plant, plant component, and / or plant extract used to treat illness or promote health.

[0097] In certain embodiments, the herbal composition may be a botanical nutritional supplement. A nutritional supplement refers to a product containing dietary ingredients intended to add additional nutritional value to a diet. Examples of botanical nutritional supplements include herbs and botanical products that add nutritional value to a diet.

[0098] As mentioned above, in certain embodiments, the N-acylated fatty amino acid acts as a subjective therapeutic enhancer. Subjective therapeutic enhancer refers to a noticeable reduction in symptoms as perceived by the subject. In certain embodiments, the subjective therapeutic enhancer increases or reduces symptoms more rapidly compared to a formulation that does not include the subjective therapeutic enhancer.

[0099] In certain embodiments, the N-acylated fatty amino acid acts as an objective therapeutic enhancer. Objective therapeutic enhancement means that when administered by a physician, it reduces clinical measures, such as nutritional deficiencies detected by blood or saliva assays or health tests. In certain embodiments, the objective therapeutic enhancer increases or more rapidly reduces the objective clinical measure compared to a formulation that does not include the objective therapeutic enhancer.

[0100] Certain embodiments include botanicals (e.g., active ingredients of turmeric, Hypericum perforatum, and / or Polygonum cuspidatum) and absorption enhancers and / or bioavailability enhancers, which can allow for rapid absorption and higher bioavailability compared to botanicals taken in currently available oral dosage forms.

[0101] In certain embodiments, the carriers disclosed herein produce a dosing benefit selected from increased absorption, increased bioavailability, faster onset of action, higher peak concentration, faster time to peak concentration, increased subjective therapeutic effect, increased objective therapeutic effect, improved taste, and improved mouthfeel. Dosing benefits associated with increased absorption, increased bioavailability, faster onset of action, higher peak concentration, and faster time to peak concentration can result in more rapid relief of adverse conditions (e.g., pain relief). "Mouthfeel" refers to the non-taste-related aspects of the pleasantness experienced by a person upon ingesting (e.g., chewing or swallowing) an oral dosage form. Aspects of mouthfeel include the hardness and friability of the composition, whether the composition is chewy, gritty, oily, creamy, watery, sticky, easily dissolving, astringent, effervescent, etc., as well as the size, shape, and form (tablet, powder, gel, etc.) of the composition.

[0102] Herbal compositions can be prepared for administration to a subject by adding the botanical material, a carrier that provides a dosage benefit, and one or more excipients, mixing, suspending, dissolving, blending, granulating, tableting, encapsulating, or performing other dosage-form specific procedures, and then packaging. For clarity, the carrier contributes to providing a dosage benefit. The excipients are not necessary, but can contribute to a dosage benefit.

[0103] Certain embodiments include herbal compositions prepared as oral formulations. Exemplary oral formulations include capsules, coated tablets, edibles, elixirs, emulsions, gels, gel caps, granules, gums, juices, liquids, oils, pastes, pellets, pills, powders, fast-dissolving tablets, sachets, semisolids, sprays, solutions, suspensions, syrups, tablets, tinctures, and the like.

[0104] Representative types of excipients include binders, buffers, chelating agents, coating agents, colorants, complexing agents, diluents (i.e., fillers), disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, release agents, surfactants, stabilizers, solubilizers, sweeteners, thickeners, wetting agents, and vehicles.

[0105] Binders are substances used to cause adhesion of powder particles during granulation. Representative binders include acacia, compressible sugars, gelatin, sucrose and its derivatives, maltodextrin, cellulose polymers such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and methyl cellulose, acrylic polymers such as insoluble acrylate ammonio methacrylate copolymer, polyacrylate or polymethacrylic copolymers, povidone, copovidone, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, guar gum, and polyethylene glycol.

[0106] Coloring agents can be included in oral dosage forms to impart color to the formulation. Representative coloring agents include grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, and paprika. Additional coloring agents include FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, FD&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide.

[0107] Diluents can enhance granulation of oral formulations. Exemplary diluents include microcrystalline cellulose, sucrose, dicalcium phosphate, starch, lactose, and polyols with less than 13 carbon atoms, such as mannitol, xylitol, sorbitol, maltitol, and pharmaceutically acceptable amino acids, such as glycine.

[0108] Disintegrants may also be included in the oral formulation to facilitate dissolution. Disintegrants, such as permeabilizing and wicking agents, can draw water or saliva into the oral formulation, facilitating dissolution from the interior as well as the exterior of the oral formulation. Examples of such disintegrants, permeation enhancers, and / or wicking agents that can be used include starches such as corn starch, potato starch, pregelatinized and modified starches, cellulosic agents such as Ac-di-sol, montmorillonite clay, cross-linked PVP, sweeteners, bentonite, microcrystalline cellulose, croscarmellose sodium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, arabic, xanthan, and tragacanth, silicas with a high affinity for aqueous solvents such as colloidal silica, precipitated silica, maltodextrin, beta-cyclodextrin, polymers such as carbopol, and cellulosic agents such as hydroxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Dissolution of oral formulations can be facilitated by including ingredients with a relatively small particle size.

[0109] Representative dispersing or suspending agents include acacia, alginate, dextran, fragacanth, gelatin, hydrogenated edible fats, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, sorbitol syrup, and synthetic natural gums.

[0110] Exemplary emulsifying agents include acacia and lecithin.

[0111] Flavorants are natural or artificial compounds used to impart a pleasant flavor and often a fragrant aroma to oral preparations. Representative flavors include natural and synthetic flavor oils, flavorings, plant, leaf, flower, and fruit extracts, and combinations thereof. Examples of flavors include anise oil, cinnamon oil, vanilla, vanillin, cocoa, chocolate, natural chocolate flavor, menthol, grape, peppermint oil, wintergreen oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cassia oil; citrus oils, such as lemon, orange, lime, and grapefruit oil; and fruit essences, such as apple, pear, peach, berry, wineberry, date, blueberry, kiwi, strawberry, raspberry, cherry, plum, pineapple, and apricot. In certain embodiments, flavoring agents that can be used include natural berry extracts and natural mixed berry flavors, as well as citric and malic acid.

[0112] Glidants improve the flow of powder blends during manufacturing and minimize oral dosage form weight variation. Typical glidants include silicon dioxide, colloidal or fumed silica, magnesium stearate, calcium stearate, stearic acid, corn starch, and talc.

[0113] Lubricants are substances used in oral formulations that reduce friction during compression of the composition. Typical 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.

[0114] Representative preservatives include methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and sorbic acid.

[0115] Representative sweeteners include aspartame, dextrose, fructose, isomerized sugar, maltodextrin, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, acesulfame potassium, sodium saccharin, stevia, sucralose, and sucrose.

[0116] Certain embodiments include swallowable compositions. Swallowable compositions do not dissolve easily when placed in the mouth and can be swallowed whole without chewing or discomfort. U.S. Patent Nos. 5,215,754 and 4,374,082 describe methods for making swallowable compositions. In certain embodiments, the swallowable composition may have a shape that does not contain sharp edges and a smooth, uniform, and substantially bubble-free outer coating.

[0117] To prepare a swallowable composition, the components can be combined into an intimate mixture with a suitable carrier according to conventional compounding techniques. In certain embodiments of the swallowable composition, the surface of the composition can be coated with a polymeric film. Such film coatings have several beneficial effects. First, they reduce adhesion of the composition to the lining of the mouth, thereby increasing the subject's ability to swallow the composition. Second, the film can help mask the unpleasant taste of certain ingredients. Third, film coatings can protect the composition from atmospheric degradation. Polymeric films that can be used to prepare swallowable compositions include vinyl polymers such as polyvinylpyrrolidone, polyvinyl alcohol and acetate, cellulose derivatives such as methyl and ethyl cellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose, acrylates and methacrylates, copolymers such as vinyl-maleic and styrene-maleic types, and natural gums and resins such as zein, gelatin, shellac, and acacia.

[0118] In certain embodiments, the oral formulation may comprise a chairable composition that has a pleasant taste and mouthfeel, is relatively soft, and after being chewed, quickly breaks into smaller pieces and begins to dissolve, resulting in a substantially liquid form that can be swallowed.

[0119] U.S. Patent No. 6,495,177 describes a method for producing a chairable composition with improved mouthfeel. U.S. Patent No. 5,965,162 describes a kit and method for producing an edible unit that disintegrates rapidly in the mouth, especially when chewed.

[0120] To create a chairable composition, certain ingredients should be included to achieve the attributes described above. For example, a chairable composition should include ingredients that create a pleasant flavor and mouthfeel and promote relative softness and dissolution in the mouth. The following discussion describes ingredients that may help achieve these properties.

[0121] Sugars such as white sugar, corn syrup, sorbitol (solution), maltitol (syrup), oligosaccharides, isomaltooligosaccharides, sucrose, fructose, lactose, glucose, lycasin, xylitol, lactitol, erythritol, mannitol, isomaltose, dextrose, polydextrose, dextrin, compressible cellulose, compressible honey, compressible molasses, and mixtures thereof may be added to improve mouthfeel and palatability. Fondants or gums such as gelatin, agar, gum arabic, guar gum, and carrageenan may be added to improve the chewiness of the composition. Fatty materials that can be used include vegetable oils (e.g., coconut oil, hydrogenated palm oil, hydrogenated corn germ oil, hydrogenated castor oil, cottonseed oil, olive oil, peanut oil, palm olein oil, and palm stearin oil), animal oils (e.g., refined oils and refined lard having a melting point in the range of 30° to 42° C.), cocoa butter, margarine, butter, and shortening.

[0122] Alkylpolysiloxanes (polymers commercially available in a variety of molecular weight ranges and with different substitution patterns) can also be used to enhance the texture, mouthfeel, or both of the chairable composition. By "enhancing texture," it is meant that the alkylpolysiloxane improves one or more of the firmness, brittleness, and chewiness of the chairable composition compared to the same formulation lacking the alkylpolysiloxane. By "enhancing mouthfeel," it is meant that the alkylpolysiloxane reduces the gritty texture of the chairable composition when liquefied in the mouth compared to the same formulation lacking the alkylpolysiloxane.

[0123] Alkylpolysiloxanes generally comprise a polymeric backbone containing silicon and oxygen, with one or more alkyl groups pendant from the silicon atoms of the backbone. Depending on their grade, they may further comprise silica gel. Alkylpolysiloxanes are generally viscous oils. Representative alkylpolysiloxanes that can be used in swallowable, chewable, or dissolvable compositions include monoalkyl or dialkylpolysiloxanes, where the alkyl groups are each independently selected from C1-C6-alkyl groups, optionally substituted with phenyl groups. A specific alkylpolysiloxane that can be used is dimethylpolysiloxane (commonly referred to as simethicone). More specifically, a granular simethicone formulation designated as Simethicone GS can be used. Simethicone GS is a formulation containing 30% simethicone USP. Simethicone USP contains up to 90.5% by weight of (CH3)3-Si{OSi(CH3)2}CH3 in admixture with 4.0% to 7.0% by weight of SiO2.

[0124] To prevent stickiness that can occur with chairable compositions and to facilitate conversion of the active ingredients into an emulsion or suspension upon ingestion, the compositions may further include emulsifiers, such as glycerin fatty acid esters, sorbitan monostearate, sucrose fatty acid esters, lecithin, and mixtures thereof. In certain embodiments, one or more such emulsifiers may be present in an amount of 0.01% to 5.0% by weight of the administered formulation. In certain embodiments, lower or higher levels of emulsifier may result in no emulsification or increased waxiness.

[0125] Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.

[0126] In addition to the above, any suitable fillers and additives may be utilized in preparing the swallowable, chewable and / or dissolvable compositions or any other oral formulation described herein, provided that they are compatible with the stated purpose.

[0127] Oral formulations also include edibles. An edible refers to any product that can be consumed as food or drink. In some cases, edibles are made into foodstuffs by infusion of plant extracts. Examples of suitable edible foods include candy, candy bars, bread, brownies, cakes, cheese, chocolate, cocoa, cookies, gummies, lollipops, mints, pastries, peanut butter, popcorn, protein bars, mochi, yogurt, etc. While not strictly edible, gum can also be used. Examples of edible beverages include beer, juice, flavored milk, flavored water, liquor, milk, punch, milkshakes, soda, tea, and water. In certain embodiments, edibles are made by combining plant extracts with ingredients used to make the edible product. Examples include butter and oil. Representative oils include coconut oil, grapeseed oil, olive oil, palm oil, papaya seed oil, peanut oil, sesame oil, germinated wheat oil, wheat germ oil, or any combination thereof.

[0128] The oral dosages may be individually wrapped or packaged as a multiple unit in one or more packages, cans, vials, blister packs, or bottles of any size. The dosage is sized to provide a therapeutically effective amount.

[0129] 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 ... 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 containing botanical material (e.g., active ingredients of Curcuma longa, Hypericum perforatum, Polygonum cuspidatum and / or Vitis species).

[0130] 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.

[0131] In certain embodiments, the oral formulation comprises an additive in at least 0.1% w / v or w / w of the oral formulation; at least 1% w / v or w / w of the oral formulation; at least 10% w / v or w / w of the oral formulation; at least 20% w / v or w / w of the oral formulation; at least 30% w / v or w / w of the oral formulation; at least 40% w / v or w / w of the oral formulation; at least 50% w / v or w / w of the oral formulation; at least 60% w / v or w / w of the oral formulation; at least 70% w / v or w / w of the oral formulation; at least 80% w / v or w / w of the oral formulation; at least 90% w / v or w / w of the oral formulation; at least 95% w / v or w / w of the oral formulation; or at least 99% w / v or w / w of the oral formulation.

[0132] In certain embodiments, 10 g of dried plant extract can be used per 150 ml of water, resulting in effective concentrations of 1-99% (w / w) plant extract, 2-80% (w / w) plant extract, and 5-50% (w / w) plant extract.

[0133] Additives are commercially available from companies such as Aldrich Chemical Co., FMC Corp, Bayer, BASF, Alexi Fres, Witco, Mallinckrodt, Rhodia, ISP, and others.

[0134] Additional information can be found in WADE & WALLER, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (2nd ed. 1994) and Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. Additionally, formulations can be manufactured to meet sterility, pyrogenicity, general safety, and purity standards required by the US FDA and / or other relevant foreign regulatory agencies.

[0135] The herbal compositions disclosed herein can be used to treat subjects (humans, veterinary animals (dogs, cats, reptiles, birds, etc.), livestock (horses, cows, goats, pigs, chickens, etc.), and research animals (monkeys, rats, mice, fish, etc.)). Treating a subject includes providing a therapeutically effective amount. A therapeutically effective amount includes those that provide effective, prophylactic, and / or therapeutic treatment.

[0136] An "effective amount" is the amount of herbal composition necessary to produce a desired physiological change in a subject. An effective amount is often administered for testing purposes. Exemplary effective amounts disclosed herein can reduce pain perception (chronic pain, acute pain, visceral pain) in an animal model, reduce insomnia in an animal model, reduce symptoms of inflammation in an animal model, improve wound healing in an animal model, improve digestion in an animal model, reduce anxiety in an animal model, and / or reduce symptoms of asthma in an animal model.

[0137] "Prophylactic treatment" includes treatment administered to a subject who does not exhibit signs or symptoms of a disease or nutritional deficiency, or who exhibits only early signs or symptoms of a disease or nutritional deficiency, for the purpose of diminishing, inhibiting, or reducing the risk of further developing the disease or nutritional deficiency. Prophylactic treatment thus serves as a preventative measure against the onset of the disease or nutritional deficiency.

[0138] As an example of preventative treatment, the oral formulations disclosed herein can be administered to a subject at risk of developing insomnia. Effective preventative treatment of insomnia is indicated when the number of insomnia episodes experienced by the subject per month is reduced by at least 10%, or in certain embodiments, by 25%.

[0139] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of suffering from pain. Effective prophylactic treatment of pain is indicated when the incidence of pain is reduced by at least 10%, or in certain embodiments, 25%, as measured by standard subjective or objective pain assessments.

[0140] As another example of preventative treatment, the oral formulations disclosed herein can be administered to subjects at risk of depression. Effective preventative treatment of depression occurs when the severity of depression is reduced by at least 10%, or in certain embodiments, 25%, as measured by standard subjective or objective depression assessments.

[0141] As another example of prophylactic treatment, the oral formulations disclosed herein can be administered to subjects at risk of inflammation. Effective prophylactic treatment of inflammation is demonstrated when the severity of inflammation is reduced by at least 10%, or in certain embodiments, 25%, as measured by standard subjective or objective inflammation assessments.

[0142] "Therapeutic treatment" includes treatment administered to a subject having a disease or nutritional deficiency, and is administered to the subject with the intent of curing or lessening the severity of the disease or nutritional deficiency.

[0143] As an example of therapeutic treatment, the oral formulations disclosed herein can be administered to a subject with inflammatory bowel disease. Effective therapeutic treatment of inflammatory bowel disease occurs when the severity of the symptoms of inflammatory bowel disease is completely reduced or alleviated.

[0144] Another example of therapeutic treatment involves administering an oral formulation disclosed herein to a subject with anxiety. Effective therapeutic treatment of anxiety is manifested when there is a complete and / or more rapid reduction or alleviation of the severity of anxiety as measured by standard subjective or objective anxiety assessments.

[0145] Another example of therapeutic treatment involves administering the oral formulations disclosed herein to a subject with inflammation. Effective therapeutic treatment of inflammation is manifested when the severity of the inflammation is completely and / or more rapidly reduced or alleviated, as measured by standard subjective or objective inflammation assessments.

[0146] Another example of therapeutic treatment involves administering the oral formulations disclosed herein to a subject with depression. Effective therapeutic treatment of depression is manifested when there is a complete and / or more rapid reduction or alleviation of the severity of depression as measured by standard subjective or objective depression assessments.

[0147] Another example of therapeutic treatment involves administering the oral formulations disclosed herein to a subject with cancer. Effective therapeutic treatment of cancer is manifested when there is a complete and / or more rapid reduction or alleviation of the severity of the cancer as measured by standard subjective or objective cancer assessments.

[0148] Therapeutic treatment can be distinguished from effective amounts based on the presence or absence of the study component upon administration, however, as will be appreciated by those skilled in the art, there may be overlap in effective amounts, prophylactic treatments, and therapeutic treatments in human clinical trials.

[0149] For administration, a therapeutically effective amount (also referred to herein as pharmacokinetics) can be estimated initially based on the results of in vitro assays and / or animal model studies. Such information can be used to more accurately determine useful doses in intended subjects.

[0150] The actual dosage administered to a particular subject can be determined by the subject, a physician, veterinarian, or researcher, taking into account parameters such as physical, physiological, and psychological factors, including the subject's target, weight, condition, previous or concurrent therapeutic interventions, and / or idiopathic diseases.

[0151] Useful dosages can range from 0.1 to 5 μg / kg or 0.5 to 1 μg / kg. In certain embodiments, dosages of botanical materials, active ingredients of plants and / or plant extracts are 1 μg / kg, 5 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg , 100μg / kg, 150μg / kg, 200μg / kg, 250μg / kg, 350μg / kg, 400μg / kg, 450μg / kg, 500μg / kg, 550μg / kg, 600μg / kg, 650μg / k g, 700 μg / kg, 750 μg / kg, 800 μg / kg, 850 μg / kg, 900 μg / kg, 950 μg / kg, 1000 μg / kg, 0.1-5 mg / kg or 0.5-1 mg / kg. In certain embodiments, dosages 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 or more.

[0152] In certain embodiments, a useful dosage comprises botanical material (e.g., active ingredient of a plant or plant extract) or active ingredient by weight per subject's body weight. In certain embodiments, a useful dosage may range from 0.1 mg / kg to 100 mg / kg, or from 0.5 mg / kg to 50 mg / kg. In certain embodiments, a useful dosage comprises 0.5 mg / kg, 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 or more of botanical material per subject's body weight.

[0153] In certain embodiments, a useful dosage includes a carrier (e.g., SNAC) by weight per subject body weight. In certain embodiments, a useful dosage may range from 0.1 mg / kg to 100 mg / kg or 0.5 mg / kg to 50 mg / kg. In certain embodiments, a useful dosage includes 0.5 mg / kg, 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 or more of carrier per subject body weight.

[0154] In certain embodiments, the total dosage volume can range from 0.25 mL to 30 mL or from 0.5 mL to 20 mL. In certain embodiments, the total dosage volume can include 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, 20 mL, 21 mL, 22 mL, 23 mL, 24 mL, 25 mL, 26 mL, 27 mL, 28 mL, 29 mL, 30 mL or more.

[0155] Dosage concentrations can be expressed as botanical material (e.g., active ingredient of a plant or plant extract) or weight of active ingredient (e.g., mg active pharmaceutical ingredient (API) / mL) per dosage volume. In certain embodiments, dosage concentrations can range from 1 mg / mL to 100 mg / mL or from 5 mg / mL to 50 mg / mL. In certain embodiments, dosage concentrations can include 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL or more.

[0156] Dosage concentrations can be expressed as weight of carrier (e.g., SNAC) per dosage volume (e.g., mg SNAC / mL). In certain embodiments, dosage concentrations can range from 1 mg / mL to 500 mg / mL or from 50 mg / mL to 300 mg / mL. In certain embodiments, dosage concentrations can range from 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 10 ... The range may include 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, 200 mg / mL, 225 mg / mL, 250 mg / mL, 275 mg / mL, 300 mg / mL, 325 mg / mL, 350 mg / mL, 375 mg / mL, 400 mg / mL, 425 mg / mL, 450 mg / mL, 475 mg / mL, 500 mg / mL or more.

[0157] In certain embodiments, the ratio (w / w) of carrier to botanical material (e.g., active ingredient of a plant or plant extract) or active ingredient can range from 1:1 to 100:1, or from 1:1 to 20:1. In certain embodiments, the ratio can include 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1 or more. In certain embodiments, the ratio may be 10:1.

[0158] A therapeutically effective amount can be achieved by administering single or multiple doses over the course of a treatment regimen (e.g., every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 9 hours, every 12 hours, every 18 hours, every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, or every month).

[0159] One or more active ingredients and / or plant extracts can be administered simultaneously or within a selected time window, such as within a 10 minute, 1 hour, 3 hour, 10 hour, 15 hour, 24 hour, or 48 hour time window, or when the complementary active agent is within a clinically relevant therapeutic window.

[0160] The following representative embodiments and examples are included to demonstrate specific embodiments of the present disclosure. Those of skill in the art will recognize in light of the present disclosure that many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0161] Representative Embodiments 1. An herbal composition with improved bioavailability formulated for oral delivery, comprising (i) capsaicin, reserpine, vinblastine, hesperidin, naringin, rutin, quercitrin, curcumin, hypericin, resveratrol, catechin, eugenol, limonene, or linalool, and (ii) N-[8-(2-hydroxybenzoyl)amino]caprylate.

[0162] 2. An herbal composition with improved bioavailability formulated for oral delivery, comprising (i) botanical material derived from turmeric, Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Camellia sinensis (Camellia sinensis) plant, Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina, Vinca spp., Citrus spp., Rheum lavalvarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., or Mentha spp., and (ii)) an N-acylated fatty amino acid or a salt thereof.

[0163] 3. An herbal composition with improved bioavailability formulated for oral delivery, comprising (i) an active ingredient of turmeric, Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Camellia sinensis, Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina, Vinca spp., Citrus spp., Rheum lavalverum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., or Mentha spp., which has low water solubility, and (ii)) an N-acylated fatty amino acid or a salt thereof.

[0164] 4. An herbal composition with improved bioavailability formulated for oral delivery, comprising (i) an extract of turmeric, Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Camellia sinensis (Camellia sinensis) plant, Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina, Vinca spp., Citrus spp., Rheum lavalvarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., or Mentha spp., and (ii)) an N-acylated fatty amino acid or a salt thereof.

[0165] 5. Santa Maria (Calophyllum brasiliense), Calophyllum caledonicurn, Calophyllum inophyllum, St. John's wort (Calophyllum soulattri), Cat's claw (Uncaria tomentosa), Thyme (Thymus vulgaris), Chamomile (Matricaria recutita), Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Wintergreen (Gaultheria procumbens), Vaccinium myrtillus, Lemon balm (Melissa officinalis), Garlic (Allium sativum), Krameria triandra 5. The herbal composition of any of embodiments 1-4, further comprising botanical material from Cannabis sativa, Cannabis indica, Cannabis ruderalis and / or Acer spp, or extracts thereof.

[0166] 6. The herbal composition of any of embodiments 2-5, comprising capsaicin, reserpine, vinblastine, hesperidin, naringin, rutin, quercitrin, curcumin, hypericin, resveratrol, catechin, eugenol, limonene or linalool.

[0167] 7. An herbal composition comprising (i) a polyphenol, alkaloid, glycoside or terpene derived from a plant and having low water solubility, and (ii) an N-acylated fatty amino acid.

[0168] 8. The herbal composition of any of embodiments 2-7, wherein the N-acylated fatty amino acid comprises one or more of compounds I-XXXV (Figure 3), or compounds a-r (Figure 4).

[0169] 9. The herbal composition of any of embodiments 2-8, wherein the N-acylated fatty amino acid comprises monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, or N-(salicyloyl)-8-aminocaprylic acid.

[0170] 10. N-acylated fatty amino acids or their salts

[0171] [ka] The herbal composition of any of embodiments 2-9, comprising: wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

[0172] 11. The herbal composition of embodiment 10, wherein the monovalent cation is sodium or potassium.

[0173] 12. The herbal composition of embodiment 10 or 11, wherein the divalent metal cation is calcium or magnesium.

[0174] 13. The herbal composition of any of embodiments 10-12, wherein the organic cation is ammonium or tetramethylammonium.

[0175] 14. The herbal composition of any of embodiments 10-13, wherein X is H.

[0176] 15. The herbal composition of any of embodiments 10-13, wherein X is a monovalent cation including sodium or potassium.

[0177] 16. The herbal composition of any of embodiments 10-13, wherein X is a divalent metal cation including calcium or magnesium.

[0178] 17. The herbal composition of any of embodiments 10-13, wherein X is an organic cation, including ammonium or tetramethylammonium.

[0179] 18. The herbal composition of any of embodiments 10-17, wherein Z is H.

[0180] 19. The herbal composition of any of embodiments 10-17, wherein Z is a monovalent cation comprising sodium or potassium.

[0181] 20. The herbal composition of any of embodiments 10-17, wherein Z is a divalent cation comprising calcium or magnesium.

[0182] 21. The herbal composition of embodiment 10, wherein X is H and Z is H.

[0183] 22. The herbal composition of embodiment 10, wherein X is H and Z is sodium.

[0184] 23. The herbal composition of embodiment 10, wherein X is sodium and Z is sodium.

[0185] 24. The herbal composition of any of embodiments 1-23, wherein the N-acylated fatty amino acid or salt thereof provides a dosage benefit.

[0186] 25. The herbal composition of embodiment 24, wherein the dosage benefit is a dose-dependent dosage benefit.

[0187] 26. The herbal composition of embodiment 25, wherein the dose-dependent administration benefit is at a dose of 100-200 mg.

[0188] 27. The herbal composition of any of embodiments 24-26, wherein the administration benefits include one or more of increased absorption of the measured component of the botanical substance, increased bioavailability of the measured component of the botanical substance, faster onset of action of the measured component of the botanical substance, higher peak concentration of the measured component of the botanical substance, faster time to peak concentration of the measured component of the botanical substance, increased subjective therapeutic effect, increased objective therapeutic effect, improved taste, and improved mouthfeel, compared to a control composition not containing an N-acylated fatty amino acid.

[0189] 28. The herbal composition of any of embodiments 1-27, comprising a botanical medicine.

[0190] 29. The herbal composition of any of embodiments 1-28, comprising a nutritional supplement.

[0191] 30. The herbal composition of any of embodiments 1-29, comprising a botanical product.

[0192] 31. The herbal composition of any of embodiments 1-30, comprising a surfactant, detergent, azone, pyrrolidone, glycol, or bile salt.

[0193] 32. The herbal composition of any of embodiments 1-31, comprising a therapeutically effective amount of botanical material.

[0194] 33. A therapeutically effective amount of a compound of formula (I) or (II) may be administered to treat acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune disease, bacterial infection, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infection, digestive disorders, glaucoma, glioma, Graves' disease, or heart disease. Hepatitis, herpes, Huntington's disease, high blood pressure, lethargy, incontinence, infant death, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, ivy 33. The herbal composition of embodiment 32 for treating symptoms of eczema, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles, sickle cell disease, seizures, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, and withdrawal.

[0195] 34. The herbal composition of any of embodiments 1-33, comprising a vitamin or mineral.

[0196] 35. The herbal composition of any of embodiments 1-33, comprising vitamins and minerals.

[0197] 36. The herbal composition of embodiment 34 or 35, wherein the vitamins are selected from one or more of vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, or vitamin K.

[0198] 37. The herbal composition of embodiment 34 or 35, wherein the minerals are selected from one or more of calcium, chromium, iodine, iron, magnesium, selenium and / or zinc.

[0199] 38. An oral formulation comprising the herbal composition of any of embodiments 1-37.

[0200] 39. The oral formulation of embodiment 38, wherein the oral formulation is swallowable or chewable.

[0201] 40. The oral formulation of embodiment 38 or 39, wherein the oral formulation is a liquid or a solid.

[0202] 41. The oral formulation of any of embodiments 38-40, wherein the oral formulation is a solution, suspension, or spray.

[0203] 42. The oral formulation of any of embodiments 38-40, wherein the oral formulation is a tablet, capsule or sachet.

[0204] 43. The oral dosage form of any of embodiments 38-42, wherein the oral dosage form is flavored.

[0205] 44. A method for producing an oral formulation of an herbal composition having improved bioavailability, the method comprising adding an absorption enhancer to the oral formulation of the herbal composition, wherein the oral formulation of the herbal composition has improved bioavailability compared to an oral formulation of the herbal composition without the absorption enhancer.

[0206] 45. The method of embodiment 44, wherein the absorption enhancer is an N-acylated fatty amino acid or a salt thereof.

[0207] 46. ​​N-acylated fatty amino acids or their salts

[0208] [ka] 46. ​​The method of embodiment 45, comprising: wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

[0209] 47. The method of embodiment 45, 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.

[0210] 48. A method of treating a subject in need thereof, comprising administering a therapeutically effective amount of the composition of any of embodiments 1-37 to the subject, thereby treating the subject in need thereof.

[0211] 49. The method of embodiment 48, wherein the therapeutically effective amount provides an effective amount, prophylactic treatment, and / or therapeutic treatment.

[0212] 50. A method for reducing or eliminating one or more symptoms of a disease or disorder in a human subject, said method comprising delivering to the subject a therapeutically effective amount of the composition of any of embodiments 1-37, thereby reducing or eliminating one or more symptoms of the disease or disorder, wherein said disease or disorder is acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, hypertension, rheumatoid arthritis ... Arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headaches, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infections, digestive disorders, glaucoma, glioma, Graves' disease, heart disease Hepatitis, herpes, Huntington's disease, hypertension, lethargy, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neurological disorders, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles, sickle cell disease, seizures, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, or withdrawal syndrome. [Example]

[0213] An oral dosage form of an herbal composition that exhibits improved bioeffect (eg, bioavailability) and reduced time to onset of action.

[0214] The observed increased intensity of action and shortened time to onset of action indicate improved bioavailability. Given the wealth of health conditions that can benefit from herbal therapies, there is a significant unmet need for fast-acting products that exhibit improved bioavailability in oral formats. Traditional pharmaceutical dosage forms of many herbal compositions suffer from low bioavailability and long onset of action. The present disclosure addresses the shortcomings of oral ingestion of herbal compositions with poor bioavailability.

[0215] Example 1: Representative Formulations. Solution Formulation. A botanical substance (e.g., a plant extract or an active ingredient of the plant, such as curcumin) and one or more N-acylated fatty amino acids are mixed in an aqueous / organic solvent mixture. The resulting blend is vigorously stirred for 1 hour. If dissolution is incomplete, a surfactant can be added and stirring continued to prepare the final formulation.

[0216] Suspension formulations. A botanical substance (e.g., a plant extract or an active ingredient of a plant, such as curcumin) and one or more N-acylated fatty amino acids are mixed in water, an aqueous / organic solvent mixture, or an organic solvent mixture. The resulting blend can be stirred to form a suspension.

[0217] Solution Formulation: A botanical (e.g., a plant extract or an active ingredient of the plant, such as curcumin) and one or more absorption enhancers are mixed in an aqueous / organic solvent mixture. The resulting blend is vigorously stirred for 1 hour. If dissolution is incomplete, a surfactant can be added and stirring continued to prepare the final formulation.

[0218] Suspension formulations: A botanical substance (e.g., a plant extract or an active ingredient of a plant such as curcumin) and one or more absorption enhancers are mixed in water, an aqueous / organic solvent mixture, or an organic solvent mixture. The resulting blend can be stirred to form a suspension.

[0219] Gel-cup compositions. Suspension or solution formulations can be filled into gel-cups to contain up to 1 g of botanical material. The gel-cups can be treated with an enteric coating or used uncoated.

[0220] Tablet / Capsule Compositions. Solution and suspension formulations can be dried by evaporation, freeze-drying, or spray-drying. The resulting dried product can be mixed with tableting excipients and compressed into tablets or caplets containing up to 1 g of botanical material. Alternatively, the dried product can be filled into capsules.

[0221] Example 2: Onset and duration of action of orally administered cannabis / SNAC compositions. This study was designed to evaluate the utility of SNAC in enabling a fast-acting oral form of an herbal composition.

[0222] Participant Selection. Six study participants were recruited to ingest the herbal composition and, in this example, the onset, duration, and intensity of cannabis-induced euphoria and / or dysphoria were recorded. Study participants participated in two separate studies: 1) use of a control substance comprising a liquid cannabis extract dissolved in aqueous ethanol, and 2) use of a test substance comprising a liquid cannabis extract dissolved in aqueous ethanol and SNAC.

[0223] Formulation. The selected cannabis concentrate was commercially available and given to participants as an ethanol solution. The concentrate contained 8 mg of THC per dose. It was chosen because it contained a high percentage of THC and had a noticeable effect on the "euphoria" reported by users. Aqueous ethanol was used as the solvent because it effectively dissolves the cannabis extract as well as SNAC.

[0224] Methods: In a control experiment, each participant mixed cannabis concentrate with 15 ml (1 tablespoon) of aqueous ethanol and immediately swallowed the mixture.

[0225] 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 swallowed the dissolved mixture.

[0226] In the control and test experiments, each participant recorded the time of dosing, the time of onset of euphoria and / or dysphoria, and the observed levels of euphoria and / or dysphoria at 15-minute intervals for 5 hours after administration of the cannabis drug dose. Euphoria and dysphoria were reported using a scale ranging from 1 to 10. Table 1 lists the euphoria and dysphoria levels for each scale value.

[0227] [Table 2]

[0228] [Table 3]

[0229] Results. The results shown below are the average scale values ​​obtained across all six participants (also shown in Figures 5A and 5B).

[0230] [Table 4]

[0231] Onset: All six participants reported euphoria within 5 minutes of ingestion of the cannabis / SNAC formulation (test), with onset ranging from 2 to 5 minutes. In contrast, the first time point of euphoria reported by participants after ingestion of the cannabis-only formulation (control) was 15 minutes after ingestion, with onset ranging from 15 minutes to 1 hour and 15 minutes (see Figures 6A-6F for individual participant results). By 15 minutes after ingestion, the mean reported euphoria scale value was 3.8 for the cannabis / SNAC formulation (test). In contrast, by 15 minutes after ingestion of the cannabis-only formulation (control), the mean reported euphoria scale value was 0.17 (see Figures 5A and 5B for means across time points).

[0232] Intensity: The mean peak euphoria scale value after ingestion of the cannabis / SNAC formulation (test) was 4.7, which occurred 30 minutes after ingestion. In contrast, the highest mean euphoria scale value after ingestion of the cannabis-only formulation (control) was 2.2, which occurred at 2 hours and 15 minutes (see Figures 5A and 5B). Thus, ingestion of the cannabis / SNAC formulation led to a higher peak intensity of euphoria, which occurred an average of 1 hour and 45 minutes earlier than when the cannabis-only formulation was ingested. The observed intensity of dysphoria was minimal in both test and control, with a mean peak scale value of 0.83 in both experiments.

[0233] Duration: The results show that adding an absorption enhancer does not shorten the effects of cannabis.

[0234] In summary, the addition of an absorption enhancer such as SNAC to an oral dosage formulation of an herbal composition exhibits a faster onset of action and a higher intensity of action at peak activity levels, without affecting the duration of action of the herbal composition.

[0235] Example 3: Orally Administered Low SNAC Dosage Herbal Composition / Onset and Duration of Action of SNAC Composition This study was designed to evaluate the usefulness of low dosage SNAC in enabling a fast-acting oral form of the herbal composition.

[0236] Participant Selection. Three study participants were recruited to ingest the herbal composition and the onset, duration, and intensity of cannabis-induced euphoria and / or dysphoria were recorded. Study participants participated in two separate studies: 1) use of a control substance comprising a liquid cannabis extract dissolved in aqueous ethanol, and 2) use of a test substance comprising a liquid cannabis extract dissolved in aqueous ethanol and SNAC.

[0237] Formulation. The selected cannabis concentrate was commercially available and given to participants as an ethanol solution. The concentrate contained 8 mg of THC per dose. It was chosen because it contains a high percentage of THC and has a pronounced effect on the "euphoria" reported by users. Aqueous ethanol was used as the solvent because it effectively dissolves the cannabis extract as well as SNAC.

[0238] Methods: In a control experiment, each participant mixed cannabis concentrate with 15 ml (1 tablespoon) of aqueous ethanol and immediately swallowed the mixture.

[0239] 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 swallowed the dissolved mixture.

[0240] In both the control and test experiments, each participant recorded the time of dose administration, the time of onset of euphoria and / or dysphoria, and the observed level of euphoria and / or dysphoria at 15-minute intervals for 5 hours after administration of the cannabis dose. Euphoria and dysphoria were reported using a scale ranging from 1 to 10. Table 1 lists the levels of euphoria and dysphoria for each scale value.

[0241] Results. Results are shown in Figure 7 for all participants, along with data from Example 2.

[0242] Onset: All three participants reported euphoria within 5 minutes of ingesting the cannabis / SNAC formulation (test), with onset ranging from 2 to 5 minutes. In contrast, the first time point of euphoria reported by participants after ingesting the cannabis-only formulation (control) was 15 minutes after ingestion, with onset ranging from 15 minutes to 1 hour and 15 minutes. By 15 minutes after ingestion, the mean reported euphoria scale value was 3.0 for the cannabis / SNAC formulation (test). In contrast, 15 minutes after ingesting the cannabis-only formulation (control), the mean reported euphoria scale value was 0.25.

[0243] Intensity: The mean peak euphoria scale score after ingestion of the cannabis / SNAC formulation (test) was 3.4, occurring 30 minutes after ingestion. In contrast, the highest mean euphoria scale score after ingestion of the cannabis-only formulation (control) was 2.2, occurring at 2 hours and 15 minutes. Compared to Example 2, where the SNAC dose was 200 mg, participants in Example 3 received only 100 mg of SNAC in combination with the same amount of cannabis used in Example 2. This reduced amount of SNAC resulted in a reduced cannabis effect, demonstrating a clear dose-response relationship between the observed cannabis effect (euphoria) and SNAC dose. As in Example 2, ingestion of the cannabis / SNAC formulation resulted in a higher peak intensity of euphoria, which occurred an average of 1 hour and 45 minutes earlier than when the cannabis-only formulation was ingested.

[0244] Duration: The results show that adding an absorption enhancer does not shorten the effects of cannabis.

[0245] Example 4: Inhaled vs. Oral Group Response (Figure 8). Comparison of the pharmacodynamic response of inhaled and orally ingested herbal compositions, in this example cannabis, measured as subject-reported euphoria. Both oral and inhaled groups reported similar times to peak effect (15-30 minutes). This is quite surprising, as oral cannabis is traditionally characterized by a very slow time to peak effect (up to 4 hours).

[0246] Example 5: Summary of herbal composition / SNAC oral rat pharmacokinetic (PK) study. This study was designed to characterize the pharmacokinetic profile of a herbal composition containing 56% THC / CBD in a 1:1 ratio (by weight) with and without the excipient SNAC after a single oral gavage administration to rats. Two doses of cannabis and SNAC and two ratios of cannabis and SNAC were tested in this study. The experimental design is shown in Table 4 below.

[0247] [Table 5]

[0248] Methods: Animals were dosed on day 1 and serial blood samples were collected over 4 hours post-dose for pharmacokinetic evaluation. Animals were euthanized after the last blood sample was collected.

[0249] Results. Mean maximum concentrations C were observed after a single oral administration of an herbal composition containing a 1:1 ratio of THC / CBD in combination with an absorption-enhancing excipient (SNAC) at 25 mg extract / kg and 250 mg SNAC / kg (Group 3), 25 mg extract / kg and 500 mg SNAC / kg (Group 4), or 50 mg extract / kg and 500 mg SNAC / kg (Group 5). max The mean time to reach maximum plasma concentration (T) ranged from 31.7 to 159.3 ng / mL for CBD and from 111.5 to 546.17 ng / mL for THC. max The AUC ranged from 0.25 to 1 hour after dosing for CBD, and was reached at 1 hour after dosing for THC in the low and medium dose groups and 2 hours after dosing for the high dose group. 0-Tlast is 13.17~382.14hr in CBD * ng / mL range, and for THC it was 170.64 to 1256.49 hr * The range was ng / mL.

[0250] In the dosage range tested, the C of THC max and AUC 0-Tlast When administered with the same cannabis extract (THC / CBD) dose (25 mg / kg cannabis total dose, 12.5 mg / kg THC / 12.5 mg / kg CBD) with and without SNAC, THC produced 1.4 times the C value of cannabis alone. max Increases in AUC were observed at either 250 or 500 mg / kg SNAC doses. AUC was 1.1-fold greater in the 250 mg / kg SNAC group but lower in the 500 mg / kg SNAC group compared to the cannabis-only group. CBD increased CUC by 2.9-fold and 2.8-fold compared to cannabis alone. maxIncreases in AUC were observed at either 250 or 500 mg / kg SNAC doses. AUC was lower in both groups compared to cannabis alone. A doubling of the dose of both cannabis and SNAC relative to 500 mg / kg SNAC and 50 mg / kg cannabis extract (25 mg / kg THC / 25 mg / kg CBD) significantly increased the CBD C max 14.2-fold increase in THC C max This resulted in a 6.9-fold increase in the AUC of CBD and THC. 0-Tlast increased by 22.1-fold and 6.3-fold, respectively (Table 5 and Figure 9).

[0251] In summary, the addition of an absorption enhancer such as SNAC to an oral formulation of an herbal composition provides a faster onset of action and greater potency at peak activity levels. These results demonstrate that SNAC improves the bioavailability of the herbal composition. Furthermore, the absorption enhancer does not affect the duration of action. Varying amounts of SNAC produce a clear dose-dependent relationship between the observed effects of the herbal composition and the SNAC dosage.

[0252] Example 6: Onset and duration of action of orally administered cannabis / NAC compositions. This study was designed to evaluate the utility of N-[8-(2-hydroxybenzoyl)amino]caprylic acid (NAC), the acid form of SNAC, in enabling a fast-acting oral form of cannabis.

[0253] Study Participants. One study participant was recruited to ingest the cannabis composition and record the onset, duration, and intensity of cannabis-induced euphoria and / or dysphoria. The study participant participated in two separate studies: 1) use of a control substance comprising an oil of cannabis concentrate in an herbal extract blend dissolved in aqueous ethanol, and 2) use of a test substance comprising an oil of cannabis concentrate in an herbal extract blend and NAC dissolved in aqueous ethanol.

[0254] Formulation. The selected cannabis concentrate oil was commercially available in capsules, and the contents of the capsules were administered to participants as an ethanol solution. Each capsule contained 9 mg of CBD, 7.7 mg of THC, an herbal extract blend (magnolia bark, ashwagandha, and astragalus), and stearic acid (derived from vegetable oils), with a nominal strength per capsule of 9.0 mg CBD, 0.0 mg THCA, and 7.6 mg THC. This formulation was selected because it demonstrated a significant effect on user-reported "euphoria," and the CBD content should ameliorate unpleasant effects if Study 2 delivers a very high dose of cannabis.

[0255] Methods: In a control experiment, participants mixed cannabis concentrate with 15 ml (1 tablespoon) of aqueous ethanol and immediately swallowed the mixture.

[0256] In the test experiment, participants mixed the cannabis concentrate with a 5 ml pre-mixed solution of aqueous ethanol and 100 mg of NAC and immediately swallowed the dissolved mixture.

[0257] In the control and test experiments, participants recorded the time of dosing, the time of onset of euphoria and / or dysphoria, and the observed levels of euphoria and / or dysphoria at 15-minute intervals for 5 hours after administration of the cannabis drug dose. Euphoria and dysphoria were reported using a scale ranging from 1 to 5. Table 5 lists the euphoria and dysphoria levels for each scale value.

[0258] [Table 6]

[0259] Results. The results shown below are the scale values ​​obtained from participants in the control experiment (Table 6) and the test experiment (Table 7). The values ​​are plotted in Figure 11.

[0260] [Table 7]

[0261] [Table 8]

[0262] Onset: Participants reported euphoria within 6 minutes of ingesting the cannabis / NAC formulation (Test, Table 7 and Figure 11). In contrast, the first time point of euphoria reported by participants after ingesting the cannabis-only formulation (Control, Table 6 and Figure 11) was 45 minutes after ingestion. By 30 minutes after ingestion, participants reported strong euphoria (scale of 4) with the cannabis / NAC formulation. In contrast, 30 minutes after ingesting the cannabis-only formulation, participants noted only mild effects (scale of 1), likely psychological in nature.

[0263] Intensity: The peak euphoria scale score after ingestion of both the cannabis-only (control) and cannabis / NAC formulations (test) was 4. However, peak intensity of euphoria was reached 30 minutes after ingestion with the cannabis / NAC formulation (test), whereas peak intensity of euphoria was reached 2 hours after ingestion with the cannabis-only formulation (control). Thus, ingestion of the cannabis / NAC formulation resulted in euphoria whose peak intensity occurred 1 hour 30 minutes earlier than with ingestion of the cannabis-only formulation. The intensity of discomfort observed was minimal in both the test and control groups, although participants noted milder discomfort with the cannabis-only formulation (control).

[0264] In summary, NAC, the acid form of SNAC, functions similarly to SNAC when included in oral cannabis dosage formulations. Cannabis / NAC formulations provide a faster onset of action compared to cannabis-only formulations.

[0265] As will be understood by those skilled in the art, each embodiment disclosed herein can comprise, consist essentially of, or consist of the specifically stated elements, steps, ingredients, or components. Accordingly, the terms "include" or "including" should be understood to mean "comprise, consist, or consist essentially of." As used herein, the transitional term "comprise" means including, but is not limited to, and may include, even in major amounts, elements, steps, ingredients, or components not specifically recited. The transitional phrase "consisting of" excludes elements, steps, ingredients, or components not specifically recited. The transitional phrase "consisting essentially of" limits the scope of an embodiment to the specifically recited elements, steps, ingredients, or components and those that do not substantially affect the embodiment. As used herein, a significant effect would result in a statistically significant reduction in the dosing benefit when evaluated using the experimental protocols disclosed herein.

[0266] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and without intending to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques. Where further clarity is needed, the term "about," when used in conjunction with a stated numerical value or range, has the meaning that one of ordinary skill in the art would expect, i.e., a value that is somewhat greater than or somewhat less than the stated value or range, a value within ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11% of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value.

[0267] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible, however, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0268] As used in describing the present invention (particularly in the claims that follow), the terms "a," "an," "the," and similar designators should be understood to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended as a shorthand method for referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if set forth individually. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to facilitate a more readily understood understanding of the invention and does not pose a limitation on the scope of the invention as set forth in the claims. No language in the specification should be construed as referring to any non-claimed element essential to the practice of the invention.

[0269] Groups of alternative elements or embodiments of the invention disclosed herein should not be considered limiting. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is understood that one or more members of a group may be included in, or omitted from, a group for reasons of convenience and / or patentability. When such inclusion or omission occurs, the specification is considered to include the group as modified to meet the recitation requirements of all Markush groups used in the appended claims.

[0270] Several embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will be apparent to those of skill in the art upon reading the foregoing description. The inventors anticipate that such variations will be employed by those of skill in the art, and the inventors intend that the invention be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of any possible variations of the elements described above is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0271] Additionally, throughout this specification, numerous patents, publications, journal articles and other documents (references) are referenced. Each of these references is individually incorporated herein by reference in its entirety for the teachings contained therein.

[0272] In closing, it should be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, and not of limitation, other aspects of the invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to what has been precisely shown and described above.

[0273] The details shown in this specification are by way of example only and are for the purpose of describing preferred embodiments of the invention, and are provided to illustrate what is believed to be the most useful and easily understood explanation of the principles and conceptual aspects of various embodiments of the invention. In this regard, it is not intended to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, and the description, taken in conjunction with the drawings and / or examples, will make clear to those skilled in the art how several forms of the invention may be implemented in practice.

[0274] The definitions and explanations used in this disclosure are meant and intended to control in future constructions unless clearly and unambiguously modified in the following examples, or when application of their meaning would render any construction meaningless or essentially meaningless. If construction of a term would render it meaningless or essentially meaningless, the definition should be derived from a dictionary known to those skilled in the art, such as Webster's Dictionary, 3rd Edition, or Oxford Dictionary of Biochemistry and Molecular Biology (Ed. Anthony Smith, Oxford University Press, Oxford, 2004).

Claims

1. 1. An herbal composition with improved bioavailability formulated for oral delivery, comprising (i) capsaicin, reserpine, vinblastine, hesperidin, naringin, rutin, quercitrin, curcumin, hypericin, resveratrol, catechin, eugenol, limonene, or linalool, and (ii) N-[8-(2-hydroxybenzoyl)amino]caprylate.

2. 1. An herbal composition with improved bioavailability formulated for oral delivery, comprising (i) botanical material derived from Turmeric, Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Camellia sinensis (Camellia sinensis) plant, Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina, Vinca spp., Citrus spp., Rheum lavalvarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., or Mentha spp.; and (ii) an N-acylated fatty amino acid or salt thereof.

3. 1. An herbal composition with improved bioavailability formulated for oral delivery, comprising: (i) an active ingredient of Curcuma longa, Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Camellia sinensis, Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina, Vinca spp., Citrus spp., Rheum lavalvarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., or Mentha spp., having a water solubility of less than 0.1 mg / ml; and (ii) an N-acylated fatty amino acid or a salt thereof.

4. 1. An herbal composition with improved bioavailability formulated for oral delivery, comprising: (i) an extract of Turmeric, Hypericum perforatum, Polygonum cuspidatum, Vitis spp., Camellia sinensis (Camellia sinensis) plant, Theobroma cacao, Capsicum spp., Rauwolfia vomitoria, Rauwolfia serpentina, Vinca spp., Citrus spp., Rheum lavalvarum, Fagopyrum tataricum, Syzygium aromaticum, Lavandula spp., or Mentha spp.; and (ii) an N-acylated fatty amino acid or salt thereof.

5. 5. The herbal composition of claim 4, further comprising botanical material from Santa Maria, Calophyllum caledonicum, Caltrop, Hypericum perforatum, Cat's claw, Thymus vulgaris, Chamomile, Salix alba, Calendula, Usnea barbata, Ligusticum porteriosa, Wintergreen, Camellia sinensis, Vaccinium myrtillus, Lemon balm, Garlic, Camellia sinensis, Chlamydia trumpetii, Pichurri, Milkweed, Cannabis sativa, Cannabis sativa, Cannabis ruderalis, and / or Maple species, or extracts thereof.

6. 5. The herbal composition of claim 4, comprising capsaicin, reserpine, vinblastine, hesperidin, naringin, rutin, quercitrin, curcumin, hypericin, resveratrol, catechin, eugenol, limonene, or linalool.

7. 5. The herbal composition of claim 4, wherein the N-acylated fatty amino acids comprise one or more of compounds I-XXXV (Figure 3), or compounds a-r (Figure 4).

8. 5. The herbal composition of claim 4, wherein the N-acylated fatty amino acid comprises monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, or N-(salicyloyl)-8-aminocaprylic acid.

9. N-acylated fatty amino acid or a salt thereof 【Chemistry 1】 5. The herbal composition of claim 4, comprising: wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

10. 10. The herbal composition of claim 9, wherein the monovalent cation is sodium or potassium.

11. 10. The herbal composition of claim 9, wherein the divalent metal cation is calcium or magnesium.

12. 10. The herbal composition of claim 9, wherein the organic cation is ammonium or tetramethylammonium.

13. 10. The herbal composition of claim 9, wherein X is H.

14. 10. The herbal composition of claim 9, wherein X is a monovalent cation including sodium or potassium.

15. 10. The herbal composition of claim 9, wherein X is a divalent metal cation including calcium or magnesium.

16. 10. The herbal composition of claim 9, wherein X is an organic cation including ammonium or tetramethylammonium.

17. 10. The herbal composition of claim 9, wherein Z is H.

18. 10. The herbal composition of claim 9, wherein Z is a monovalent cation including sodium or potassium.

19. 10. The herbal composition of claim 9, wherein Z is a divalent cation including calcium or magnesium.

20. 10. The herbal composition of claim 9, wherein X is H and Z is H.

21. 10. The herbal composition of claim 9, wherein X is H and Z is sodium.

22. 10. The herbal composition of claim 9, wherein X is sodium and Z is sodium.

23. 5. The herbal composition of claim 4, wherein the N-acylated fatty amino acid or salt thereof provides a convenient administration benefit.

24. 24. The herbal composition of claim 23, wherein the dosage benefit is a dose-dependent dosage benefit.

25. 25. The herbal composition of claim 24, wherein the dose-dependent administration benefit is at a dose of 100-200 mg.

26. 24. The herbal composition of claim 23, wherein the administration benefits include one or more of increased absorption of the measured component of the botanical substance, increased bioavailability of the measured component of the botanical substance, faster onset of action of the measured component of the botanical substance, higher peak concentration of the measured component of the botanical substance, faster time to peak concentration of the measured component of the botanical substance, increased subjective therapeutic effect, increased objective therapeutic effect, improved taste, and improved mouthfeel when compared to a control composition without the N-acylated fatty amino acid.

27. 5. The herbal composition of claim 4, comprising a botanical medicine.

28. 5. The herbal composition of claim 4, comprising a nutritional supplement.

29. 5. The herbal composition of claim 4, comprising a botanical product.

30. 5. The herbal composition of claim 4, comprising a surfactant, detergent, azone, pyrrolidone, glycol or bile salt.

31. 5. The herbal composition of claim 4, comprising a therapeutically effective amount of botanical material.

32. A therapeutically effective amount may be administered to treat acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infections, digestive disorders, glaucoma, glioma, Graves' disease, heart disease Hepatitis, herpes, Huntington's disease, high blood pressure, lethargy, incontinence, infant death, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, poison ivy 32. The herbal composition of claim 31 for treating symptoms of allergies, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles), sickle cell disease, seizures, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, and withdrawal.

33. 5. The herbal composition of claim 4, further comprising a vitamin or mineral.

34. 5. The herbal composition of claim 4, comprising vitamins and minerals.

35. 34. The herbal composition of claim 33, wherein the vitamins are selected from one or more of vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, or vitamin K.

36. 34. The herbal composition of claim 33, wherein the minerals are selected from one or more of calcium, chromium, iodine, iron, magnesium, selenium and / or zinc.

37. An oral formulation comprising the herbal composition of claims 1-36.

38. 38. The oral formulation of claim 37, wherein the oral formulation is swallowable or chewable.

39. 38. The oral formulation of claim 37, wherein the oral formulation is a liquid or a solid.

40. 38. The oral formulation of claim 37, wherein the oral formulation is a solution, suspension, or spray.

41. 38. The oral formulation of claim 37, wherein the oral formulation is a tablet, capsule or sachet.

42. 38. The oral formulation of claim 37, wherein the oral formulation is flavored.

43. A method for producing an oral formulation of an herbal composition having improved bioavailability, said method comprising adding an absorption enhancer to the oral formulation of the herbal composition, wherein the oral formulation of the herbal composition has improved bioavailability compared to an oral formulation of the herbal composition that does not include the absorption enhancer.

44. 44. The method of claim 43, wherein the absorption enhancer is an N-acylated fatty amino acid or a salt thereof.

45. N-acylated fatty amino acid or a salt thereof 【Chemistry 2】 45. The method of claim 44, comprising the formula: wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.

46. 45. The method of claim 44, 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.

47. 10. A method of treating a subject in need thereof, comprising administering a therapeutically effective amount of the composition of claim 4 to the subject in need thereof, thereby treating the subject.

48. 48. The method of claim 47, wherein the therapeutically effective amount provides an effective amount, prophylactic treatment, and / or therapeutic treatment.

49. 10. A method of reducing or eliminating one or more symptoms of a disease or disorder in a human subject, the method comprising delivering a therapeutically effective amount of the composition of claim 4 to the subject, thereby reducing or eliminating one or more symptoms of the disease or disorder, wherein the disease or disorder is acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), rigidity, anxiety, arthritis. , Asperger's syndrome, asthma, atherosclerosis, autism, autoimmune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury / stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disc disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headaches, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infections, digestive disorders, glaucoma, glioma, Graves' disease, heart disease Hepatitis, herpes, Huntington's disease, hypertension, lethargy, incontinence, infant death, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail-patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive-compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neurological disorders, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless legs syndrome, schizophrenia, scleroderma, septic shock, shingles), sickle cell disease, seizures, sleep apnea, sleep disorders, spinal cord injury, stress, stuttering, temporomandibular joint disorder (TMJ), tension headache, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, or withdrawal syndrome.

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