Oral formulation

Abstract

The present disclosure relates to oral formulations, methods for making oral formulations, and uses of oral formulations containing L-theanine, ginseng, and lemon balm.

Description

[Technical Field]

[0001] The present disclosure relates to oral formulations, methods for making oral formulations, and uses of said oral formulations. [Background technology]

[0002] The present disclosure relates to formulations and compositions intended for human use that are configured for pharmaceutical use and deliver substances such as flavorings and / or active ingredients during use.

[0003]

[0003] Pharmaceutical preparations that are easy to administer orally and can have a beneficial effect on specific mood states in humans or animals have become popular in recent years. For example, confectionery-type preparations (e.g., gummies or soft lozenges) containing vitamins or other mood-improving active ingredients provide a convenient and comfortable mode of administration for such active ingredients. Other convenient modes of administration are foods and beverages, such as energy drinks. Such preparations can contain active ingredients that are delivered to the user to elicit a biological response in the user that can improve the user's physical or mental function.

[0004] Beverages containing theanine and caffeine are described in U.S. Patent Nos. 5,780,086 and 6,268,009. More recently, European Patent No. 1819241 describes a beverage containing theanine and caffeine in a ratio of 5:1 to 1:1.5. Other beverages, such as chamomile tea and other herbal teas, are consumed by some users to aid sleep and relaxation. A method for treating extreme physical or mental stress using L-theanine is described in U.S. Patent Application Publication No. 20050090512.

[0005] It would be desirable to provide an oral formulation adapted for oral use that can deliver an active ingredient to the consumer in a palatable and effective form, such as in the form of a liquid shot. Summary of the Invention

[0006] The present disclosure generally provides formulations adapted for oral use, comprising a combination of active ingredients. The oral formulation may be in any form suitable for oral use, for example, in the form of a tablet or lozenge, a loose powder, or in liquid form (e.g., a drink such as a shot).

[0007] According to some embodiments described herein, there is provided an oral formulation comprising a combination of active ingredients, the combination comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm.

[0008] According to some embodiments described herein, there is provided a method of preparing an oral formulation, comprising: (a) combining active ingredients, the active ingredients including (i) L-theanine, (ii) ginseng, and (iii) lemon balm; (b) contacting the active ingredient with water; (c) mixing the active ingredient with water to prepare the oral formulation.

[0009] According to some embodiments described herein, there is provided use of a combination of active ingredients to provide a relaxation effect to a human or animal, the combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm.

[0010] According to some embodiments described herein, there is provided a use of a combination of active ingredients for sedating a human or animal, the combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm.

[0011] According to some embodiments described herein, there is provided an oral formulation in liquid form comprising a combination of active ingredients, wherein the combination of active ingredients comprises lemon balm in an amount of about 1000 ppm to about 2000 ppm.

[0012] According to some embodiments described herein, there is provided an oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising (i) lemon balm and (ii) ginseng.

[0013] According to some embodiments described herein, there is provided an oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising (i) L-theanine and (ii) ginseng, wherein the L-theanine and ginseng are present in a weight ratio of about 5:1 to about 1:1.

[0014] These and other features, aspects, and advantages of the present disclosure will become apparent upon reading the following detailed description. The present invention includes any combination of two, three, four, or more of the above-described embodiments, as well as combinations of any two, three, four, or more features or elements described in this disclosure, regardless of whether such features or elements are explicitly combined in the description of a particular embodiment herein. The present disclosure is intended to be read as a whole such that any separable features or elements of the disclosed invention, in any of its various aspects and embodiments, should be considered as intended to be combinable unless the context clearly dictates otherwise.

[0015] For ease of reference, these and further aspects of the present invention are discussed herein under appropriate section headings, however, the teachings under each section are not necessarily limited to each particular section.

[0016] Having thus described aspects of the present disclosure in general terms above, reference is now made to the accompanying drawings, which are not necessarily drawn to scale, and which are illustrative only and are not to be construed as limiting the disclosure.

[0017] Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0018] [Figure 1] 1 is a graph showing the galvanic skin response (GSR) of the oral formulation of Example 2 compared to placebo. [Figure 2] 1 is a graph showing results for subjective negative mood states in POMS comparing placebo with Example 2. [Figure 3] 1 is a graph showing results for subjective positive mood state in SAM comparing placebo with Example 2. [Figure 4] 1 is a graph showing the results of the change in subjective stress over time (minutes) in the STAI State Anxiety Test, comparing placebo with Example 5. The time of formulation intake is t=0 min, and the time of the stop test is t=100 min. Both time points are indicated by dashed lines. A double asterisk (**) indicates a statistically significant difference compared to placebo across all sessions. [Figure 5] 1 is a graph showing the results for subjective stress in the STAI State Anxiety Test, comparing placebo with Example 5. An asterisk (*) indicates a statistically significant difference versus placebo across all sessions. [Figure 6] 1 is a graph showing the results for subjective tension on a VAS comparing placebo with Example 5. An asterisk (*) indicates a statistically significant difference versus placebo across all sessions. [Figure 7] 1 is a graph showing the results for subjective fatigue on a VAS comparing placebo with Example 5. An asterisk (*) indicates a statistically significant difference versus placebo across all sessions. [Figure 8]1 is a graph showing results for subjective "sense of control" on a VAS comparing placebo with Example 5. An asterisk (*) indicates a statistically significant difference versus placebo across all sessions. [Figure 9] 1 is a graph showing the results for subjective attention in the VAMS comparing placebo with Example 5. An asterisk (*) indicates a statistically significant difference versus placebo across all sessions. [Figure 10] 1 is a graph showing results for subjective calmness on the VAMS comparing placebo with Example 5. An asterisk (*) indicates a statistically significant difference versus placebo across all sessions. [Figure 11] 1 is a graph showing the results of the change in subjective initiative over time (minutes) in SAM, comparing placebo with Example 5. The time of formulation intake is t=0 min, and the time of stope test is t=100 min. Both time points are indicated by dashed lines. An asterisk (*) indicates a statistically significant difference compared to placebo at that time point. A double asterisk (**) indicates a statistically significant difference compared to placebo across all sessions. [Figure 12] 1 is a graph showing the results of the time course of subjective calmness (minutes) in the VAMS, comparing placebo with Example 5. The time of formulation intake is t=0 min, and the time of stope test is t=100 min. Both time points are indicated by dashed lines. A double asterisk (**) indicates a statistically significant difference compared to placebo across all sessions. [Figure 13] 1 is a graph showing the results of the change in subjective tension over time (minutes) on the VAS comparing placebo with Example 5. The time of formulation intake is t=0 min and the time of stope test is t=100 min. Both time points are indicated by dashed lines. A double asterisk (**) indicates a statistically significant difference compared to placebo across all sessions. [Figure 14]1 is a graph showing the results of the time course of subjective alertness (minutes) in the VAMS, comparing placebo with Example 5. The time of formulation intake is t=0 min, and the time of the stope test is t=100 min. Both time points are indicated by dashed lines. An asterisk (*) indicates a statistically significant difference compared to placebo at that time point. A double asterisk (**) indicates a statistically significant difference compared to placebo across all sessions. [Figure 15] 1 is a graph showing the results of the change in subjective fatigue sensation over time (minutes) on the VAS, comparing placebo with Example 5. The time of formulation intake is t=0 min, and the time of stope test is t=100 min. Both time points are indicated by dashed lines. A double asterisk (**) indicates a statistically significant difference compared to placebo across all sessions. DETAILED DESCRIPTION OF THE INVENTION

[0019] It is to be understood that the invention is not limited to the particular configurations, method steps, and materials disclosed herein, as the configurations, method steps, and materials may vary slightly. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the invention will be limited only by the appended claims and their equivalents.

[0020] As used herein and in the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. References to "% by weight" or "dry weight basis" refer to weight based on dry ingredients (i.e., all ingredients excluding water). References to "wet weight" refer to the weight of the formulation or composition including water. Unless otherwise specified, references to "% by weight" (or "wt %") of a formulation or composition reflect the total wet weight (i.e., including water) of the formulation or composition.

[0021] As used herein, unless otherwise specified, the term "about" modifying the amount of an ingredient in an oral formulation or used in a method of the present invention refers to variations in numerical value that may occur due, for example, to typical measuring procedures and liquid handling procedures used to prepare the actual concentrate or use the solution, inadvertent errors in these procedures, differences in the manufacture, source, or purity of the ingredients used to prepare the oral formulation or practice the method, etc. The term "about" also encompasses amounts that differ due to different equilibrium conditions for a formulation or composition resulting from a particular initial mixture. Whether modified by the term "about," the claims include equivalents of the amounts.

[0022] Oral formulation As described herein, there is provided an oral formulation comprising a combination of active ingredients, the combination comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm.

[0023] Oral formulations are designed for oral use, and thus for insertion into the user's mouth (i.e., oral cavity). As used herein, unless otherwise specified, the term "oral" in relation to a formulation refers to a formulation that is suitable for ingestion or retention anywhere in the user's oral cavity in normal use. For example, the formulation may be in the form of a liquid (i.e., in the form of a drink) that can be orally ingested by the user, or the formulation may be retained in the oral cavity.

[0024] The ranges provided herein provide preferred amounts of each component. Each of these ranges can be used alone or in combination with one or more other component ranges to provide preferred embodiments of the present invention.

[0025] Active ingredient combination The formulations disclosed herein comprise an active ingredient.

[0026] As used herein, an active substance may be a bioactive substance, which is a substance intended to achieve or enhance a physiological response. The active substance may be selected from, for example, nutritional active substances, nootropic substances, and psychoactive substances. The active substance may be naturally derived or synthetically obtained.

[0027] The active ingredient combination includes suitable active ingredients that elicit a biological response in humans or animals. As used herein, an active ingredient may be a bioactive agent, which is a substance intended to achieve or enhance a physiological response.

[0028] According to the present invention, the combination of active ingredients includes at least L-theanine, ginseng, and lemon balm.

[0029] Each active ingredient may be present in an amount suitable to elicit the desired biological response in a human animal. The inventors have discovered that a specific combination of active ingredients contained in an oral formulation provides improved relaxation benefits to the user compared to previously known formulations. The inventors have discovered that the specific combination of active ingredients of the present invention can enhance relaxation and calmness and reduce stress and anxiety. For example, the combination of active ingredients allows the user to restore mental and physical harmony after stressful situations, resulting in a short-term improvement in mood when taken by the user. The combination of active ingredients can also, in some instances, aid sleep. For example, the combination of active ingredients allows the user to restore mental and physical harmony after stressful situations, resulting in a short-term improvement in mood when taken by the user.

[0030] It has also been found that the combination of active ingredients described herein can provide a safe formulation with desirable pharmacokinetics (Tmax, Cmax, half-life), bioavailability, and metabolism.

[0031] L-theanine is a compound of L-γ-glutamylethylamide and N 5L-theanine is an amino acid analogue also known as α-ethyl-L-glutamine. The inclusion of L-theanine can enhance the relaxation effects of oral formulations. For example, the inclusion of L-theanine can help reduce anxiety and stress levels.

[0032] L-theanine can be present in any suitable amount, such as at least about 0.001%, at least about 0.01%, or at least about 0.1% by weight of the oral formulation, hi some embodiments, L-theanine can be present in an amount of no more than about 20%, no more than about 10%, or no more than about 5% by weight of the oral formulation.

[0033] L-theanine may be present in an amount of about 0.001% to about 20% by weight of the oral formulation. In some embodiments, L-theanine may be present in an amount of about 0.001% to about 10% by weight of the oral formulation.

[0034] Preferably, L-theanine may be present in an amount of about 0.01% to about 5% by weight of the oral formulation. In some embodiments, L-theanine is present in an amount of about 0.05% to about 4% by weight of the oral formulation, e.g., about 0.1% to about 3% by weight of the oral formulation, e.g., about 0.2% to about 2.5% by weight of the oral formulation, e.g., about 0.25% to about 2% by weight of the oral formulation, e.g., about 0.3% to about 1.5% by weight of the oral formulation, e.g., about 0.5% to about 1% by weight of the oral formulation.

[0035] Ginseng is the root of plants of the genus Panax, characterized by the presence of unique steroidal saponin phytochemicals (ginsenosides) and gintonin. The putative major active ingredients of ginseng include over 100 specific triterpene saponins, or "ginsenosides." Ginseng and ginseng extracts also contain a variety of other potentially bioactive compounds, including alkaloids, phytosterols, sesquiterpenes, and polyphenols. Ginseng is used as a nutritional supplement in energy drinks or herbal teas and in traditional medicine.

[0036] Ginseng may include any suitable form of ginseng, such as Panax ginseng (Korean ginseng), Panax notoginseng (Tianqi ginseng), and Panax quinquefolius (American ginseng). Ginseng may also include Ashwagandha (Withania somnifera), commonly known as Indian ginseng. Ginseng may be present in the form of ginseng extract, shredded ginseng, shredded ginseng, or powdered ginseng. Preferably, ginseng is included in the form of ginseng extract or powdered ginseng extract. Ginseng may be white ginseng, raw ginseng, or red ginseng. In some embodiments, the ginseng is red ginseng, such as red ginseng extract or powdered red ginseng extract. The inclusion of ginseng has been found to be beneficial in enhancing the cognitive effects of the composition and increasing calmness / reducing stress in users. For example, ginseng may reduce stress and blood pressure, improving cognitive function and mood. Ginseng has also traditionally been found to improve quality of life.

[0037] In particular, the combination of L-theanine and ginseng is believed to improve the relaxation effect on users and reduce stress and anxiety levels after administration.

[0038] Ginseng can be present in any suitable amount, such as at least about 0.0001% by weight, at least about 0.001% by weight, or at least about 0.01% by weight of the oral formulation. In some embodiments, ginseng can be present in an amount of about 0.0001% to about 10% by weight of the oral formulation. In some embodiments, ginseng can be present in an amount of about 0.001% to about 5% by weight of the oral formulation. In some embodiments, ginseng can be present in an amount of about 0.001% to about 3% by weight of the oral formulation. In some embodiments, ginseng can be present in an amount of about 0.01% to about 2% by weight of the oral formulation. Ginseng can be present in an amount of about 10% by weight or less, e.g., about 5% by weight or less, of the oral formulation.

[0039] In some embodiments (e.g., when the oral formulation is a liquid oral dosage form), ginseng may be present in an amount of about 0.01% to about 1.5% by weight of the oral formulation. In some embodiments (e.g., when the oral formulation is a liquid oral dosage form), ginseng is present in an amount of about 0.02% to about 1% by weight of the oral formulation, such as about 0.05% to about 0.75% by weight, e.g., about 0.1% to about 0.5% by weight.

[0040] Lemon balm, also known as Melissa officinalis, is a perennial herbaceous plant in the Lamiaceae family. Lemon balm contains a complex mixture of terpenes, terpenoids, flavonoids, polyphenols, and other molecules. Lemon balm can be in the form of leaves, stems, or roots from the lemon balm plant. In some embodiments, lemon balm is included in the form of lemon balm leaf, such as chopped, shredded, or powdered lemon balm leaf. In some embodiments, lemon balm is included in the form of lemon balm extract, such as lemon balm water extract. In some embodiments, lemon balm is included in the form of lemon balm essential oil. The inclusion of lemon balm can improve stress levels and aid sleep in users. Lemon balm has previously been found to exhibit antioxidant, anti-inflammatory, and neuroprotective properties.

[0041] Lemon balm can be present in any suitable amount, such as at least about 0.001% by weight, at least 0.01% by weight, or at least 0.1% by weight of the oral formulation. In some embodiments, lemon balm can be present in an amount of about 0.001% to about 10% by weight of the oral formulation. In some embodiments, lemon balm can be present in an amount of about 0.001% to about 5% by weight of the oral formulation. In some embodiments, lemon balm can be present in an amount of about 0.001% to about 3% by weight of the oral formulation. Lemon balm can be present in an amount of about 10% by weight or less, e.g., about 5% by weight or less, of the oral formulation.

[0042] Preferably, lemon balm may be present in an amount of about 0.01% to about 3% by weight of the oral formulation, hi some embodiments, lemon balm is present in an amount of about 0.05% to about 2% by weight, such as about 0.1% to about 1% by weight, such as about 0.1% to about 0.75% by weight, for example, about 0.1% to 0.5% by weight.

[0043] In some embodiments, the amount of lemon balm may be at least 0.1% by weight of the oral formulation, i.e., the oral formulation may contain at least about 1000 ppm of lemon balm. In some embodiments, the amount of lemon balm is about 0.1% to about 0.2% by weight of the oral formulation (i.e., 1000 ppm to 2000 ppm). In some embodiments, the amount of lemon balm may be about 0.1% to about 0.15% by weight of the oral formulation, or about 1000 ppm to about 1500 ppm.

[0044] In addition to L-theanine, ginseng, and lemon balm, the active ingredient combination may include one or more additional active ingredients. The additional active ingredient may be any suitable active ingredient that aids relaxation or calmness, and may be selected from, for example, nutritional active ingredients, nootropic ingredients, and psychoactive ingredients. The additional active ingredient may be naturally occurring or synthetically obtained.

[0045] Non-limiting examples of additional active ingredients include those in the categories of botanical ingredients, amino acids, and / or nutritional active ingredients, and pharmaceutical ingredients (e.g., vitamins such as vitamins A, B3, B6, B12, and C and / or cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD)).

[0046] Additional active ingredients may include, for example, taurine, theine, vitamins such as B vitamins (e.g., B2, B3, B6, B9, and / or B12), vitamin A, vitamin D, vitamin E, vitamin K, or vitamin C, melatonin, gamma aminobutyric acid (GABA), cannabinoids, or components, derivatives, or combinations thereof.

[0047] In some embodiments, the one or more additional active ingredients are selected from botanicals (e.g., lavender, peppermint, chamomile, basil, rosemary, ginger, maca, and herbal tea ingredients), amino acids (e.g., taurine, phenylalanine, tyrosine, GABA, and tryptophan), cannabinoids, and / or nutritional or pharmaceutical active ingredients (e.g., vitamins such as B vitamins and / or vitamin C).

[0048] In some preferred embodiments, the combination of active ingredients further includes vitamin C (ascorbic acid). Vitamin C acts as an antioxidant, helping to protect cells from damage caused by free radicals. The body also utilizes vitamin C for the production of collagen, a protein that can aid in wound healing. Additionally, vitamin C promotes iron absorption from plant-based foods and helps the immune system function properly, protecting the body from disease.

[0049] The inclusion of vitamin C may reduce tiredness and fatigue.

[0050] Vitamin C may be present in an amount of about 0.001% to about 10% by weight of the oral formulation, such as about 0.01% to about 5% by weight, for example, about 0.05% to about 2.5% by weight, for example, about 0.1% to 2% by weight, for example, about 0.5% to 1% by weight. If present, vitamin C may be included in an amount preferably of about 0.01% to about 5% by weight, more preferably about 0.1% to about 5% by weight of the oral formulation.

[0051] In some preferred embodiments, the combination of active ingredients further comprises chamomile. Chamomile (Matricaria recuita) is a flowering plant of the Asteraceae family. It is native to Europe and Western Asia and is now found throughout the world. There are two different species of chamomile plants: German chamomile and Roman chamomile. German chamomile is generally considered to be the more effective variety and the most widely used type for medical purposes. Various types of bioactive components are present in chamomile, such as flavanols (apigenin, luteolin, quercetin), coumarins, and terpenoids. Research has shown that chamomile is beneficial in reducing anxiety.

[0052] Chamomile may be in the form of a chamomile extract. Chamomile (e.g., chamomile extract) may be present in an amount of about 0.0001% to about 5% by weight of the oral formulation, for example, about 0.0001% to about 3% by weight, for example, about 0.0001% to about 1% by weight. Chamomile (e.g., chamomile extract) may be present in an amount of about 0.001% to about 5% by weight of the oral formulation, for example, about 0.01% to about 2.5% by weight, for example, about 0.02% to about 1% by weight, for example, about 0.03% to about 0.5% by weight. When present, chamomile (e.g., chamomile extract) may preferably be present in an amount of about 0.01% to about 3% by weight of the oral formulation.

[0053] In some embodiments, the active ingredient combination consists essentially of L-theanine, ginseng, lemon balm, and chamomile extract. In a preferred embodiment, the active ingredient combination consists of L-theanine, ginseng, lemon balm, and chamomile extract.

[0054] In another preferred embodiment, the combination of active ingredients further comprises L-tryptophan. L-tryptophan may be present in an amount of about 0.001% to about 10% by weight of the oral formulation, e.g., about 0.01% to about 5% by weight, e.g., about 0.05% to about 2.5% by weight, e.g., about 0.1% to 1% by weight, e.g., about 0.1% to 0.5% by weight. When present, L-tryptophan is preferably present in an amount of about 0.05% to about 3% by weight of the oral formulation.

[0055] In some preferred embodiments, the combination of active ingredients includes L-theanine, ginseng, lemon balm, and vitamin C.

[0056] In some embodiments, the combination of active ingredients includes L-theanine, ginseng, lemon balm, and chamomile extract. In some embodiments, the combination of active ingredients includes L-theanine, ginseng, lemon balm, vitamin C, and chamomile extract.

[0057] In some embodiments, the combination of active ingredients includes L-theanine, ginseng, lemon balm, and L-tryptophan. In some embodiments, the combination of active ingredients includes L-theanine, ginseng, lemon balm, vitamin C, and L-tryptophan.

[0058] In some embodiments, the active ingredient combination includes (i) about 0.001% to about 10% L-theanine by weight of the oral formulation, (ii) about 0.001% to about 5% ginseng by weight of the oral formulation, and (iii) about 0.001% to about 5% lemon balm by weight of the oral formulation. In some embodiments, the active ingredient combination includes (i) about 0.01% to about 5% L-theanine by weight of the oral formulation, (ii) about 0.001% to about 3% ginseng by weight of the oral formulation, and (iii) about 0.001% to about 3% lemon balm by weight of the oral formulation. In some embodiments, the active ingredient combination includes: (i) about 0.1% to about 2.5% L-theanine by weight of the oral formulation; (ii) about 0.01% to about 1% ginseng by weight of the oral formulation; and (iii) about 0.1% to about 1% lemon balm by weight of the oral formulation.

[0059] In any of these embodiments, the active ingredient combination may further include vitamin C in an amount of about 0.01% to about 5% by weight of the oral formulation. In any of these embodiments, the active ingredient combination may further include chamomile (e.g., chamomile extract) in an amount of about 0.01% to about 3% by weight of the oral formulation. In any of these embodiments, the active ingredient combination may further include L-tryptophan in an amount of about 0.05% to about 3%.

[0060] In some embodiments, the active ingredient combination includes (i) about 0.01% to about 5% L-theanine by weight of the oral formulation, (ii) about 0.001% to about 3% ginseng by weight of the oral formulation, (iii) about 0.001% to about 3% lemon balm by weight of the oral formulation, and (iv) about 0.01% to about 5% vitamin C by weight of the oral formulation. In some embodiments, the active ingredient combination includes (i) about 0.1% to about 2.5% L-theanine by weight of the oral formulation, (ii) about 0.01% to about 1% ginseng by weight of the oral formulation, (iii) about 0.1% to about 1% lemon balm by weight of the oral formulation, and (iv) about 0.1% to about 2.5% vitamin C by weight of the oral formulation.

[0061] In some embodiments, the active ingredient combination includes (i) L-theanine at about 0.01% to about 5% by weight of the oral formulation; (ii) ginseng at about 0.001% to about 3% by weight of the oral formulation; (iii) lemon balm at about 0.001% to about 3% by weight of the oral formulation; (v) chamomile (e.g., chamomile extract) at about 0.001% to about 3% by weight of the oral formulation; and optionally (iv) vitamin C at about 0.01% to about 5% by weight of the oral formulation. In some embodiments, the active ingredient combination includes: (i) L-theanine at about 0.1% to about 2.5% by weight of the oral formulation; (ii) ginseng at about 0.01% to about 1% by weight of the oral formulation; (iii) lemon balm at about 0.1% to about 1% by weight of the oral formulation; (v) chamomile (e.g., chamomile extract) at about 0.01% to about 3% by weight of the oral formulation; and, optionally, (iv) vitamin C at about 0.1% to about 2.5% by weight of the oral formulation. In some embodiments, the active ingredient combination includes: (i) L-theanine at about 0.1% to about 2.5% by weight of the oral formulation; (ii) ginseng at about 0.01% to about 1% by weight of the oral formulation; (iii) lemon balm at about 0.1% to about 1% by weight of the oral formulation; (v) chamomile (e.g., chamomile extract) at about 0.0001% to about 1% by weight of the oral formulation; and optionally (iv) vitamin C at about 0.1% to about 2.5% by weight of the oral formulation.

[0062] In some embodiments, the active ingredient combination includes (i) L-theanine at about 0.01% to about 5% by weight of the oral formulation; (ii) ginseng at about 0.001% to about 3% by weight of the oral formulation; (iii) lemon balm at about 0.001% to about 3% by weight of the oral formulation; (v) L-tryptophan at about 0.01% to about 5% by weight of the oral formulation; and optionally (iv) vitamin C at about 0.01% to about 5% by weight of the oral formulation. In some embodiments, the active ingredient combination includes (i) from about 0.1% to about 2.5% L-theanine by weight of the oral formulation; (ii) from about 0.01% to about 1% ginseng by weight of the oral formulation; (iii) from about 0.1% to about 1% lemon balm by weight of the oral formulation; (v) from about 0.05% to about 3% L-tryptophan by weight of the oral formulation; and optionally (iv) from about 0.1% to about 2.5% vitamin C by weight of the oral formulation.

[0063] In some embodiments, the active ingredient combination includes (i) from about 0.1% to about 2.5% L-theanine by weight of the oral formulation; (ii) from about 0.01% to about 1% ginseng by weight of the oral formulation; (iii) from about 0.1% to about 1% lemon balm by weight of the oral formulation; (v) from about 0.01% to about 0.5% L-tryptophan by weight of the oral formulation; and optionally (iv) from about 0.1% to about 2.5% vitamin C by weight of the oral formulation.

[0064] The inventors have found that the above amounts of active ingredient provide a formulation that provides a beneficial effect of relaxation / stress reduction to the user while also providing a highly safe formulation. The amount of active ingredient can be adjusted so that the formulation is highly effective while ensuring safety for the user and avoiding overdosing on the active ingredient.

[0065] Other suitable additional active ingredients are described below.

[0066] In some embodiments, the combination of active ingredients further comprises a botanical active ingredient. As used herein, the terms "botanical ingredient" or "botanical material" refer to any plant or fungal-derived material, including plant material in its natural form and plant material derived from natural plant material, such as an extract or isolate of the plant material, or processed plant material (e.g., plant material that has been subjected to heat treatment, fermentation, bleaching, or other treatment processes that can alter the physical and / or chemical properties of the material). For purposes of this disclosure, "botanical material" includes, but is not limited to, "herbal material," which refers to seed-producing plants that do not develop permanent woody tissue and are typically valued for their pharmacological or organoleptic properties (e.g., tea or herbal tea). Botanical materials useful in this disclosure can include, but are not limited to, any of the compounds and materials (including mixtures thereof) described herein. Certain botanical materials of this type are sometimes referred to as supplements, dietary supplements, "phytochemicals," or "functional foods." Certain botanical materials, either as plant materials or extracts thereof, are used in traditional herbal medicine and are further described herein.Non-limiting examples of botanical or plant-derived materials include ashwagandha, Bacopa monniera, baobab, basil, Centella asiatica, Bupleurum Root, chamomile, cherry blossom, chlorophyll, cinnamon, citrus fruits, clove, cocoa, cordyceps, curcumin, damiana, Dorstenia arifolia, Dorstenia odorata, essential oils, eucalyptus, fennel, Galphimia glauca, ginger, Ginkgo biloba, ginseng (e.g., ginseng), Grifonia simplicifolia, guarana, cannabis, hemp, hops, jasmine, Kaempferia parviflora, black ginger), kava, lavender, lemon balm, lemongrass, licorice, lutein, maca, matcha powder, pepper (Nardostachys chinensis), sweet violet (Viola odorata) oil extract, peppermint, quercetin, resveratrol, tema (Rhizoma gastrodiae), rhodiola (Rhodiola), rooibos, rose essential oil, rosemary, kana (Sceletium tortuosum), schisandra (Schisandra), skullcap, spearmint extract, spikenard, terpenes, herbal tea ingredients, turmeric, damiana (Turnera aphrodisiaca), valerian, white mulberry, echinacea, and yerba mate.

[0067] The active ingredient combination may include B vitamins (e.g., one or more of vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, preferably vitamin B6 and vitamin B12). When present, the B vitamins (such as vitamin B6 and / or vitamin B12) may be present in an amount of about 0.001% to about 5% by weight of the oral formulation, preferably about 0.01% to about 2.5% by weight of the oral formulation.

[0068] The combination of active ingredients may further comprise a vitamin selected from vitamin A, vitamin D, vitamin E, and vitamin K, or a mixture thereof.

[0069] The combination of active ingredients may include melatonin, which, if present, may be present in an amount of from about 0.001% to about 5% by weight of the oral formulation.

[0070] The active ingredient combination may further include an amino acid, such as an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, gamma-aminobutyric acid (GABA), taurine (2-aminoethanesulfonic acid), hydroxyproline, and beta-alanine. In some embodiments, the active ingredient combination includes GABA.

[0071] In some embodiments, the combination of active ingredients includes a cannabinoid. The cannabinoid may be a derivative or extract of cannabis. Cannabinoids are a group of natural or synthetic chemical compounds that act on intracellular cannabinoid receptors (i.e., CB1 and CB2) to inhibit the release of neurotransmitters in the brain. Cannabinoids are cyclic molecules that exhibit certain properties, such as the ability to easily cross the blood-brain barrier. Cannabinoids may be naturally occurring in plants such as cannabis (phytocannabinoids), present in animals (endocannabinoids), or artificially produced (synthetic cannabinoids). Cannabis species exhibit at least 85 different phytocannabinoids, which can be subdivided into cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabinol, and cannabinodiol, as well as other cannabinoids.In some embodiments, the cannabinoid is selected from the group consisting of cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN), and cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), cannabinol propyl variants (Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabimolic acid (THCA), tetrahydrocannabivarinic acid (THCV A), and mixtures thereof. In some embodiments, the cannabinoid is tetrahydrocannabinol (THC) or comprises at least tetrahydrocannabinol (THC). In some embodiments, the cannabinoid is cannabidiol (CBD) or comprises at least cannabidiol (CBD).

[0072] In some embodiments, the active ingredient combination comprises a cannabinoid (such as cannabidiol) in an amount ranging from at least about 0.001% by weight of the oral formulation, e.g., from about 0.001% to about 10% by weight of the oral formulation, e.g., from about 0.01% to about 5% by weight, e.g., from about 0.1% to about 2.5% by weight, e.g., from 0.5% to about 1% by weight.

[0073] In some embodiments, the active ingredient combination includes magnesium glycinate, which, when present, may be included in an amount of about 0.1% to about 10% by weight of the oral formulation, such as about 0.5% to about 5% by weight, or about 0.5% to about 1% by weight.

[0074] For the avoidance of doubt, combinations of the above final formulation amounts are expressly contemplated by this disclosure, as are any of the ranges disclosed herein.

[0075] Active ingredient ratio The ratio of active ingredients in the oral formulation may be selected to enhance the relaxation effect of the oral formulation on the recipient.

[0076] In some embodiments, the L-theanine and ginseng are present in a weight ratio of about 250:1 to about 1:10, such as about 200:1 to about 1:5.

[0077] In some embodiments (e.g., when the oral formulation is in liquid or beverage form), the L-theanine and ginseng are present in a weight ratio of about 50:1 to about 1:5, such as about 50:1 to about 1:2, e.g., about 25:1 to about 1:1. Preferably (e.g., in embodiments when the oral formulation is in liquid or beverage form), the L-theanine and ginseng are present in a weight ratio of about 20:1 to about 1:2, such as about 15:1 to about 1:2, e.g., about 10:1 to about 1:1, e.g., about 5:1 to about 1:1. In some embodiments (e.g., in embodiments when the oral formulation is in liquid or beverage form), the L-theanine and ginseng are present in a weight ratio of about 10:1 to about 1:1.

[0078] The inventors have found that the amount of lemon balm included in the formulation can have a desirable effect on reducing stress and anxiety levels. In some embodiments, the L-theanine and lemon balm are present in a weight ratio of about 1:5 to about 50:1, e.g., about 1:2 to about 25:1. Preferably, the L-theanine and lemon balm are present in a weight ratio of about 1:1 to about 20:1, e.g., about 2:1 to about 15:1, e.g., about 2.5:1 to about 10:1, e.g., about 2.5:1 to about 5:1. Preferably, the L-theanine and lemon balm are present in a weight ratio of about 1:1 to about 10:1.

[0079] In some embodiments (e.g., when the oral formulation is in liquid or beverage form), the ginseng and lemon balm are present in a weight ratio of about 10:1 to about 1:50, such as about 10:1 to about 1:10, e.g., about 2:1 to about 1:2. In some embodiments, the ginseng and lemon balm are present in a weight ratio of about 10:1 to about 1:1, e.g., about 5:1 to about 1:1. Preferably (e.g., in embodiments where the oral formulation is in liquid or beverage form), the ginseng and lemon balm are present in a weight ratio of about 2:1 to about 1:1.

[0080] When present, vitamin C may be included such that the weight ratio of vitamin C to L-theanine is about 10:1 to about 1:10, e.g., about 5:1 to about 1:5. In some preferred embodiments, the weight ratio of vitamin C to L-theanine is about 2:1 to about 1:2. When present, vitamin C may be included such that the weight ratio of vitamin C to ginseng is about 1:1 to about 100:1, e.g., about 2:1 to about 50:1. In some preferred embodiments, the weight ratio of vitamin C to ginseng is about 2:1 to about 10:1. When present, vitamin C may be included such that the weight ratio of vitamin C to lemon balm is about 1:1 to about 10:1, e.g., about 1:1 to about 5:1. In some preferred embodiments, the weight ratio of vitamin C to lemon balm is about 1:1 to about 5:1.

[0081] When present, chamomile extract may be included such that the weight ratio of L-theanine to chamomile extract is about 5:1 to about 20:1.When present, chamomile extract may be included such that the weight ratio of ginseng to chamomile extract is about 1:1 to about 10:1.When present, chamomile extract may be included such that the weight ratio of lemon balm to chamomile extract is about 1:1 to about 5:1.

[0082] In some embodiments, the oral formulation comprises: A combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm, The weight ratio of L-theanine to ginseng is about 50:1 to about 1:2. The weight ratio of L-theanine to lemon balm is about 1:1 to about 20:1, It contains a combination of active ingredients, with a weight ratio of ginseng to lemon balm of about 10:1 to about 1:50.

[0083] In some embodiments, the oral formulation comprises: A combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm, The weight ratio of L-theanine to ginseng is about 10:1 to about 1:1. The weight ratio of L-theanine to lemon balm is about 10:1 to about 1:1, It contains a combination of active ingredients, with a weight ratio of ginseng and lemon balm of about 5:1 to about 1:1.

[0084] In some embodiments, the oral formulation comprises: A combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm, The weight ratio of L-theanine to ginseng is about 10:1 to about 1:1. The weight ratio of L-theanine to lemon balm is about 10:1 to about 1:1, It contains a combination of active ingredients, with a weight ratio of ginseng to lemon balm of about 5:1 to about 1:2.

[0085] In some embodiments, the oral formulation comprises: 1. A liquid oral dosage form comprising a combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm; The weight ratio of L-theanine to ginseng is about 10:1 to about 1:1. The weight ratio of L-theanine to lemon balm is about 10:1 to about 1:1, A liquid oral dosage form containing a combination of active ingredients, wherein the weight ratio of ginseng to lemon balm is about 5:1 to about 1:1.

[0086] In some embodiments, the oral formulation comprises: A combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; (iii) lemon balm; and (iv) vitamin C; It contains a combination of active ingredients in which the weight ratio of vitamin C to L-theanine is about 10:1 to about 1:10.

[0087] In some embodiments, the oral formulation comprises: A combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; (iii) lemon balm; and (iv) vitamin C; The weight ratio of L-theanine to ginseng is about 10:1 to about 1:1. The weight ratio of L-theanine to lemon balm is about 10:1 to about 1:1, The weight ratio of ginseng to lemon balm is about 5:1 to about 1:1. It contains a combination of active ingredients in which the weight ratio of vitamin C to L-theanine is about 10:1 to about 1:10.

[0088] In each of the above embodiments, chamomile extract may be included, and if present, the chamomile extract may be included such that the weight ratio of L-theanine to chamomile extract is about 5:1 to about 20:1, the weight ratio of ginseng to chamomile extract is about 1:1 to about 10:1, and / or the weight ratio of lemon balm to chamomile extract is about 1:1 to about 5:1. Preferably, the weight ratio of L-theanine to chamomile extract is about 5:1 to about 20:1, and the weight ratio of ginseng to chamomile extract is about 1:1 to about 10:1.

[0089] additives Depending on the type of oral formulation being processed, the formulation may contain one or more additional ingredients in addition to the combination of active ingredients. For example, the oral formulation may further contain an additive selected from the group consisting of flavorings, sweeteners, buffering agents, acidifying agents, thickeners, fillers, binders, humectants, preservatives, salts, coloring agents, oral care additives, disintegration aids, antioxidants, water, or mixtures thereof. In some embodiments, the oral formulation further contains one or more additives selected from the group consisting of flavorings, sweeteners, acidifying agents, thickeners, fillers, binders, humectants, preservatives, and mixtures thereof.

[0090] In some embodiments, the oral formulation is preservative-free, ie, there are no preservatives present in the oral formulation.

[0091] Filler Depending on the formulation, oral formulations may contain fillers, which can serve multiple functions, for example, improving certain sensory properties such as texture and mouthfeel, or improving the cohesiveness or compressibility of the formulation.

[0092] In some embodiments, the filler is a porous granular material and is cellulosic. For example, the filler or excipient may be a non-tobacco plant material or a derivative thereof, including a cellulosic material derived from the materials described below. Examples of cellulosic non-tobacco plant materials include grains (e.g., corn, oats, barley, rye, buckwheat, etc.), sugar beet (e.g., FIBREX® brand filler available from International Fiber Corporation), bran fiber, and mixtures thereof. In some embodiments, the filler is a cellulosic material selected from the group consisting of corn fiber, oat fiber, barley fiber, rye fiber, buckwheat fiber, sugar beet fiber, bran fiber, bamboo fiber, wood pulp fiber, cotton fiber, citrus pulp fiber, grass fiber, willow fiber, poplar fiber, cocoa fiber, derivatives thereof, and combinations thereof. In some embodiments, the filler is a cellulosic material selected from the group consisting of sugar beet fiber, wood pulp fiber, bamboo fiber, derivatives thereof, and combinations thereof.

[0093] In some embodiments, the filler is derived from wood pulp fibers. One particularly suitable filler for use in the formulations described herein is microcrystalline cellulose (MCC). MCC can be synthetic, semi-synthetic, or derived entirely from natural cellulose. MCC can be selected from the group consisting of AVICEL® PH-100, PH-101, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-301, and PH-302 grades, VIVACEL® 101, 102, 12, and 20 grades, and EMOCEL® 50M and 90M grades, and mixtures thereof.

[0094] In some embodiments, the filler is a non-tobacco plant material or a derivative thereof. Non-limiting examples of derivatives of non-tobacco plant materials include starch (e.g., from potato, wheat, rice, corn), natural cellulose, and modified cellulosic materials. Additional examples of fillers that can be used include maltodextrin, dextrose, calcium carbonate, calcium phosphate, lactose, mannitol, xylitol, and sorbitol. Combinations of these fillers can also be used.

[0095] As used herein, "starch" can refer to pure starch, modified starch, or starch derivatives derived from any source. Starch, typically in granular form, is present in almost all green plants in various plant tissues and organs (e.g., seeds, leaves, rhizomes, roots, tubers, shoots, fruits, grains, and stems). Starch composition, granule shape, and particle size can vary. Starches derived from different sources often have different chemical and physical properties. A particular starch can be selected for inclusion in a formulation based on the ability of the starch-based material to impart specific sensory properties to the formulation. Starch derived from a variety of sources can be used. For example, major sources of starch include cereals (e.g., rice, wheat, and corn) and root vegetables (e.g., potato and cassava). Other examples of starch sources include acorn, arrowroot, arracacha, banana, barley, beans (e.g., broad beans, lentils, mung beans, peas, chickpeas), breadfruit, buckwheat, canna, chestnut, taro, potato, kudzu, malanga, millet, oats, oka, Polynesian arrowroot, sago, sorghum, sweet potato, quinoa, rye, tapioca, taro, tobacco, water chestnut, and yam. Certain starches are modified starches. Modified starches have undergone one or more structural modifications, generally designed to alter their high-temperature properties. Some starches have been developed through genetic engineering and are considered "modified" starches. Other starches are modified after they are obtained. For example, modified starches can be starches that have undergone chemical reactions such as esterification, etherification, oxidation, acid-catalyzed or base-catalyzed depolymerization (thinning), bleaching, transglycosylation and depolymerization (e.g., dextrinization in the presence of a catalyst), cross-linking, enzyme treatment, acetylation, hydroxypropylation, and / or partial hydrolysis. Other starches are modified by pregelatinization, dextrinization, and / or thermal treatments such as cold water swelling.Specific modified starches include phosphated starch, glycerol cross-linked starch, phosphate cross-linked starch esterified with sodium trimetaphosphate, phosphate monoesterified phosphate cross-linked starch, acetylated phosphate cross-linked starch, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated adipate cross-linked starch, acetylated glycerol cross-linked starch, hydroxypropyl starch, hydroxypropylglycerol cross-linked starch, and starch sodium octenyl succinate.

[0096] Other suitable bulking agents include sugar alcohols. Sugar alcohols are polyols derived from monosaccharides or disaccharides, either partially or fully hydrogenated. Sugar alcohols have, for example, from about 4 to about 20 carbon atoms and include erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof. In some embodiments, the bulking agent, if present, may be selected from the group consisting of isomalt, maltitol, and mixtures thereof.

[0097] water The moisture content (eg, water content) of an oral formulation can be varied depending on the desired properties prior to use by the recipient of the formulation.

[0098] Typically, for solid oral dosage forms, prior to insertion into the user's oral cavity, the moisture content is less than about 60% by weight, generally about 1 to about 60% by weight, e.g., about 5 to about 55% by weight, about 10 to about 50% by weight, about 20 to about 45% by weight, or about 25 to about 40% by weight of the oral dosage form, including at least about 5% by weight, at least about 10% by weight, at least about 15% by weight, and at least about 20% by weight of the oral dosage form.

[0099] In the case of liquid oral formulations, the water content may be higher, for example, at least about 50% by weight of the oral formulation, for example, at least about 60% by weight, for example, at least about 75% by weight. Preferably, the water content of the liquid oral formulation may be at least about 90% by weight of the oral formulation. Preferably, the water content of the liquid oral formulation may be about 60% to about 99.5% by weight of the oral formulation, for example, about 75% to about 99% by weight, for example, about 80% to about 98% by weight.

[0100] fragrance As used herein, the term "flavoring agent" (or "flavor" or "flavorant") refers to an ingredient that can be used, where local regulations permit, to evoke a desired taste, aroma, or other somatosensory sensation in a formulation intended for adult consumption. Examples of somatosensory sensations that can be altered by flavorings include taste, mouthfeel, moistness, cool / warm sensation, and / or scent / aroma. Flavorings can be natural or synthetic, and the flavor characteristics imparted by flavorings can be described as, but are not limited to, cool, sweet, herbal, confectionery, floral, fruity, or spicy.

[0101] Flavoring agents may be any naturally occurring flavoring material, botanical material, extracts of botanical material, synthetically derived material, or combinations thereof (e.g., tobacco, cannabis, licorice, hydrangea, eugenol, magnolia leaf, chamomile, fenugreek, clove, maple, matcha powder, menthol, Japanese mint, aniseed, cinnamon, turmeric, Indian spices, Asian spices, herbs, wintergreen, cherry, berry, red berry, cranberry, raspberry, strawberry, peach, apple, orange, mango, pineapple, etc.). Apple, clementine, lemon, lime, tropical fruits, papaya, rhubarb, grapes, durian, dragon fruit, cucumber, blueberry, mulberry, citrus fruits, Drambuie, bourbon, scotch, whiskey, gin, tequila, rum, spearmint, peppermint, lavender, aloe vera, cardamom, coconut, celery, cascarilla, nutmeg, sandalwood, bergamot, geranium, khat, eggplant, betel nut, shisha, pine, honey essence, rose oil, vanilla, lemon oil, orange oil, orange blossom, cherry blossom, cassia, Caraway, cognac, jasmine, ylang-ylang, sage, fennel, wasabi, bell pepper, ginger, coriander, coffee, hemp, peppermint oil from any species of the genus Mentha, eucalyptus, star anise, cocoa, lemongrass, rooibos, flax, ginkgo, hazel, hibiscus, bay leaf, yerba mate, orange peel, rose, tea such as green tea or black tea, thyme, juniper, elderflower, basil, bay leaf, cumin, oregano, paprika, rosemary, saffron, lemon peel, mint, shiso, curcuma, cilantro, myrtle squid, blackcurrant, valerian, pimento, mace, damiane, marjoram, olive, lemon balm, lemon basil, chives, Calvi, verbena, tarragon, limonene, thymol, camphene), flavor enhancers, bitter taste receptor antagonists, sensory receptor activators or stimulants, sugars and / or sugar substitutes (e.g., honey, sucralose, acesulfame potassium, aspartame, saccharin, cyclamate, lactose, sucrose, glucose, fructose, sorbitol, or mannitol), as well as charcoal, chlorophyll, minerals, botanical ingredients,or other additives such as breath fresheners. The flavoring agent may be an imitation, synthetic, or natural ingredient, or a combination thereof. The flavoring agent may be in any suitable form, for example, a liquid such as an oil, a solid such as a powder, or a gas.

[0102] In some embodiments, the flavoring agent comprises a natural flavoring agent, such as berry (e.g., raspberry, blueberry, or strawberry), honey, citrus (e.g., lemon, bergamot, orange, or lime), or other botanical source.

[0103] In some embodiments, the flavoring agent comprises menthol, spearmint, and / or peppermint. In some embodiments, the flavoring agent comprises cucumber, blueberry, citrus, and / or red berry flavor components. In some embodiments, the flavoring agent comprises eugenol. In some embodiments, the flavoring agent comprises flavor components extracted from tobacco. In some embodiments, the flavoring agent comprises flavor components extracted from cannabis.

[0104] In some embodiments, fragrances may include sensuous ingredients intended to produce somatosensory sensations, typically chemically induced and perceived by stimulating the fifth cranial nerve (trigeminal nerve), in addition to or instead of the nerves involved in aroma or taste, and may include ingredients that produce a warming effect, a cooling effect, a tingling sensation, or a numbing sensation. A suitable warming ingredient may be, but is not limited to, vanillyl ethyl ether, and a suitable cooling ingredient may be, but is not limited to, eucalyptol, WS-3.

[0105] In some embodiments, the fragrance may include a terpene. In some embodiments, the fragrance may include a monoterpene, and / or a diterpene, and / or a sesquiterpene. In some embodiments, the fragrance may include a monoterpene. In some embodiments, the terpene is selected from pinene (alpha and beta), geraniol, linalool, limonene, carvone, eucalyptol, menthone, isomenthone, piperitone, myrcene, beta-bourbonene, germacrene, thymol, citral, eugenol, and mixtures thereof. In some embodiments, the fragrance is selected from the group consisting of geraniol, citronellol, nerol, maltol, ethyl maltol, fenchol, homofuraneol, furaneol, norfuraneol, 1-octen-3-ol, borneol, linalool, farnesol, hydroxycyclonerol, 3,7-dimethyloctanol, myrcenol, lavandulol, nerolidol, terpineol, alpha terpineol, menthol, thymol, carvacrol, myrtenol, carveol, san The hydroxybenzoate is selected from the group consisting of talol, piperitol, perillyl alcohol, patchouli alcohol, hexanol, 1-hexanol, 3-cis-hexanol, cis-3-hexen-1-ol, phenylethanol, eugenol, sesamol, sotolon, maple furanone, methyl anthranilate, guaiacol, raspberry ketone, 2-methoxy-4-vinylphenol, 4-ethylguaiacol, benzyl alcohol, homofuranol, vanillin, ethyl vanillin, and combinations thereof.In some embodiments, the fragrance is selected from the group consisting of geraniol, citronellol, nerol, maltol, ethyl maltol, fenchol, homofuraneol, furaneol, norfuraneol, 1-octen-3-ol, borneol, linalool, farnesol, hydroxycyclonerol, 3,7-dimethyloctanol, myrcenol, lavandulol, nerolidol, terpineol, alpha terpineol, menthol, thymol, carvacrol, myrtenol, carveol, santalol, piperitol, perillyl alcohol, patchouli alcohol, hexanol, 1-hexanol, 3-cis-hexanol, cis-3-hexen-1-ol, phenylethanol, eugenol, sesamol, sotolon, maple furanone, methyl anthranilate, guaiacol, raspberry ketone, 2-methoxy-4-vinylphenol, 4-ethylguaiacol, benzyl alcohol, homofuranol, and combinations thereof.

[0106] When present, flavoring agents may be included in the oral formulation in an amount of up to about 10% by weight of the oral formulation, such as up to about 5% by weight, e.g., up to about 1% by weight. In some embodiments, flavoring agents are present in an amount of about 0.01% to about 5% by weight, preferably about 0.1% to about 2.5% by weight of the oral formulation, and more preferably about 0.25% to about 1% by weight of the oral formulation.

[0107] Binder In some embodiments, the oral dosage form may further comprise at least one binder. A binder (or combination of binders) may be used in the dosage form in certain embodiments in an amount sufficient to impart desired physical properties and physical integrity to the dosage form.

[0108] The binder can be organic or inorganic, or a combination thereof. Representative binders include cellulose derivatives, povidone, sodium alginate, starch-based binders, pectin, carrageenan, pullulan, zein, and the like, and combinations thereof. The amount of binder used in the formulation can vary but may be up to about 30% by weight, with certain embodiments being characterized by a binder content of at least about 0.1% by weight, e.g., from about 1% to about 30% by weight, or from about 1% to about 10% by weight, based on the total weight of the oral formulation.

[0109] In some embodiments, the binder comprises pectin. Pectin is a natural polymer that is an acidic heteropolysaccharide (a polysaccharide composed of multiple monosaccharide units) related to carbohydrates. Unlike common carbohydrates, pectin contains a carboxylic acid group (or the corresponding methyl ester or carboxamide group) at the C-6 position instead of a hydroxymethyl group. The main subunit is known as galacturonic acid, which can copolymerize with L-rhamnose. Other sugars are present as side-chain substituents. Pectin acts as a thickening and gelling agent. Pectin isolated from raw materials, such as apple pomace, citrus peel, sugar beet waste from the sugar processing process, sunflower flower discs discarded after seed harvesting, mango residue, and other commercially available pectins, can be used. In combination with certain sugars, under acidic conditions (e.g., pH of about 2.5 to about 5) or in the presence of gelling agents (calcium or other divalent alkaline earth elements), pectin can impart a gel-like or gummy consistency to the formulations disclosed herein. In some embodiments, the binder comprises low-methoxy pectin. Suitable low-methoxy pectins include, for example, "GENU® pectin type LM-104 AS" available from CP Kelco, Atlanta, GA, USA. In some embodiments, the binder comprises low-methoxy pectin in combination with a gelling agent. In some embodiments, the gelling agent comprises calcium ions, such as, but not limited to, calcium diphosphate. In some embodiments, the binder comprises high-methoxy pectin in combination with an organic acid, as described herein below. In some embodiments, the binder comprises high-methoxy pectin in combination with citric acid.

[0110] When present, the pectin-based binder is typically present in an amount of up to about 3% by weight, e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, or about 3% by weight, based on the total weight of the oral dosage form.

[0111] In some embodiments, the binder comprises a cellulose derivative. In certain embodiments, a cellulose derivative is a cellulose ether (including a carboxyalkyl ether), which refers to a cellulose polymer in which the hydrogen atoms of one or more hydroxyl groups in the cellulose structure have been replaced with an alkyl group, a hydroxyalkyl group, or an aryl group. Non-limiting examples of such cellulose derivatives include methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, and carboxymethylcellulose (CMC). In some embodiments, the cellulose derivative is or includes HPC. In some embodiments, the cellulose derivative is a combination of HPC and HPMC. In some embodiments, the oral formulation comprises about 1% to about 10% by weight of the cellulose derivative (e.g., HPC), and in certain embodiments, about 1% to about 5% by weight of the cellulose derivative (e.g., HPC) based on the weight of the formulation.

[0112] In certain embodiments, the binder comprises a gum, such as a natural gum. As used herein, natural gum refers to a naturally occurring polysaccharide material that has binding properties and is also useful as a thickening or gelling agent. Representative natural gums derived from plants, which are typically somewhat water-soluble, include xanthan gum, guar gum, gum arabic, gum ghatti, gum tragacanth, gum karaya, locust bean gum, gellan gum, and combinations thereof. When present, the natural gum binder material may be present in an amount of up to about 5% by weight, e.g., from about 0.1% by weight, from about 0.2% by weight, from about 0.3% by weight, from about 0.4% by weight, from about 0.5% by weight, from about 0.6% by weight, from about 0.7% by weight, from about 0.8% by weight, from about 0.9% by weight, from about 1% by weight to about 2% by weight, from about 3% by weight, from about 4% by weight, or from about 5% by weight, based on the total weight of the formulation.

[0113] Wetting agent In some embodiments, the oral formulation comprises at least one humectant. Examples of suitable humectants that may be included in the formulation include, but are not limited to, glycerin, 1,2-propanediol (propylene glycol), 1,3-propanediol, dipropylene glycol, sorbitol, xylitol, mannitol, and the like. In some embodiments, the humectant is or includes glycerin. In some embodiments, the oral formulation comprises glycerin. In some embodiments, the humectant is or includes propylene glycol. In some embodiments, the oral formulation comprises propylene glycol. The amount of humectant used in the oral formulation can vary but may be up to about 5% by weight, with certain embodiments being characterized by a humectant content of at least about 1% by weight of the oral formulation, e.g., from about 2 to about 5% by weight. In some embodiments, the humectant (such as glycerin and / or propylene glycol) can be present in an amount of about 0.01% to about 25% by weight of the oral formulation, e.g., about 0.1% to about 20% by weight of the oral formulation, e.g., about 0.5% to about 15% by weight of the oral formulation, e.g., about 1% to about 10% by weight of the oral formulation, e.g., about 5% to about 10% by weight of the oral formulation.

[0114] sweetener One or more sweeteners may be added to improve the sensory properties of the oral formulation. The sweetener may be any sweetener or combination of sweeteners, whether natural or artificial, or a combination of natural and artificial sweeteners. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, etc. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, etc.

[0115] In some embodiments, the sweetener comprises one or more sugar alcohols. The sugar alcohols may comprise erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, or a combination thereof. In some embodiments, the sweetener is selected from the group consisting of fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and mixtures thereof.

[0116] In some embodiments, the sweetener is selected from the group consisting of sucralose, acesulfame K, aspartame, maltodextrin, mannitol, sucrose, and mixtures thereof. Preferably, the sweetener can be sucralose and / or acesulfame K. When present in the oral formulation, the sweetener (such as sucralose and / or acesulfame K) can be present in an amount of about 0.001% to about 5% by weight of the oral formulation, for example, about 0.01% to about 3% by weight, and preferably about 0.01% to about 1% by weight.

[0117] buffer Non-limiting examples of suitable buffering agents that may be included in the oral formulation include alkali metal acetates, glycinates, phosphates, glycerophosphates, citrates, carbonates, bicarbonates, borates, or mixtures thereof. In some embodiments in which a buffering agent is present, the buffering agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium phosphate, ammonium phosphate, dicalcium phosphate, tricalcium phosphate, and mixtures thereof. In some embodiments, the buffering agent is sodium bicarbonate and / or sodium carbonate. When present, the buffering agent (e.g., sodium bicarbonate and / or sodium carbonate) may be included in an amount less than about 5% by weight of the oral formulation, such as about 0.5% to about 5% by weight, e.g., about 0.75% to about 4% by weight, about 0.75% to about 3% by weight, or about 1% to about 2% by weight, based on the total weight of the oral formulation.

[0118] organic acid In some embodiments, the formulation includes an organic acid. As used herein, the term "organic acid" refers to an organic (i.e., carbon-based) compound characterized by acidic properties. Typically, organic acids are relatively weak acids (i.e., they do not completely dissociate in the presence of water), such as carboxylic acids (-COH) or sulfonic acids (-SOHO). As used herein, reference to an organic acid refers to an organic acid that is intentionally added. In this regard, the organic acid may be intentionally added as a particular mixed component, rather than being inherently present simply as a component of another mixed component (e.g., a small amount of organic acid that may be inherently present in a mixed component such as tobacco raw material). In some embodiments, one or more organic acids are added neat (i.e., in free acid form, or in native solid or liquid form) or as a solution, such as, for example, an aqueous solution. In some embodiments, one or more organic acids are added in the form of a salt.

[0119] In some embodiments, the organic acid is a carboxylic acid or a sulfonic acid. The carboxylic acid or sulfonic acid functional group can be, for example, a group having 1 to 20 carbon atoms (C1 to C6). 20In some embodiments, the organic acid is an alkyl carboxylic acid, a cycloalkyl carboxylic acid, a heterocycloalkyl carboxylic acid, an aryl carboxylic acid, a heteroaryl carboxylic acid, an alkyl sulfonic acid, a cycloalkyl sulfonic acid, a heterocycloalkyl sulfonic acid, an aryl sulfonic acid, or a heteroaryl sulfonic acid.

[0120] In some embodiments, the organic acid is an alkyl carboxylic acid. Non-limiting examples of alkyl carboxylic acids include formic acid, acetic acid, propionic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, etc. In some embodiments, the organic acid is an alkyl sulfonic acid. Non-limiting examples of alkyl sulfonic acids include propane sulfonic acid and octane sulfonic acid.

[0121] In some embodiments, the alkyl carboxylic acid or alkyl sulfonic acid is substituted with one or more hydroxyl groups. Non-limiting examples include glycolic acid, 4-hydroxybutyric acid, and lactic acid.

[0122] In some embodiments, the organic acid may contain two or more carboxylic acid groups or two or more sulfonic acid groups (e.g., two, three, or more carboxylic acid groups). Non-limiting examples include oxalic acid, fumaric acid, maleic acid, and glutaric acid. In organic acids containing multiple carboxylic acids (e.g., two to four carboxylic acid groups), one or more carboxylic acid groups may be esterified. Non-limiting examples include succinic acid monoethyl ester, monomethyl fumarate, monomethyl citrate, dimethyl citrate, etc.

[0123] In some embodiments, the organic acid may contain two or more carboxylic acid groups and one or more hydroxyl groups. Non-limiting examples of such acids include tartaric acid, citric acid, etc. In some preferred embodiments, the organic acid is citric acid, sodium citrate, calcium citrate, or a combination thereof.

[0124] In some embodiments, the organic acid is an aryl carboxylic acid or aryl sulfonic acid. Non-limiting examples of aryl carboxylic acids and aryl sulfonic acids include benzoic acid, toluene acid, salicylic acid, benzene sulfonic acid, and p-toluene sulfonic acid.

[0125] Additional non-limiting examples of suitable organic acids include 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), camphoric acid (+), camphor-10-sulfonic acid (+), capric acid, caproic acid, caprylic acid, cinnamic acid, cyclamic acid, decanoic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanes ... Sulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactobionic acid, lauric acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, pyroglutamic acid, sebacic acid, stearic acid, and undecylenic acid.

[0126] Preferably, the organic acid is selected from the group consisting of citric acid, malic acid, lactic acid, benzoic acid, tartaric acid, and mixtures thereof, hi some preferred embodiments, the organic acid is or includes citric acid or a salt thereof.

[0127] In some embodiments, the formulation includes an alkali metal salt of an organic acid. For example, at least a portion of the organic acid may be present in the formulation in the form of an alkali metal salt. Suitable alkali metal salts include lithium, sodium, and potassium. In some embodiments, the alkali metal is sodium or potassium. In some embodiments, the alkali metal is sodium. In some embodiments, the formulation includes an organic acid and a sodium salt of the organic acid. In some embodiments, the organic acid is or includes sodium citrate, such as trisodium citrate.

[0128] The amount of organic acid present in the formulation can vary. The oral formulation can contain from about 0.01% to about 10% by weight of an organic acid present as one or more organic acids, based on the total weight of the oral formulation. In some embodiments, the oral formulation contains at least about 0.01%, at least about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or at least about 10% by weight of an organic acid, based on the total weight of the oral formulation. In some preferred embodiments, the oral formulation contains from about 0.01% to about 5% by weight of an organic acid, based on the weight of the oral formulation. For example, the oral formulation may contain an organic acid in an amount of about 0.1% to about 2.5% by weight of the oral formulation. When a salt of an organic acid is added (e.g., citric acid anhydrous), the weight percent is calculated based on the weight of the free acid, without any counterion that may be present.

[0129] In certain embodiments, the inclusion of an organic acid is sufficient to adjust the pH of the formulation to about 4.0 to about 9.0, e.g., about 4.5 to about 7.0, or about 5.5 to about 7.0, about 4.0 to about 5.5, or about 7.0 to about 9.0. In some embodiments, the inclusion of an organic acid is sufficient to adjust the pH of the formulation to about 4.5 to about 6.5, e.g., about 4.5 to about 5.0 to about 5.5 to about 6.0, or about 6.5. In some embodiments, the organic acid is used in an amount sufficient to adjust the pH of the formulation to about 5.5 to about 6.5, e.g., about 5.5 to about 5.6 to about 5.7 to about 5.8 to about 5.9 to about 6.0 to about 6.1, to about 6.2 to about 6.3 to about 6.4, or to about 6.5.

[0130] In other embodiments, the pH of the formulation is adjusted to the desired value by adding a mineral acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, etc.).

[0131] The organic acid (e.g., citric acid) can be added neat (i.e., as a solid) or as a solution, such as an aqueous solution. In some embodiments, the organic acid is added as a 50% aqueous solution.

[0132] salt The oral formulation may further comprise a salt. The salt may be included in an amount sufficient to impart desired organoleptic properties to the formulation. Non-limiting examples of suitable salts include sodium chloride, potassium chloride, ammonium chloride, flour salt, sodium acetate, sodium citrate, and the like. The salt may be included in any suitable amount, for example, at least about 0.5% by weight of the oral formulation, for example, at least about 1% by weight, for example, at least about 1.5% by weight. In some embodiments, the oral formulation may comprise the salt in an amount of about 0.5% by weight to about 10% by weight, for example, about 1% by weight to about 7.5% by weight, for example, about 1.5% by weight to about 5% by weight, based on the total weight of the oral formulation.

[0133] thickener In some embodiments, the oral formulation may contain a thickener. Suitable thickeners may include hydrocolloids such as xanthan gum, guar gum, konjac gum, tragacanth gum, and gum arabic. For example, xanthan gum is understood to be a thickener that thickens the composition when added during non-heat processing (i.e., without the application of heat).

[0134] If present, thickening agents (eg, xanthan gum) may be included in an amount from about 0.001% to about 5%, preferably from about 0.01% to about 1% by weight of the oral dosage form.

[0135] coloring agent Coloring agents can be used in an amount sufficient to impart the desired physical properties to the formulation. Examples of coloring agents include various dyes and pigments, such as caramel coloring and titanium dioxide. In addition to natural coloring agents such as curcumin, beet juice extract, and spirulina, various synthetic pigments may also be used. The amount of coloring agent used in oral formulations can vary, but when present, is typically up to about 3% by weight, e.g., about 0.1% to about 0.5% by weight, or about 1% to about 3% by weight, based on the total weight of the oral formulation.

[0136] Other additives Other ingredients, such as preservatives (e.g., potassium sorbate), disintegration aids (e.g., croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized corn starch, etc.), and / or antioxidants, can also be used. Typically, such ingredients, when used, are used in an amount of up to about 10% by weight of the oral formulation, e.g., at least about 0.1% by weight, e.g., about 0.5 to about 10% by weight. Disintegration aids can be used in an amount sufficient to adjust the desired physical properties of the oral formulation, for example, by causing the formulation to lose its physical integrity upon contact with water, dispersing various components (e.g., by swelling upon contact with water), etc.

[0137] Further exemplary types of additives include zinc or magnesium salts, or combinations thereof, selected to be relatively water-soluble to provide a highly water-soluble composition (e.g., magnesium gluconate or zinc gluconate), or relatively insoluble to provide a less water-soluble composition (e.g., magnesium oxide or zinc oxide). See, for example, U.S. Pat. No. 9,237,769 to Mua et al., U.S. Pat. No. 7,861,728 to Holton, Jr. et al., U.S. Patent Application Publication No. 2010 / 0291245 to Gao et al., and U.S. Patent Application Publication No. 2007 / 0062549 to Holton, Jr. et al., each of which is incorporated herein by reference, for representative additive components, combinations of components, relative amounts of components, and aspects and methods of using the components. Typical content ranges of such additional additives can vary depending on the nature and function of the additive and the intended effect on the final formulation, and include, for example, a range of up to about 10% by weight (e.g., about 0.1 to about 5% by weight) based on the total weight of the oral formulation.

[0138] In some embodiments, the oral formulation comprises a magnesium salt. A non-limiting example of a suitable magnesium salt is magnesium gluconate. In some embodiments, the oral formulation comprises magnesium in an amount of about 0.1% to about 2% by weight, or about 0.2% to about 1% by weight, based on elemental magnesium.

[0139] The aforementioned additives can be used together (e.g., as an additive blend) or separately (e.g., individual additive components can be added at different stages in the preparation of the final formulation). Additionally, additives of the aforementioned types can be encapsulated for addition to the final formulation or composition. For example, exemplary encapsulated additives are described in International Publication No. 2010 / 132444 by Atchley, which is incorporated herein by reference.

[0140] Oral formulation The formulations or compositions described herein are adapted for oral use. As used herein, the term "adapted for oral use" means that the formulation is provided in a form such that, during use, one or more components of the formulation (e.g., active ingredient) are dispersed in the user's oral cavity by saliva in the user's mouth. In certain embodiments, the formulation is designed to deliver the active ingredient and optionally a flavoring agent to the user through the user's oral mucosa, the user's digestive system, or both. In some examples, the active ingredient and optionally a flavoring agent can be absorbed through the oral mucosa or through the digestive tract upon use of the formulation.

[0141] In some embodiments, the oral formulation comprises the combination of active ingredients in an amount of at least about 0.01% by weight of the oral formulation, e.g., at least about 0.1% by weight, preferably at least about 1% by weight. The oral formulation may comprise, for example, at least about 0.25% by weight, at least about 0.3% by weight, at least about 0.5% by weight, at least about 0.75% by weight, at least about 1% by weight, at least about 1.5% by weight, at least about 2% by weight, at least about 3% by weight, at least about 4% by weight, or at least about 5% by weight of the oral formulation. The combination of active ingredients may be present in an amount of about 50% by weight or less of the oral formulation, e.g., about 40% by weight or less, e.g., about 30% by weight or less, e.g., about 20% by weight or less, e.g., about 10% by weight or less.

[0142] The active ingredient combination may be present in an amount of about 0.01% to about 20% by weight. For example, the active ingredient combination may be present in an amount of about 0.05% to about 15% by weight of the oral formulation, such as about 0.1% to about 10% by weight, or about 0.5% to about 5% by weight. Preferably, the active ingredient combination is present in an amount of about 0.1% to about 10% by weight of the oral formulation. Preferably, the active ingredient combination is present in an amount of about 0.5% to about 5% by weight of the oral formulation, more preferably about 1% to about 5% by weight of the oral formulation.

[0143] In some embodiments, the combination of active ingredients may be present in an amount of about 1.5% to about 20% by weight of the oral formulation, such as about 2.5% to about 15% by weight, for example, about 5% to about 10% by weight.

[0144] Oral formulations can be in any form suitable for application to the oral cavity of a human or animal. In some embodiments, oral formulations are oral dosage forms in the form of solids, gels, or liquids. In some embodiments, oral formulations are solid oral dosage forms. In some embodiments, oral formulations are liquid oral dosage forms.

[0145] The oral formulations described herein can take a variety of forms, including gels, melt-types, tablets, lozenges, powders, pouches, and liquids (eg, beverages).

[0146] Liquid oral dosage forms In some preferred embodiments, the oral formulation is in the form of a liquid dosage form, which is suitable for oral ingestion, sometimes referred to as a beverage, because it can be ingested (i.e., drunk) by the user.

[0147] The liquid oral dosage form may be in the form of a shot, i.e., a beverage that can be consumed quickly, for example, in one or two sips. Alternatively, the liquid oral dosage form may be in the form of a larger volume beverage that can be consumed more slowly over several sips. The liquid oral dosage form may have a volume of about 1 mL to about 250 mL, for example, about 1 mL to about 200 mL. The liquid oral dosage form may have a volume of about 100 mL to about 250 mL and may be provided in packaging such as a liquid carton, cup, can, or bottle.

[0148] The liquid oral dosage form may have a volume of about 10 mL to about 100 mL, for example, about 25 mL to about 75 mL. In such embodiments, the liquid oral dosage form may be considered a shot. In some preferred embodiments, the liquid oral dosage form may have a volume of about 50 mL to about 100 mL. For example, the volume of the liquid oral dosage form may be about 50 mL to about 75 mL. The volume of the liquid may be about 60 mL.

[0149] When in the form of a liquid oral dosage form, the oral formulation may further comprise water in an amount of about 50% to about 99.9% by weight of the oral formulation. In some embodiments, the oral formulation comprises water in an amount of about 75% to about 99.5% by weight of the oral formulation, e.g., about 80% to about 99% by weight, e.g., about 90% to about 97.5% by weight. In some embodiments, the oral formulation comprises water in an amount of about 90% to about 99.5% by weight of the oral formulation, and may comprise water in an amount of about 95% to about 99% by weight of the oral formulation.

[0150] If present, the water may include tap water, rainwater, mineral-containing water, or distilled water. Preferably, the water is distilled water.

[0151] The liquid oral dosage form may comprise the active ingredient combination in an amount of about 0.1% to about 10% by weight of the oral formulation, and water in an amount of about 90% to about 99.9% by weight of the oral formulation. The liquid oral dosage form may comprise the active ingredient combination in an amount of about 0.5% to about 5% by weight of the oral formulation, and water in an amount of about 90% to about 99.5% by weight of the oral formulation.

[0152] In some embodiments, the combination of active ingredients in the liquid oral dosage form includes (i) L-theanine, (ii) ginseng, (iii) lemon balm, (iv) vitamin C, and optionally (v) chamomile extract. The combination of active ingredients in the liquid oral dosage form may include (i) L-theanine, (ii) ginseng, (iii) lemon balm, (iv) vitamin C, and (v) chamomile extract.

[0153] A liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) may contain L-theanine in an amount of about 50 mg to about 500 mg, preferably about 100 mg to about 250 mg, and more preferably about 150 mg to about 200 mg.

[0154] A liquid oral dosage form (eg, in the form of a shot having a volume of 50 mL to 100 mL) may contain ginseng in an amount of about 10 mg to about 300 mg, preferably about 25 mg to about 200 mg, and more preferably about 50 mg to about 150 mg.

[0155] The inventors have found that increasing the amount of lemon balm in the formulation enhances the relaxation effect and has a synergistic effect on reducing stress and anxiety levels. A liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) may contain lemon balm in an amount of about 1 mg to about 200 mg, preferably about 25 mg to about 150 mg, and more preferably about 50 mg to about 100 mg.

[0156] When present, the liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) may contain vitamin C in an amount of about 50 mg to about 500 mg, e.g., about 200 mg to about 400 mg. In some preferred embodiments, the liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) may contain vitamin C in an amount of about 250 mg to about 350 mg.

[0157] When present, a liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) may contain chamomile extract in an amount of about 1 mg to about 50 mg, for example, about 10 mg to about 50 mg.

[0158] In some embodiments, the liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) comprises: (i) about 50 mg to about 500 mg of L-theanine and / or (ii) about 10 mg to about 300 mg of ginseng and / or (iii) about 1 mg to about 200 mg of lemon balm and / or Optionally, (iv) about 50 mg to about 500 mg of vitamin C and / or Optionally, (v) about 1 mg to about 50 mg of chamomile extract.

[0159] In some embodiments, the liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) comprises: (i) about 150 mg to about 200 mg of L-theanine and / or (ii) about 50 mg to about 150 mg of ginseng and / or (iii) about 50 mg to about 100 mg of lemon balm and / or Optionally, (iv) about 250 mg to about 350 mg of vitamin C and / or Optionally, (v) about 10 mg to about 50 mg of chamomile extract.

[0160] In some embodiments, the liquid oral dosage form (e.g., in the form of a shot having a volume of 50 mL to 100 mL) comprises: (i) about 150 mg to about 200 mg of L-theanine; (ii) about 50 mg to about 150 mg of ginseng; (iii) about 50 mg to about 100 mg of lemon balm; (iv) about 250 mg to about 350 mg of vitamin C; (v) about 10 mg to about 50 mg of chamomile extract.

[0161] The inventors have found that the above amounts of active ingredient provide the user with a beneficial effect of relaxation / stress reduction while reducing side effects. The amount of active ingredient can be adjusted so that the formulation is highly effective while ensuring safety for the user and avoiding overdosing on the active ingredient.

[0162] In some embodiments, the liquid oral dosage form may further comprise an acidifying agent. The acidifying agent may be an organic acid as described hereinabove. In some embodiments, the acidifying agent is citric acid or a salt thereof (e.g., citric acid anhydride) or includes citric acid or a salt thereof. In some embodiments, the liquid oral dosage form has a pH of about 2 to about 6, e.g., about 2.5 to about 4 or about 2.5 to about 3.5.

[0163] The liquid oral dosage form may contain any additional suitable additives. Suitable additives are described in detail above, and all of the additives described herein may be included in the liquid oral dosage form. In some embodiments, the liquid oral dosage form may further contain an additive selected from the group consisting of flavoring agents, sweeteners, acidifiers, thickeners, humectants, preservatives, and mixtures thereof. Examples of the various additives mentioned above are described herein above.

[0164] solid oral dosage forms In some embodiments, the oral formulation is in a solid form. As used herein, the term "solid" means that the formulation can substantially maintain its physical shape when not supported by external means, such as packaging. Thus, the formulation is considered to be solid, solid-like, in solid form, or in solid-like form at room temperature. For the avoidance of doubt, a solid formulation remains substantially solid up to 30°C. In some embodiments, the oral formulation is in a solid form such as moist loose snuff, dry loose snuff, chewing tobacco-type form, pellet-like pieces, extruded or molded strips, pieces, rods, or sticks, finely divided powders, powder-like pieces, and micronized or comminuted agglomerates of ingredients, flake-like pieces, molded pieces, films, films or strips that are readily soluble or dispersible in water, capsule-like articles, tablets, or lozenges. In some embodiments, the oral formulation is in the form of moist snuff or snus, which may or may not contain tobacco.

[0165] The oral dosage forms disclosed herein can be formed into a variety of shapes, including various tablets, spheres, strips, films, sheets, coins, cubes, beads, ovoids, ellipsoids, cylinders, beans, sticks, or rods. The cross-sectional shape of the dosage form can vary, with exemplary cross-sectional shapes including circle, square, oval, rectangle, etc. Such shapes can be formed in a variety of ways using equipment such as moving belts, nip devices, extruders, granulators, and compactors.

[0166] In some embodiments, the solid oral formulation is in a form selected from the group consisting of a melt-type, a tablet, or a lozenge.

[0167] Melt Type In some embodiments, the formulations can be meltable, for example, as described in U.S. Patent Application Publication No. 2012 / 0037175 to Cantrell et al., which is incorporated herein by reference in its entirety.

[0168] As used herein, "melt," "melting," and "meltable" refer to the ability of a formulation to change from a solid state to a liquid state. That is, melting occurs when a substance (e.g., a formulation disclosed herein) changes from a solid to a liquid, usually by heating.

[0169] The heating of the formulations disclosed herein is provided by the temperature inside the user's mouth. Thus, the term "meltable" refers to a formulation that can be liquefied in the user's mouth when the formulation undergoes a phase change from solid to liquid, and is intended to distinguish it from a formulation that simply disintegrates in the mouth due to the loss of cohesion of the formulation, which simply dissolves in the mouth when the water-soluble components of the formulation interact with moisture.

[0170] Generally, meltable formulations include lipids. In some embodiments, the composition includes lipids. Lipids are fatty, oily, or waxy components typically derived from animal or plant sources (e.g., plant-derived fats) and typically contain primarily triglycerides with minor amounts of free fatty acids and monoglycerides or diglycerides. In certain embodiments, the lipids are solid or semi-solid at room temperature (i.e., 25°C) and can be at least partially liquefied (i.e., "melted") upon exposure to the temperature of a user's mouth. Exemplary plant-derived fats are primarily composed of saturated or unsaturated fatty acid chains (mostly attached in triglyceride structures) having carbon chain lengths of about 10 to about 26 carbon atoms, or about 14 to about 20 carbon atoms, or about 14 to about 18 carbon atoms.

[0171] In some embodiments, the lipid comprises an oil, particularly a food-grade oil, including fractionated oils. Such oils include vegetable oils (e.g., acai oil, almond oil, amaranth oil, apricot oil, apple seed oil, argan oil, avocado oil, babassu oil, beechnut oil, ben oil, bitter melon seed oil, black seed oil, black currant seed oil, borage seed oil, Borneo taro nut oil, bottle gourd seed oil, Brazil nut oil, buffalo gourd oil, butternut squash seed oil, Cape chestnut oil, canola oil, carob oak seed oil, and the like). Dew oil, cocoa butter, oakleber oil, coconut oil, corn oil, cosun oil, coriander seed oil, cottonseed oil, date seed oil, zika oil, egus seed oil, evening primrose oil, eggplant oil, linseed oil, grape seed oil, grapefruit seed oil, hazelnut seed oil, hemp oil, kapok seed oil, kenaf seed oil, lalemantia oil, lemon oil, linseed oil, macadamia oil, mafra oil, marula oil, meadowfoam seed oil, mongongo nut Oil, Mustard Oil, Niger Seed Oil, Nutmeg Butter, Okra Seed Oil, Olive Oil, Orange Oil, Palm Oil, Papaya Seed Oil, Groundnut Oil, Pecan Oil, Perilla Seed Oil, Perilla Seed Oil, Pequi Oil, Pili Nut Oil, Pine Nut Oil, Pistachio Oil, Pomegranate Seed Oil, Poppy Seed Oil, Praxi Oil, Prune Seed Oil, Pumpkin Seed Oil, Quinoa Oil, Rapeseed Oil, Rice Bran Oil, Royle Oil, Sacha Inchi Oil, Safflower Oil, Sapote Oil, Seji oil, sesame oil, shea butter, soybean oil, sunflower oil, tarramilla oil, tea seed oil, thistle oil, tiger nut oil, tobacco seed oil, tomato seed oil, walnut oil, watermelon seed oil, wheat germ oil, and combinations thereof), animal oils (e.g., beef tallow, buffalo tallow, mutton tallow, goat tallow, lard, camel tallow, tallow, liquid margarine, fish oil, fish liver oil, whale oil, seal oil, and combinations thereof), and mineral oils.

[0172] In certain embodiments, the plant-derived fats of the present disclosure include palm oil, palm kernel oil (including fractionated palm oil), soybean oil, cottonseed oil, and mixtures thereof. In one embodiment, the lipid is a blend of palm oil and palm kernel oil. The lipid may be, for example, hydrogenated, partially hydrogenated, or non-hydrogenated. Exemplary embodiments of lipids can be purchased under the trade names CEBES®, CISAO®, or CONF AO®, available from AarhusKarlshamn USA Inc.

[0173] The melting point of the lipid is typically about 29°C or higher, e.g., about 29°C to about 49°C, or about 36°C to about 45°C, or about 38°C to about 41°C. In some embodiments, the use of lipids with melting points below about 36°C is not suitable due to the possibility of melting during storage or handling of the formulation. One test for determining the melting point of a lipid is the Mettler Dropping Point Method (ASTM D3954-15, Standard Test Method for Dropping Point of Waxes, ASTM International, West Conshohocken, PA, 2015, www.astm.org.).

[0174] When present, the amount of lipid in the composition may vary. In certain embodiments, the amount of lipid is at least about 10%, at least about 20%, or at least about 30% by dry weight of the composition. In certain embodiments, the amount of lipid is less than about 70%, less than about 60%, or less than about 50% by dry weight. Exemplary lipid weight ranges include about 10 to about 70% by dry weight, e.g., about 35 to about 50% by dry weight. In some embodiments, the amount of lipid is about 35, about 40, about 45, or about 50% by weight of the total oral formulation.

[0175] In some embodiments, the oral formulation comprises a lipid. In one embodiment, the lipid is an oil selected from the group consisting of palm oil, palm kernel oil, soybean oil, sunflower oil, cottonseed oil, coconut oil, and combinations thereof, and the oil may be hydrogenated, partially hydrogenated, or non-hydrogenated. In one embodiment, the lipid is a medium-hardness trans-hydrogenated filling fat such as Confao® 5, available from AarhusKarlshamn USA Inc., 131 Marsh Street, Port Newark, NJ 07114.

[0176] In some embodiments, the dissolvable formulation comprises lipid in an amount of about 35% to about 50% by weight of the oral formulation and sugar alcohol in an amount of about 35% to about 55% by weight of the oral formulation. In some embodiments, the sugar alcohol is isomalt, erythritol, sorbitol, arabitol, ribitol, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is or includes isomalt. In some embodiments, a sugar substitute may be a sugar alcohol substitute or may be used in combination with one or more sugar alcohols. Suitable sugar substitutes include allulose, water-soluble tapioca fiber, inulin, and combinations thereof.

[0177] tablet In certain embodiments, the formulation is in the form of a compressed or molded tablet. Exemplary tablet dosage forms have a weight of about 250 mg to about 1500 mg, e.g., about 250 mg to about 700 mg, or about 700 mg to about 1500 mg. Tablets can have any of a variety of shapes, including conventional tablet shapes.

[0178] Generally, tablet formulations comprise a glucose-polysaccharide blend and a sugar alcohol. In some embodiments, the glucose-polysaccharide blend is present in an amount of about 35 to about 50% by weight, based on the total weight of the formulation, and the sugar alcohol is present in an amount of about 30 to about 45% by weight, based on the total weight of the formulation. In some embodiments, the sugar alcohol is isomalt, erythritol, sorbitol, arabitol, ribitol, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, or a combination thereof. In some embodiments, the sugar alcohol is or comprises isomalt.

[0179] When in tablet form, the formulation may be dissolvable. As used herein, the terms "dissolve," "dissolving," and "dissolvable" refer to a formulation having water-soluble components that interact with the moisture in the oral cavity and dissolve into solution, allowing the formulation to be gradually ingested. In one aspect, a dissolvable formulation can remain in the user's oral cavity for a given period of time until completely dissolved. The dissolution rate can vary over a wide range, from about 1 minute or less to about 60 minutes. For example, immediate-release formulations typically dissolve and / or release the desired components (e.g., active ingredient, flavor, etc.) in about 2 minutes or less, often about 1 minute or less (e.g., about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, or about 20 seconds or less). Dissolution can occur by melting, mechanical disruption (e.g., chewing), enzymatic or other chemical degradation, or by disruption of interactions between the components of the formulation. In other embodiments, the formulation does not dissolve while the formulation remains in the user's oral cavity.

[0180] Lozenges In some embodiments, the formulations disclosed herein may be in the form of dissolvable lozenges adapted for oral use. Exemplary lozenge-shaped formulations of the present invention have the form of lozenges, tablets, microtablets, or other tablet-like formulations. See, for example, U.S. Patent No. 4,967,773 to Shaw, U.S. Patent No. 5,110,605 to Acharya, U.S. Patent No. 5,733,574 to Dam, U.S. Patent No. 6,280,761 to Santus, U.S. Patent No. 6,676,959 to Andersson et al., U.S. Patent No. 6,248,760 and U.S. Patent No. 7,374,779 to Wilhelmsen, and U.S. Patent Application Publication No. 2001 / 0016593 to Wilhelmsen, all of which are incorporated herein by reference. and U.S. Patent Application Publication No. 2010 / 0004294 to Axelsson et al., ...

[0181] Troche formulations are generally described as "hard" and are distinguished from soft troches (i.e., soft-type troches) as follows: Hard troches are mixtures of sugars and / or carbohydrates in an amorphous state. Hard troches are made from an aqueous sugar solution; however, the water initially present evaporates as the sugar solution boils during processing, so the moisture content of the final formulation is very low, e.g., 0.5% to 1.5% by weight. To obtain a hard, non-sticky troche, the temperature of the melt must generally reach a hard crack stage, an exemplary temperature range of 149° to 154°C.

[0182] In some embodiments, the lozenge formulation may exhibit translucency or transparency. The desired transparency or translucency of a formulation can be quantified by any known technique. For example, optical measurements such as turbidity (or scattered light measurement) and colorimetry can be used to quantify the turbidity (light scattering) and color (light absorption) of the formulation, respectively. Translucency can also be confirmed by visual inspection by simply holding the formulation level with a light source and determining whether light diffusely passes through the material or formulation.

[0183] The lozenge formulations of the present disclosure can incorporate a variety of different additives in addition to the combination of active ingredients and can be prepared by a variety of different methods for preparing lozenges that are generally known in the art. Exemplary compositions, formulations, and methods for preparing such formulations are detailed herein below.

[0184] The lozenge formulations of the present disclosure typically comprise a composition comprising a combination of an active ingredient in an amount of less than about 2% by weight, a sugar substitute in an amount of at least about 80% by weight, and a sugar alcohol solution. Any active ingredient discussed herein is suitable for use as an active ingredient in the lozenge formulations provided herein. In some embodiments, the active ingredient may be provided in liquid form or in dry powder or particulate form. As described above, the active ingredient is typically present in an amount of about 0.1% by weight to about 10% by weight, for example, about 0.1% by weight to about 10% by weight, such as about 0.1% by weight, about 0.5% by weight, about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight to about 5.5% by weight, about 6% by weight, about 6.5% by weight, about 7% by weight, about 7.5% by weight, about 8% by weight, about 8.5% by weight, about 9% by weight, about 9.5% by weight, about 10% by weight, etc. In some embodiments, the active ingredient may be present in an amount of less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, or less than about 1% by weight, based on the total weight of the formulation.

[0185] In some embodiments, the lozenge formulation comprises a sugar substitute. The sugar substitute is typically provided in a pure solid form (e.g., granular or powdered form). In certain embodiments, the sugar substitute is dry and has a very low moisture content. For example, the sugar substitute may contain less than about 5% water by weight, less than about 3% water by weight, less than about 2% water by weight, or less than about 1% water by weight. In certain embodiments, the sugar substitute is capable of forming a glassy matrix. The formation of a glassy matrix is ​​generally characterized by a translucent / transparent appearance.

[0186] Typically, sugar substitutes are substantially non-hygroscopic. Non-hygroscopic materials typically do not absorb, adsorb, and / or retain substantial amounts of moisture from the air. Non-hygroscopic materials can provide the advantage of reducing the tendency of the lozenge formulation to stick when exposed to moisture. Sugar substitutes can be any sugar-free material (i.e., sucrose-free material) and can be natural or synthetically produced. Sugar substitutes used in the formulations described herein can be nutritive or non-nutritive. For example, sugar substitutes are generally sugar alcohols. Sugar alcohols that may be useful according to the present invention include, but are not limited to, erythritol, threitol, arabitol, xylitol, ribotol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, polyglycitol, and mixtures thereof. For example, in certain embodiments, the sugar alcohol is selected from the group consisting of erythritol, sorbitol, and isomalt. The amount of sugar substitute in a lozenge formulation can vary, but is typically at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or at least about 95% by weight of the formulation.

[0187] In certain embodiments, the sugar substitute comprises one or more sugar alcohols, for example, in one embodiment the sugar substitute is isomalt.

[0188] In some embodiments, the sugar substitute is one or more of allulose, water-soluble tapioca fiber, and inulin. Such sugar substitutes may be substitutes for sugar alcohols or may be used in combination with one or more sugar alcohols.

[0189] In some embodiments, the lozenge formulations of the present disclosure may contain a sugar solution, such as a sugar syrup or a sugar alcohol solution. As used herein, "sugar alcohol solution" is intended to refer to a highly concentrated aqueous solution of a sugar alcohol, e.g., having a solids content of greater than about 40%, preferably greater than about 50%, greater than about 60%, greater than about 70%, or greater than about 80%. Typically, the solids of a sugar alcohol solution are predominantly composed of a particular sugar alcohol (i.e., a maltitol solution typically contains greater than about 80%, greater than about 85%, or greater than about 90% by weight of maltitol on a dry basis). Sugar alcohol solutions are generally prepared by heating an aqueous solution of a sugar alcohol and cooling the mixture to obtain a viscous composition. The resulting sugar solution is typically characterized by a relatively high concentration of sugar alcohol and a relatively high stability (i.e., the sugar alcohol typically does not crystallize from solution, e.g., at room temperature).

[0190] Sugar solutions, such as sugar alcohol solutions, can desirably affect the recrystallization of melted sugar substitutes. One example of a particularly useful sugar alcohol solution according to the present disclosure is maltitol solution. Other sugar alcohol solutions can be used, including, but not limited to, corn solution, golden syrup, molasses, xylitol solution, mannitol solution, glycerol solution, erythritol solution, threitol solution, arabitol solution, ribitol solution, mannitol solution, sorbitol solution, dulcitol solution, iditol solution, isomalt solution, lactitol solution, and polyglycitol solution. Such sugar alcohol solutions can be prepared or obtained commercially. For example, maltitol solution is commercially available from suppliers such as Corn Products Specialty Ingredients. While sugar alcohol solutions may be preferred, in certain embodiments, sugar syrups can be used in place of or in combination with the sugar alcohol solution. For example, in some embodiments, corn syrup, golden syrup, and / or molasses can be used.

[0191] The amount of sugar alcohol solution added to the lozenge formulation mixture is typically an amount necessary to slow the recrystallization of the molten sugar substitute. It should be noted that the amount of sugar alcohol solution can be varied depending on the composition of the remaining ingredients to ensure that recrystallization is sufficiently slow to yield a material with the desired properties (e.g., a desired level of translucency / transparency). Thus, the amount of sugar alcohol solution can vary, but typically ranges from about 0.1% to about 2% by weight of the lozenge formulation mixture, often from about 0.5% to about 1.5% by weight, and more often about 1% by weight. In certain embodiments, the amount of sugar alcohol solution is higher, e.g., up to about 2% by weight of the mixture, up to about 5% by weight of the mixture, up to about 10% by weight of the mixture, or up to about 20% by weight of the mixture.

[0192] Representative lozenge compositions and formulations may incorporate up to about 10% by weight of a combination of active ingredients, about 0.01 to about 2% by weight of an artificial sweetener, about 1% to about 5% by weight of a humectant, about 1% to about 5% by weight of a natural sweetener, at least about 80% by weight of a sugar substitute, about 0.1% to about 10% by weight of a sugar alcohol solution, one or more flavorings in an amount up to about 5% by weight, and salt in an amount up to about 3% by weight, based on the total weight of the formulation. The specific proportions and selection of ingredients will vary depending on the flavor, texture, and other characteristics desired.

[0193] The oral formulations in the form of lozenges of the present disclosure may contain various amounts of water. The water content of the lozenges described herein can vary within the ranges described below depending on the desired properties and characteristics, and can determine the final form of the formulation before use by a consumer. For example, lozenge-shaped formulations typically have a water content in the range of about 0.1 to about 5% by weight of the formulation. Preferably, the water content of the lozenge formulation present in one unit of formulation before insertion into the user's oral cavity is less than about 5%, less than about 3%, less than about 2%, or less than about 1% by weight of the formulation. In some embodiments, the water content of the lozenge formulations described herein can be within the range of about 0.1% to about 5%, about 0.5 to about 3%, or about 1 to about 2% by weight of the formulation.

[0194] Powder or pouch-packaged preparations In some embodiments, the oral formulation may be in the form of a powder. The powder may be a free-flowing powder. The powder may be contained in a loose form in a container and thus may be used in a form similar to snuff, when the user takes a pinch of powder from the container and retains it in the oral cavity. Alternatively or additionally, the powder may be incorporated into a moisture-permeable (e.g., saliva-permeable) pouch similar to snus-type products. The pouch-packaged formulation may be configured to be inserted into the oral cavity of the user, i.e., may be a pouch-packaged oral formulation.

[0195] In some embodiments, the formulations of the present disclosure are in the form of pouch-packaged oral formulations. Such pouch-packaged formulations include an oral formulation described herein placed in a moisture-permeable container (e.g., a water-permeable pouch or a saliva-permeable pouch). For example, the pouch-packaged formulation may include an oral formulation in powder form incorporated into a saliva-permeable pouch.

[0196] Such compositions in the form of breathable pouches are typically used by retaining one pouch containing the composition in the oral cavity of a human subject / user. Generally, the pouch is retained somewhere in the user's oral cavity, for example, under the lips, in a manner similar to the normal use of moist snuff products. The pouch is preferably not chewed or swallowed. Upon exposure to saliva, some of the components of the composition therein (e.g., active ingredient and / or any flavoring) pass through, for example, the breathable pouch, providing flavor and a satisfying sensation to the user, without the user having to expectorate any portion of the composition. After about 10 to about 60 minutes of use / enjoyment, typically about 15 to about 45 minutes, once a significant amount of the composition has been ingested by the human subject, the pouch can be removed from the human subject's mouth for disposal.

[0197] In some embodiments, the pouch is saliva-permeable. This means that the pouch is made of a saliva-permeable pouch material. Pouch materials used in oral pouch-packaged formulations are typically dry-bonded nonwovens containing viscose rayon fibers (i.e., regenerated cellulose) and an acrylic polymer, which acts as a binder in the nonwoven material and allows the pouch to be heat-sealed during manufacturing. The pouch material may also contain synthetic fibers (e.g., polyester) in addition to viscose fibers. The viscose nonwoven material typically used in smokeless tobacco pouches is similar to the fibrous material used in tea bags. Nonwovens are fibrous materials that are neither woven nor knitted. Methods for manufacturing nonwoven materials are generally known in the art. For more information on nonwovens, see "Handbook of Nonwovens" by S. Russell, published by Woodhead Pub I. Ltd. in 2007. In some embodiments, the pouch material is a fleece material. In some embodiments, the pouch material is a nonwoven material. In some embodiments, the pouch material is a nonwoven fleece material. In some embodiments, the pouch material comprises viscose, e.g., viscose rayon fibers. In some embodiments, the pouch material comprises regenerated cellulose fibers. In some embodiments, the pouch material comprises polyester fibers, which may comprise the pouch material or may be included in combination with viscose (e.g., regenerated cellulose fibers).

[0198] In some embodiments, the pouch material includes a binder that allows the pouch to be heat sealed during manufacturing. In some embodiments, the pouch material includes an acrylic binder. In some embodiments, the pouch material includes an acrylic binder in combination with viscose and / or polyester fibers.

[0199] Suitable sachets, pouches, or containers of the type used to manufacture smokeless tobacco products are available under the trade names CatchDry, Ettan, General, Granit, Goteborgs Rape, Grovsnus White, Metropol Kaktus, Mocca Anis, Mocca Mint, Mocca Wintergreen, Kicks, Probe, Prince, Skruf, and TreAnkrare. The composition can be contained and packaged in a pouch in a manner similar to that used to manufacture conventional snus-type products, using various ingredients used in the manufacture of conventional snus-type products. The pouch functions as a moisture-permeable container, the type of which may be considered similar in characteristics to the mesh material used to manufacture tea bags. The ingredients of the composition readily diffuse through the pouch into the user's mouth. Non-limiting examples of suitable types of pouches are described, for example, in U.S. Pat. No. 5,167,244 to Kjerstad, U.S. Pat. No. 8,931,493 to Sebastian, U.S. Patent Application Publication No. 2016 / 0000140 to Sebastian et al., U.S. Patent Application Publication No. 2016 / 0073689 to Sebastian et al., U.S. Patent Application Publication No. 2016 / 0157515 to Chapman et al., and U.S. Patent Application Publication No. 2016 / 0192703 to Sebastian et al., each of which is incorporated herein by reference. The pouches can be provided as individual pouches or multiple pouches (e.g., 2, 4, 5, 10, 12, 15, 20, 25, or 30 pouches) can be connected or joined together (e.g., end to end) so that a single pouch or individual portion can be easily removed for use from an integral band or matrix of pouches.

[0200] Exemplary pouches can be manufactured from materials that allow controlled dispersion or dissolution of the pouch during use by the user. Such pouch materials can be in the form of mesh, screen, perforated paper, permeable fabric, etc. For example, a pouch material made from mesh-like rice paper or perforated rice paper can dissolve in the user's mouth. As a result, the pouch and composition can each completely disperse in the user's mouth under normal use conditions, and thus both the pouch and the composition can be ingested by the user. Other examples of pouch materials can be manufactured using water-dispersible film-forming materials (e.g., binders such as alginate, carboxymethylcellulose, xanthan gum, pullulan, etc.) and combinations of water-dispersible film-forming materials with comminuted cellulose (e.g., finely divided wood pulp). While preferred pouch materials are water-dispersible or soluble, they may also be designed and manufactured so that a significant amount of the composition contents can permeate the pouch material under normal use conditions before the pouch loses its physical integrity. If desired, flavoring ingredients, disintegration aids, and other desired ingredients may be incorporated into or applied to the pouch material.

[0201] The amount of oral formulation contained in each pouch-packaged formulation unit, e.g., one pouch, can vary. In some embodiments, the weight of the composition in each pouch is at least about 50 mg, e.g., about 50 mg to about 1 gram (1000 mg), e.g., about 100 mg to about 900 mg, e.g., about 200 mg to about 800 mg, e.g., about 500 mg to about 700 mg. In some smaller embodiments, the weight of the composition in each pouch can be about 100 mg to about 300 mg. In larger embodiments, the weight of the composition in each pouch can be about 300 mg to about 700 mg. If desired, other ingredients can be included in each pouch.

[0202] The moisture content of an oral formulation may vary depending on the form in which the composition is provided. In some embodiments described hereinabove, the oral formulation may be in the form of moist snuff or snus, and may be provided in pouch form. In some embodiments (e.g., in the case of snus-like formulations), the moisture content of the composition (before inserting the formulation into the user's oral cavity) may be at least about 20% by weight of the oral formulation, such as at least 30% by weight, for example at least 40% by weight, for example at least 50% by weight. In some embodiments (e.g., in the case of snus-like formulations, e.g., non-pouch or pouch-packaged snus-like formulations), the moisture content of the composition (before inserting the formulation into the user's oral cavity) may be about 20% by weight to about 70% by weight of the oral formulation, such as about 30% by weight to about 60% by weight, for example about 40% by weight to about 55% by weight.

[0203] In some embodiments, the oral formulation may be a "dry" snus- or snuff-like formulation. In such embodiments, the moisture content of the oral formulation may be about 10% or less, e.g., about 5% or less, by weight of the oral formulation. For example, the moisture content may be about 0.1% to about 10% by weight of the oral formulation, e.g., about 1% to about 5% by weight.

[0204] When in the form of a pouch-packaged oral formulation, the oral formulation typically contains a filler. The filler may be a cellulosic material, preferably selected from the suitable materials described above. In some preferred embodiments, the filler is or at least includes MCC. The amount of filler can vary, but is typically at least about 5% to about 95% by weight of the oral formulation, based on the total weight of the oral formulation. In some embodiments, the filler (e.g., a cellulosic material such as MCC) is present in the oral formulation in an amount of about 5% to about 95% by weight, e.g., about 10% to about 90% by weight, e.g., about 15% to about 85% by weight, e.g., about 20% to about 80% by weight, e.g., about 25% to about 75% by weight, e.g., about 30% to about 70% by weight, e.g., about 35% to about 65% by weight, e.g., about 40% to about 60% by weight. In some embodiments, the filler (eg, a cellulosic material such as MCC) may be present in an amount of about 45% to about 55% by weight of the oral dosage form.

[0205] packaging According to some embodiments described herein, a package containing the oral formulation described herein is provided. For example, the package may contain the oral formulation in powder form. In such embodiments, the package may be in the form of a tinplate or plastic container. Alternatively or additionally, the package may contain the oral formulation in the form of a lozenge, tablet, or the like. The package may be in the form of a blister pack, tinplate, or plastic container containing such oral dosage forms.

[0206] According to some embodiments described herein, there is provided a package containing at least one pouch-packaged oral formulation described herein. The pouch-packaged formulation described herein can be packaged in any suitable inner wrapper and / or outer container. See, for example, U.S. Pat. No. 7,014,039 to Henson et al., U.S. Pat. No. 7,537,110 to Kutsch et al., U.S. Pat. No. 7,584,843 to Kutsch et al., U.S. Pat. No. 8,397,945 to Gelardi et al., U.S. Design Patent No. D592,956 to Thiellier, U.S. Design Patent No. D594,154 to Patel et al., U.S. Design Patent No. D625,178 to Bailey et al., U.S. Patent Application Publication No. 2008 / 0173317 to Robinson et al., U.S. Patent Application Publication No. 2009 / 0014343 to Clark et al., U.S. Patent Application Publication No. 2009 / 0014343 to Bjorkholm, all of which are incorporated herein by reference. See also various smokeless product containers described in U.S. Patent Application Publication Nos. 4450 to Bellamah et al., 2009 / 0250360 to Bellamah et al., 2009 / 0266837 to Gelardi et al., 2009 / 0223989 to Gelardi, 2009 / 0230003 to Thiellier, 2010 / 0084424 to Gelardi, 2010 / 0133140 to Bailey et al., 2010 / 0264157 to Bailey et al., and 2011 / 0168712 to Bailey et al. For example, the package may be a tinplate or plastic container containing a plurality of pouch-packaged oral dosage forms.

[0207] In some preferred embodiments, where the oral formulation is in liquid form, a package in the form of a bottle or can containing the liquid oral dosage form is provided. The package may be a bottle containing a desired volume of the liquid oral dosage form.

[0208] method The manner in which the various components of the composition (e.g., active ingredient and optional additives) are combined can vary. Thus, for example, the overall formulation, including powdered composition components, can be relatively uniform (e.g., homogeneous) in nature. The above components, which may be in liquid or dry solid form, can be added by mixing in a pre-processing step before mixing with any remaining components of the formulation, or can simply be mixed with all other liquid or dry ingredients.

[0209] The various components of the formulation can be contacted, combined, or mixed using any mixing technique or device known in the art. Any mixing method that allows for intimate contact of the formulation components can be used, such as a mixing device featuring an impeller or other agitating structure. Examples of mixing devices include casing drums, adjusting cylinders or drums, liquid spray devices, conical blenders, ribbon blenders, mixers such as FKM130, FKM600, FKM1200, FKM2000, and FKM3000 available from Littleford Day, Inc., plowshare-type mixing cylinders, Hobart mixers, and the like. See also, for example, the various techniques described in U.S. Pat. No. 4,148,325 to Solomon et al., U.S. Pat. No. 6,510,855 to Korte et al., and U.S. Pat. No. 6,834,654 to Williams, each of which is incorporated herein by reference. In some embodiments, the components forming the formulation are prepared so that the mixture can be used in the starch forming method to form the formulation.The manner and method of formulating the product will be clear to those skilled in the art.See, for example, the various methods described in U.S. Patent No. 4,148,325 by Solomon et al., U.S. Patent No. 6,510,855 by Korte et al., U.S. Patent No. 6,834,654 by Williams, U.S. Patent No. 4,725,440 by Ridgway et al., and U.S. Patent No. 6,077,524 by Bolder et al., each of which is incorporated herein by reference.

[0210] Method for preparing a liquid oral dosage form According to some embodiments described herein, there is provided a method of preparing an oral formulation described herein, comprising: (a) combining active ingredients; (b) contacting the active ingredient with water; (c) mixing the active ingredient with water to prepare the oral formulation.

[0211] The combination of active ingredients may be as described herein above. The combination of active ingredients may also be as described below in connection with "Further Broad Aspects."

[0212] The active ingredient may be provided in the form of a liquid extract, a liquid oil, or a powder. If in powder form, step (c) may comprise mixing the active ingredient with water until the active ingredient is dissolved in the water.

[0213] Step (b) and / or step (c) may preferably be carried out at ambient or room temperature (20-25°C). Alternatively, the temperature may be elevated to aid in the dispersion or dissolution of the active ingredient in water. For example, step (b) may involve contacting the active ingredient with water at a temperature of about 20-100°C, e.g., about 30-90°C, or about 40-80°C. Step (b) may involve mixing the active ingredient with water at a temperature of about 20-100°C, e.g., about 30-90°C, or about 40-80°C.

[0214] The method may include adding optional additional additives at any stage. For example, optional additives may be added to the active ingredients before combining with water and / or after combining the active ingredients with water. Additives may be added to the water before contacting the water with the active ingredient combination. Step (a) may include the optional step of combining optional additives (e.g., acidifying agents) with the active ingredient combination. Step (b) may include the optional step of contacting the active ingredients with water and additives. Step (c) may include the optional step of adding additives to the mixture and mixing the additives with the active ingredient and water combination.

[0215] In some embodiments, the oral formulation further comprises one or more additives selected from a thickener, an organic acid, or a mixture thereof. In such embodiments, the one or more additives can be combined with water prior to the addition of the active ingredient. Optionally, combining the one or more additives with water can include heating the combination to a temperature of, for example, about 60°C to about 80°C to achieve dissolution of the additives. Additional additives, such as sweeteners, humectants, colorants, etc., can be added at this stage, during and / or after combining the active ingredient with water.

[0216] The resulting liquid formulation may be in the form of an aqueous solution or dispersion of the active ingredient.

[0217] Method for preparing tablet formulations In some embodiments, the formulation is in the form of compressed pellets or tablets. In one embodiment, the method for making pellets or tablets involves first mixing the active ingredient with a bulk filler (e.g., EMDEX®). The remaining composition ingredients (e.g., sugar alcohol and any other desired ingredients such as binders, colorants, sweeteners, flavors, etc.) are then added. Optionally, the colorant can be added to one of the composition ingredients in a separate step before mixing with the remaining composition ingredients. Mixing of the composition can be accomplished using any mixing equipment. The final composition is then compressed into pellet or tablet form using conventional tableting techniques and optionally coated. Compressed pellets of the composition can be made by compressing the composition, including any relevant formulation ingredients, into pellet form and optionally coating each pellet with an overcoat material. Exemplary compaction equipment, such as compaction molding machines, are available from Vector Corporation as Colton 2216 and Colton 2247, and from Fette Compacting as 1200i, 2200i, 3200, 2090, 3090, and 4090. Equipment for applying outer coatings to compacted pelletized compositions is available from Thomas Engineering as CompuLab 24, CompuLab 36, Accela-Cota 48, and Accela-Cota 60.

[0218] If present, the coating typically comprises a film-forming polymer such as a cellulose-based polymer, an optional plasticizer, and any flavoring, coloring, salt, sweetener, or other additive described herein. The coating composition is usually aqueous in nature and can be applied using any pellet or tablet coating technique known in the art, such as pan coating. Examples of film-forming polymers include cellulose-based polymers such as methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethyl cellulose, and carboxymethyl cellulose. Examples of plasticizers include aqueous solutions or emulsions of glyceryl monostearate and triethyl citrate. Additional coatings that can be used include food-grade shellac, waxes such as carnauba wax, and combinations thereof.

[0219] Method for preparing a lozenge formulation The methods and techniques used to formulate and manufacture the lozenge formulations described herein above can vary. For example, the compositions can be prepared by any method commonly used to manufacture hard candies. For example, exemplary methods for manufacturing hard candies can be found in LFRA Ingredients Handbook, Sweeteners, edited by Janet M. Dalzell, Leatherhead Food RA (December 1996), pages 21-44, which is incorporated herein by reference.

[0220] Typically, a first component mixture is prepared. The composition of the first component mixture can vary, but typically includes a sugar substitute and may contain various additional substances (e.g., sugar alcohol solution, NaCl, preservatives, additional sweeteners, water, and / or flavorings). In certain embodiments, the composition of the first component mixture includes a sugar substitute, salt, and vanillin. In other embodiments, the first mixture includes a sugar substitute and a sugar alcohol solution. Typically, the first component mixture does not contain an active ingredient, but in some embodiments, an active ingredient may be incorporated into the first component mixture.

[0221] The first component mixture is heated until melted, and then the mixture is heated to or past the hard crack stage. In confectionery, the hard crack stage is defined as the temperature at which a string-like strip of the heated mixture (obtained by pulling a cooled molasses sample between the thumb and index finger) becomes brittle or the molasses cracks when attempted to be molded. According to the present method, the temperature at which the hard crack stage is achieved may vary depending on the specific composition of the formulation mixture, but is generally between about 145°C and about 170°C. Typically, the mixture is not heated above about 171°C, the temperature at which caramelization begins to occur. In the method of the present disclosure, the mixture is typically cooled after being heated to or above the hard crack stage temperature. Heating can be performed at atmospheric pressure or under vacuum. Typically, the method of the present invention is performed at atmospheric pressure.

[0222] In one exemplary embodiment, the first component mixture includes a high percentage of isomalt, and the mixture is heated to about 143° C. Once all of the components have dissolved, the temperature is raised beyond the hard crack stage (e.g., to about 166° C.). After the mixture is heated to this temperature, heating is terminated and the mixture is allowed to cool.

[0223] In certain embodiments, the active ingredient(s) and optionally additional ingredients (e.g., additional sweeteners, fillers, flavors, and water) are individually combined in a second mixture. The second mixture is typically added to the first component mixture after the first component mixture has finished heating. In some embodiments, the addition of the second mixture may occur only after the heated first component mixture has cooled to a predetermined temperature (e.g., to about 132°C in certain embodiments). In certain embodiments, one or more flavors are added to the second mixture just before adding the second mixture to the heated first component mixture. Certain flavors are volatile, and therefore are preferably added after the mixture has cooled to a certain extent. The combined mixture is then formed into a desired shape. In certain embodiments, the mixture is poured directly into a mold, formed (e.g., rolled or pressed) into a desired shape, or extruded. If desired, the mixture can be extruded or injection molded. In certain embodiments, the mixture is formed into a mold of the desired shape or extruded in a closed system that requires low temperatures and can limit evaporation of certain mixture components. For example, such a system can limit evaporation of volatile ingredients, including, but not limited to, flavorings. Other methods of making lozenges are also intended to be encompassed herein.

[0224] Typical conditions associated with the manufacture of food-grade lozenge formulations as described herein include control of heat and temperature (i.e., the degree of heat to which the various ingredients are exposed during manufacture and the temperature of the manufacturing environment), moisture content (e.g., the degree of moisture present in the individual ingredients and in the final composition), humidity of the manufacturing environment, atmospheric control (e.g., nitrogen atmosphere), airflow experienced by the various ingredients during the manufacturing process, and other similar factors. Additionally, the various process steps involved in manufacturing the formulation may include selection of specific solvents and processing aids, use of heat and radiation, refrigeration and cryogenic conditions, ingredient mixing speed, etc. Manufacturing conditions can also be controlled by selection of the form (e.g., solid, liquid, or gas) of the various ingredients, the particle size or crystallinity of ingredients in solid form, the concentration of ingredients in liquid form, etc. The ingredients can be processed into the desired composition by techniques such as extrusion, compression, spraying, etc.

[0225] In certain embodiments, the lozenge formulation may be transparent or translucent. As used herein, "translucent" or "translucency" refers to a material that allows some light to pass through it diffusely. In certain embodiments, the lozenge formulations of the present disclosure may have a high degree of transparency, which may result in a material classified as "transparent" or exhibiting "transparency," which is defined as a material that allows light to pass freely through it without significant diffusion. The transparency of a lozenge formulation is in contrast to opacity, which refers to a material that cannot transmit light, and which exhibits some degree of translucency.

[0226] Transparency / translucency can be measured by any technique commonly used in the art, but is typically measured by spectrophotometric light transmittance over a wavelength range (e.g., about 400-700 nm). Optical techniques, such as turbidity (or scattered light measurement) and colorimetry, can also be used to quantify the turbidity (light scattering) and color (light absorption), respectively, of the lozenge formulations provided herein. Translucency can also be confirmed by visual inspection by simply holding a material (e.g., an extract) or formulation level with a light source and determining whether light diffusely passes through the formulation.

[0227] Method for preparing melt-type formulations In some embodiments, the formulation is in a meltable form. To prepare a meltable formulation, the lipid is typically heated to just above its melting temperature so that the lipid is liquefied. Optionally, active ingredients, flavorings, and / or lecithin can be added to the liquefied lipid at this stage. All or part of the liquefied lipid can then be blended into the dry blend and mixed until the product reaches the desired homogeneity or until the desired texture characteristics are achieved. The mixture is milled (e.g., in a dry roll mill) until the particle size is less than about 20 microns. The milled isomalt-palm oil mixture is combined with any remaining lipid, and the dry ingredients and flavorings are mixed. The base is generally heated until a flowable consistency is achieved.

[0228] In some embodiments, a sugar alcohol (eg, isomalt) is added to a mixer bowl, and a portion of the total lipid (eg, melted palm oil) is added along with salt and an emulsifier.

[0229] Additional lipid is added with mixing until a cohesive clump forms. The clumped mixture is divided and transferred to a three-roll mill and processed to a particle size of less than 50 microns, or about 20 microns. The adjusted mixture is transferred to a mixer bowl and the remaining lipid is added with mixing. The mixture is warmed as needed to maintain fluidity.

[0230] The sweetener, flavoring, and active ingredient are added while mixing. Mixing is continued until a homogeneous composition is obtained. The mixture is allowed to stand for a period of time, for example, about 10-15 minutes. The composition can be divided into individual portions, for example, by pouring the composition into a sheet-like structure, cooling, and cutting the structure into individual portions, or by filling the composition into a mold and allowing it to cool. The mold can be starch or non-starch. In certain embodiments, the mold is non-starch.

[0231] The molten composition may be held in a mold (starch or non-starch) for a predetermined time, for example, about 1 to about 15 minutes, to cool and solidify the molten composition. Optionally, the mold containing the melt may be cooled by refrigeration to accelerate solidification.

[0232] According to another aspect of the present disclosure, rather than using a mold to prepare the melt-type formulation, an extrusion process can be used in which the final melt-type formulation is extruded. In some examples, a melt composition in slurry form can be formed into a sheet and dried, for example, to a moisture content of about 15% to about 25% by weight of water, to form a sticky or other paste-like material in a physically manageable form. The paste-like material can then be chopped or otherwise cut into small pieces, for example, using a mixer. The chopped material can then be extruded in an extrusion device into any desired shape / size, including shapes that may be difficult or impossible to achieve with a mold. In some examples, the extruded product can then be dried to achieve the desired moisture content. A similar process is described, for example, in U.S. Pat. No. 3,806,617 to Smylie et al., which is incorporated herein by reference in its entirety. Additionally, the melt composition can be subjected to a coextrusion process with another composition.

[0233] For example, shapes such as rods and cubes can be formed by first extruding the material through a die having the desired cross-section (e.g., circular or square), and then optionally cutting the extruded material to the desired length. Techniques and equipment for extruding tobacco feedstock are described in U.S. Patent No. 3,098,492 to Wursburg, U.S. Patent No. 4,874,000 to Tamol et al., U.S. Patent No. 4,880,018 to Graves et al., U.S. Patent No. 4,989,620 to Keritsis et al., U.S. Patent No. 5,072,744 to Luke et al., U.S. Patent No. 5,829,453 to White et al., and U.S. Patent No. 6,182,670 to White et al., each of which is incorporated herein by reference. Exemplary extrusion equipment suitable for use includes a food or gum extruder, or an industrial pasta extruder such as the Model TP200 / 300 available from Emiliomiti, LLC, Italy. In some instances, it may be possible to accomplish multiple steps of the methods described herein in a single machine, such as, for example, a kneading apparatus available from Buss AG.

[0234] While the above description focuses on a uniform composition throughout each dosage unit, a product can also be formed from multiple different formulations with different properties within the same dosage unit. For example, two different compositions can be filled into a single mold to produce a layered dosage form. Furthermore, two different compositions can be co-extruded to form a dosage form with different cross-sectional properties. Such a method can be used to provide a dosage form with two different compositions characterized by different dissolution rates, such that one portion of the dosage form dissolves at a first rate (e.g., a faster rate) and the second portion dissolves at a second, slower rate.

[0235] Method for preparing pouch-packaged oral preparations When the formulation is in the form of a pouch-packaged oral formulation, the method comprises: (a) combining active ingredients; (b) contacting the combination of active ingredients with at least one filler to obtain an oral dosage form.

[0236] The combination of active ingredients may be as described herein above. The combination of active ingredients may also be as described below in relation to "Further Broad Embodiments."

[0237] In some embodiments, step (b) comprises mixing the active ingredient combination with at least one filler. In some embodiments, the active ingredient combination is in solid form (e.g., powder form). The active ingredient combination may be mixed directly with the filler to obtain an oral formulation. In some embodiments, the active ingredient combination may be dissolved in a hydrophilic solvent (e.g., water and / or alcohol) before contacting with the filler. For example, the active ingredient combination may be dissolved in water or alcohol (e.g., ethanol or propylene glycol) before mixing with the filler. In such embodiments, the method may comprise a step of drying the product to remove the solvent. For example, the product can be dried by heating, freeze-drying, spray-drying, or simply by leaving the product at room temperature for a period of time. Preferably, the drying step comprises leaving the product at room temperature for 1 hour to 48 hours to remove the solvent.

[0238] The method may then further comprise the step of pouching the oral formulation using a pouch material as described herein above.

[0239] use According to some embodiments described herein, there is provided use of a combination of active ingredients to provide a relaxation effect to a human or animal, the combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm.

[0240] In some embodiments, the active ingredient combination further comprises any of the additional active ingredients described herein above. For example, the active ingredient combination may further comprise vitamin C, chamomile extract, and / or L-tryptophan. The active ingredient combination may further comprise vitamin C, among others.

[0241] The combination of active ingredients may provide an improved relaxation effect to the consumer compared to previously known formulations. The inventors have found that the particular combination of active ingredients of the present invention may improve relaxation and calmness, reduce stress and anxiety, and improve sleep.

[0242] According to some embodiments described herein, there is provided a use of a combination of active ingredients for sedating a human or animal, the combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm.

[0243] Further broad aspects According to some embodiments described herein, there is provided an oral formulation in liquid form comprising a combination of active ingredients, wherein the combination of active ingredients comprises lemon balm in an amount of about 1000 ppm to about 2000 ppm.

[0244] Such oral formulations may further comprise other active ingredients. All active ingredients and / or additives described hereinabove with respect to the first aspect are equally applicable to such an embodiment and will not be repeated here for the sake of brevity. All amounts and combinations described hereinabove apply equally to this embodiment.

[0245] In some embodiments, the amount of lemon balm may be from about 1000 ppm to about 1500 ppm.

[0246] Also described herein is an oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising (i) lemon balm and (ii) ginseng.

[0247] Also described herein is an oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising (i) lemon balm and (ii) chamomile extract.

[0248] Also described herein is an oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising (i) ginseng and (ii) chamomile extract.

[0249] Also described herein is an oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients including (i) L-theanine and (ii) ginseng, wherein the L-theanine and ginseng are present in a weight ratio of about 5:1 to about 1:1.

[0250] In any of the above embodiments, the oral formulation may further comprise the additional active ingredients described herein above for the first aspect. In particular, the oral formulation may further comprise L-theanine, ginseng, lemon balm, and / or chamomile extract. The ranges and combinations of these additional active ingredients described herein above apply equally to these embodiments.

[0251] The methods and uses herein above are equally applicable to the broader aspects described above.

[0252] Example Aspects of the present invention will be more fully described by the following examples, which are set forth to illustrate particular aspects of the invention and are not to be construed as limitations thereof.

[0253] Example 1 - Liquid Dosage Form An oral formulation in liquid form is prepared containing the following ingredients:

[0254] [Table 1]

[0255] The oral formulation has a volume of 60 mL per serving.

[0256] The oral formulation is prepared by adding xanthan gum and citric acid to water under stirring and heating the mixture to a temperature of 60-80°C.

[0257] Once the xanthan gum and citric acid are dissolved, the mixture is cooled to ambient temperature. All remaining ingredients are then added and the resulting mixture is stirred until a uniform dispersion or clear solution is obtained.

[0258] The formulation is then packaged in bottles with each serving containing 60 mL of liquid.

[0259] Example 2 - Liquid Dosage Form An oral formulation in liquid form is prepared containing the following ingredients: ·water L-theanine Vitamin C - 90mg Chamomile flower extract ·Ginseng root extract Lemon balm leaf extract ·Coloring agent ·Fragrance Citric acid Thickener (xanthan gum) Potassium sorbate Sucralose

[0260] The combined amount of L-theanine, chamomile flower extract, ginseng root extract, and lemon balm leaf extract is 415 mg. The oral formulation has a volume of 60 mL per serving.

[0261] Oral formulations are prepared as described in Example 1.

[0262] Example 3 - Consumer Test Results A study was conducted comparing the formulation prepared in Example 2 to a placebo (Kool-Aid). A blinded study was conducted in which some subjects received the shot of Example 2 and some subjects received Kool-Aid.

[0263] Study participants were aged 18-30 years and considered healthy adults.

[0264] The following elements were evaluated:

[0265] [Table 2]

[0266] Prior to administration of either formulation, baseline measurements were performed (POMS, SAM), and physiological information was recorded using a Biopac monitor. Each participant then ingested one of the oral formulations. The formulations were blinded. Approximately 15-24 minutes later, participants were retested using the assessment procedures described above. 29-31 minutes after shot administration, participants were retested using SAM. All analyses were repeated 36-45 minutes after administration. Approximately 50-55 minutes after administration, participants were subjected to a controlled, simulated stressor (a computer game - Stroop task), and measurements were taken immediately after the stressor and again approximately 15-25 minutes later.

[0267] The following results were obtained: Galvanic Skin Response (GSR) - The formulation of Example 2 was shown to result in a decrease in GSR compared to placebo prior to the stressor. Subjective Negative Mood States - Placebo showed the most dramatic changes in negative mood states, while participants taking Example 2 did not show similar changes in self-reported subjective anger or confusion following the stressor. Subjective positive mood states - Placebo showed the most dramatic decrease in positive mood states, while Example 2 resulted in a more rapid recovery, returning subjective well-being to pre-stress levels.

[0268] The test results are shown in Figures 1 to 3.

[0269] Example 4 - Liquid Dosage Form An oral formulation in liquid form is prepared containing the following ingredients:

[0270] [Table 3]

[0271] The oral formulation has a volume of 60 mL per serving.

[0272] The oral formulation is prepared by adding xanthan gum and citric acid to water under stirring and heating the mixture to a temperature of 60-80°C. Once the xanthan gum and citric acid are dissolved, the mixture is cooled to ambient temperature. All remaining ingredients are then added and the resulting mixture is stirred until a uniform dispersion or clear solution is obtained. The formulation is then packaged in bottles with each serving containing 60 mL of liquid.

[0273] Example 5 - Liquid Dosage Form An oral formulation in liquid form is prepared containing the following ingredients: ·water L-theanine – 200mg Ginseng extract - 120mg Lemon balm extract - 75mg Chamomile extract ·Coloring agent ·Fragrance Citric acid Thickener Potassium sorbate Sucralose

[0274] The combined amount of L-theanine, chamomile extract, ginseng extract, and lemon balm extract is 505 mg. The oral formulation has a volume of 60 mL per serving.

[0275] Oral formulations are prepared as described in Example 4.

[0276] Example 6 - Results of consumer testing A study was conducted comparing the formulation prepared in Example 5 with a placebo (a shot containing no active ingredient). A blinded study was conducted, with one group of subjects receiving the shot of Example 5 and the other receiving a placebo. The study investigated the acute effects (approximately 2 hours) of the liquid dosage form on measures of subjective stress and related mood domains after completing a controlled, emotionally activating (mild stress / irritability / high stress) computer game. These measures assessed the effect of the liquid dosage form on mood and relaxation.

[0277] The following elements were evaluated:

[0278] [Table 4]

[0279] Study participants (n = 48 in the active ingredient and placebo groups combined) were aged 29–45 years and considered healthy adults. Key exclusion criteria included: a score above 59 on the Zung Self-Rating Depression Scale (participant mean score 22 / 80), nicotine and CBD use, allergens listed in the formulation, high caffeine intake (>400 mg / day), excessive alcohol consumption (>14 units / week), recreational drug users, prescription medication (excluding contraceptives), breastfeeding / pumping / pregnancy, self-reported moderate to severe anxiety / depression, self-reported sleep disturbances (e.g., night shift work), and the presence of life events that may cause emotional instability / fluctuations (e.g., job change, moving, international travel, divorce, surgery). A total of 48 participants participated, and 43 completed all sessions. Two sessions were missed due to a traffic strike, and four sessions were missed for personal reasons. Partial datasets were also included in the analysis. Participants refrained from eating or drinking anything within one hour prior to the test. Baseline measurements were performed (e.g., POMS, SAM) before administration of any formulation. These baseline measurements were performed 5 minutes after participants arrived at the test (i.e., a 5-minute waiting period was allowed). Baseline measurements were performed for the endpoints A-E listed above.

[0280] Each participant then received one of the oral formulations. The formulations were tested under a double-blind design. After ingestion, participants watched a 45-minute documentary before conducting a baseline test (i.e., a test identical to A-E above, midpoint: T50). After the midpoint measurements, participants watched a second 40-minute documentary and then performed tests A-E (pre-task: T95) again before receiving a stressor (a computer game designed to induce controlled emotional activation, the Stroop task). Measurements A-E (post-task: T105) were taken immediately after the stressor, and then again approximately 15 minutes (recovery (1): T120) and 30 minutes (recovery (2): T135) after the stressor. Participants watched the documentary between measurements.

[0281] The following results were obtained: State Trait Anxiety Inventory-State (STAI-S) - Comparing the post-game and adjusted pre-game measures on the STAI-S, a statistically significant reduction in stress response (2 points) was observed compared to placebo (p=0.006), as well as a shorter recovery time and return to pre-game levels compared to placebo. The test results are shown in Figure 4. Stress - Subjective stress measured by the STAI-S was significantly lower than that of the placebo. The test results are shown in Figure 5. When all combined evaluation items after intake were compared with the true baseline, a statistically significant reduction in stress response was observed compared to the placebo (p=0.023). The STAI-S was the primary endpoint of this study. Tension - Subjective tension measured using a visual analog scale (VAS) was significantly lower than in the placebo group. This reduction in tension showed a significant difference compared to the placebo group over the course of the study. The test results are shown in Figures 6 and 13. Fatigue - Subjective fatigue measured using a visual analog scale (VAS) was significantly lower compared to placebo. This reduction in fatigue was significant compared to placebo at 95-135 minutes and over the course of the study. The test results are shown in Figures 7 and 15. Sense of control - Subjective sense of control, measured using a visual analogue scale (VAS), indicated that participants felt more in control compared to the placebo group. The results are shown in Figure 8. Attention - Subjective attention, as measured using the Visual Analog Mood Scale (VAMS), was significantly higher than in the placebo group. This reduction in attention deficit was significantly greater than in the placebo group at each time point and over the course of the study. The test results are shown in Figures 9 and 14. Calmness - Subjective calmness, measured using the Visual Analog Mood Scale (VAMS), was significantly higher compared to placebo. This increase in calmness was significant over the course of the study compared to placebo. The results are shown in Figures 10 and 12. Subjective sense of initiative, measured using the Social Activity Measure (SAM), was significantly higher than placebo over the course of the study. The results are shown in Figure 11.

[0282] The test results are shown in FIGS.

[0283] Compared to placebo, significant main effects (average across all post-intake time points for each domain) were observed for multiple assessments (STAI-S, calmness, tension, sense of initiative, and sense of "self-control"). Interestingly, greater alertness and less drowsiness were observed compared to placebo, indicating that the liquid dosage form of the present invention provides relaxation, mood maintenance, and stress management without sedation or drowsiness.

[0284] The various embodiments described herein are presented solely to aid in the understanding and teaching of the claimed features. These embodiments are provided only as a representative sample of embodiments and are not exhaustive and / or exclusive. The advantages, embodiments, examples, functions, features, structures, and / or other aspects described herein should not be construed as limitations on the scope of the invention as defined by the claims or limitations on the equivalents of the claims, and it should be understood that other embodiments may be utilized and modifications may be made without departing from the scope of the claimed invention. Various embodiments of the present invention may suitably comprise, consist of, or consist essentially of any suitable combination of the disclosed elements, components, features, parts, steps, means, etc., other than those specifically described herein. Furthermore, the present disclosure may include other inventions not currently claimed but which may be claimed in the future.

[0285] Numbered clauses 1. An oral formulation comprising a combination of active ingredients, the combination comprising: (i) L-theanine, (ii) ginseng, (iii) Lemon balm. 2. The oral formulation of clause 1, wherein the L-theanine is present in an amount of about 0.01% to about 5% by weight of the oral formulation. 3. The oral formulation of clause 1 or 2, wherein the ginseng is present in an amount of about 0.001% to about 3% by weight of the oral formulation. 4. The oral formulation of any one of clauses 1-3, wherein the lemon balm is present in an amount of about 0.001% to about 3% by weight of the oral formulation. 5. The oral formulation of any one of clauses 1 to 4, wherein the L-theanine and ginseng are present in a weight ratio of about 50:1 to about 1:2. 6. The oral formulation of any one of clauses 1 to 5, wherein the L-theanine and lemon balm are present in a weight ratio of about 1:1 to about 20:1. 7. The oral formulation of any one of clauses 1 to 6, wherein the ginseng and lemon balm are present in a weight ratio of about 10:1 to about 1:10. 8. The oral formulation of any one of clauses 1 to 7, wherein the combination of active ingredients further comprises vitamin C, optionally wherein the vitamin C is present in an amount of about 0.01% to about 5% by weight of the oral formulation. 9. The oral formulation of clause 8, wherein the vitamin C and L-theanine are present in a weight ratio of about 10:1 to about 1:10. 10. The oral formulation of any one of clauses 1-9, wherein the combination of active ingredients further comprises chamomile extract, optionally in an amount of about 0.0001% to about 1% by weight of the oral formulation. 11. The oral formulation according to any one of clauses 1 to 10, wherein the oral formulation comprises the combination of active ingredients in an amount of about 0.1% to about 10% by weight of the oral formulation. 12. The oral formulation of any one of clauses 1 to 11, further comprising one or more additives selected from the group consisting of flavorings, sweeteners, acidifying agents, thickeners, fillers, binders, humectants, preservatives, and mixtures thereof. 13. The oral formulation according to clause 12, wherein the oral formulation comprises an acidifying agent. 14. The oral formulation according to any one of clauses 1 to 13, wherein the oral formulation is an oral dosage form in the form of a solid, gel, or liquid. 15. The oral formulation according to any one of clauses 1 to 14, wherein the oral formulation is in the form of a loose powder, a troche, a tablet, a film, or a drink. 16. The oral formulation according to any one of clauses 1 to 15, wherein the oral formulation is a liquid oral dosage form having a volume of from about 1 mL to about 200 mL. 17. The oral formulation according to clause 16, wherein the oral formulation is in the form of a liquid oral dosage form having a volume of about 50 mL to about 100 mL. 18. The combination of active ingredients is (i) L-theanine, (ii) ginseng, (iii) lemon balm; (iv) Vitamin C; (v) a chamomile extract. 19. The oral formulation of any one of clauses 16-18, wherein the oral formulation further comprises water in an amount of about 50% to about 99.9% by weight of the oral formulation. 20. The oral formulation according to any one of clauses 16 to 19, wherein the oral formulation comprises the combination of active ingredients in an amount of about 0.5% to about 10% by weight of the oral formulation, and wherein the oral formulation comprises water in an amount of about 90% to about 99.5% by weight of the oral formulation. 21. Oral formulations are (a) a combination of active ingredients in an amount of about 0.5% to about 5% by weight of the oral formulation, wherein the combination of active ingredients is (i) L-theanine, (ii) ginseng, (iii) lemon balm; (iv) Vitamin C; (v) a combination of active ingredients comprising chamomile extract; (b) the oral formulation according to any one of clauses 16 to 20, which is a liquid oral dosage form comprising water in an amount of about 90% to about 99.5% by weight of the oral formulation. 22. The oral formulation of any one of clauses 16 to 21, wherein the oral formulation has a pH of about 2.5 to about 3.5. 23. The liquid dosage form is (i) about 50 mg to about 500 mg of L-theanine and / or (ii) about 10 mg to about 300 mg of ginseng and / or (iii) The oral formulation of any one of clauses 16 to 22, comprising from about 1 mg to about 200 mg of lemon balm. 24. A method for preparing an oral formulation as defined in any one of clauses 1 to 23, comprising: (a) combining active ingredients, the active ingredients including (i) L-theanine, (ii) ginseng, and (iii) lemon balm; (b) contacting the active ingredient with water; (c) mixing the active ingredient with water to prepare an oral formulation. 25. Use of a combination of active ingredients to provide a relaxation effect to a human or animal, the combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm. 26. Use of a combination of active ingredients for sedating a human or animal, the combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm. 27. An oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising lemon balm in an amount of about 1000 ppm to about 2000 ppm. 28. An oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising (i) lemon balm and (ii) ginseng. 29. An oral formulation in liquid form comprising a combination of active ingredients, the combination of active ingredients comprising (i) L-theanine and (ii) ginseng, wherein the L-theanine and ginseng are present in a weight ratio of about 5:1 to about 1:1.

Claims

1. 1. An oral formulation comprising a combination of active ingredients, said combination comprising: (i) L-theanine, (ii) ginseng, (iii) Lemon balm.

2. 10. The oral formulation of claim 1, wherein the L-theanine is present in an amount of about 0.01% to about 5% by weight of the oral formulation.

3. 3. The oral formulation of claim 1, wherein the ginseng is present in an amount of about 0.001% to about 3% by weight of the oral formulation.

4. 4. The oral formulation of claim 1, wherein the lemon balm is present in an amount of about 0.001% to about 3% by weight of the oral formulation.

5. 5. The oral formulation of claim 1, wherein the L-theanine and the ginseng are present in a weight ratio of about 50:1 to about 1:

2.

6. 6. The oral formulation of claim 1, wherein the L-theanine and the lemon balm are present in a weight ratio of about 1:1 to about 20:

1.

7. 7. The oral formulation of claim 1, wherein the ginseng and lemon balm are present in a weight ratio of about 10:1 to about 1:

10.

8. 8. The oral formulation of any one of claims 1 to 7, wherein the combination of active ingredients further comprises vitamin C, optionally present in an amount of about 0.01% to about 5% by weight of the oral formulation.

9. 9. The oral formulation of claim 8, wherein the vitamin C and the L-theanine are present in a weight ratio of about 10:1 to about 1:

10.

10. 10. The oral formulation of any one of claims 1 to 9, wherein the combination of active ingredients further comprises chamomile extract, optionally in an amount of about 0.0001% to about 1% by weight of the oral formulation.

11. 11. The oral formulation of any one of claims 1 to 10, wherein the oral formulation comprises the combination of active ingredients in an amount of about 0.1% to about 10% by weight of the oral formulation.

12. 12. The oral formulation of any one of claims 1 to 11, further comprising one or more additives selected from the group consisting of flavoring agents, sweeteners, acidifying agents, thickeners, fillers, binders, humectants, preservatives, and mixtures thereof.

13. 13. The oral formulation of claim 12, wherein the oral formulation comprises an acidifying agent.

14. The oral formulation according to any one of claims 1 to 13, wherein the oral formulation is an oral dosage form in the form of a solid, gel, or liquid.

15. The oral formulation according to any one of claims 1 to 14, wherein the oral formulation is a liquid oral dosage form having a volume of about 1 mL to about 200 mL.

16. 16. The oral formulation of claim 15, wherein the oral formulation is in the form of a liquid oral dosage form having a volume of about 50 mL to about 100 mL.

17. The combination of active ingredients is (i) L-theanine, (ii) ginseng, (iii) lemon balm; (iv) optionally, vitamin C; and 17. The oral formulation of claim 15 or 16, comprising (v) a chamomile extract.

18. 18. The oral formulation of claim 16 or 17, wherein the oral formulation further comprises water in an amount of about 50% to about 99.9% by weight of the oral formulation.

19. The oral formulation (a) a combination of active ingredients in an amount of about 0.5% to about 5% by weight of the oral dosage form, wherein the combination of active ingredients comprises: (i) L-theanine, (ii) ginseng, (iii) lemon balm; (iv) optionally, vitamin C; and (v) a combination of active ingredients comprising chamomile extract; and (b) water in an amount of about 90% to about 99.5% by weight of the oral formulation, wherein the combination of active ingredients is a liquid oral dosage form consisting essentially of L-theanine, ginseng, lemon balm, and chamomile extract.

20. 20. The oral formulation of any one of claims 15 to 19, wherein the oral formulation has a pH of about 2.5 to about 3.

5.

21. the liquid dosage form comprising: (i) about 50 mg to about 500 mg of L-theanine and / or (ii) about 10 mg to about 300 mg of ginseng and / or (iii) The oral formulation of any one of claims 15 to 20, comprising from about 1 mg to about 200 mg of lemon balm.

22. A method for preparing the oral formulation according to any one of claims 1 to 21, comprising the steps of: (a) combining active ingredients, the active ingredients including (i) L-theanine, (ii) ginseng, and (iii) lemon balm; (b) contacting the active ingredient with water; (c) mixing the active ingredient with water to prepare an oral formulation.

23. 1. Use of a combination of active ingredients to provide a relaxation effect to a human or animal, the combination of active ingredients comprising (i) L-theanine, (ii) ginseng, and (iii) lemon balm.

24. 1. Use of a combination of active ingredients for sedating a human or animal, said combination of active ingredients comprising: (i) L-theanine; (ii) ginseng; and (iii) lemon balm.

25. 1. An oral formulation in liquid form comprising a combination of active ingredients, said combination of active ingredients comprising lemon balm in an amount of about 1000 ppm to about 2000 ppm.

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