Thermal energy system for administering active drugs

Abstract

Described herein is an intraoral composition for delivering an active agent, comprising a core, wherein the core comprises at least one active agent, a phase change material, an exothermic material, and optionally a permeation enhancer, and less than 0.5% water, according to one embodiment. Further described herein is a method for treatment, comprising administering an intraoral composition for delivering an active agent, comprising a core, wherein the core comprises at least one active agent, a phase change material, and an exothermic material, and less than 0.5% water, to a subject requiring such treatment.

Description

Technical Field

[0001] Cross - reference to Related Applications [1]This application claims the benefit of U.S. Provisional Patent Application No. 63 / 461,284, filed on April 23, 2023, the content of which is hereby incorporated by reference in its entirety.

[0002] Technical Field [2]Embodiments of the present invention relate to compositions for oral administration comprising an active agent and a thermal energy system.

Background Art

[0003] [3]Mouse washes / rinses and oral gels containing a wide variety of active agents / components have been widely used and topically applied for many years. Many drugs or dietary supplements have been applied in this manner both topically and in the oral cavity. Additionally, oral mucoadhesive patches and chewing gums containing active agents on surfaces facing tissues have been used to deliver drugs or dietary supplements through oral tissues.

[0004] [4]Delivery of exogenous materials via oral administration through the oral cavity, particularly the oral mucosa, is considered a safe and convenient strategy, especially for affected individuals with needle phobia and dysphagia, both in the clinic or at home. Oral tissue delivery without degradation in the digestive tract and first - pass degradation by hepatic metabolism is an alternative route of administration for feasible polymer absorption when compared to parenteral oral (PO) or injection by needle.

[0005] [5] Two systems that can be used for oral administration to the oral mucosa are functional chewing gum and oral mucosal adhesive patches. Chewing gum is a cohesive substance that softens when chewed and is designed to be chewed rather than swallowed. Functional chewing gum contains active agents, such as drugs or dietary supplements, that are released from the chewing gum substrate and administered while the subject chews the gum. Chewing gum generally contains a gum base, sweeteners, softeners, and flavorings. Oral mucosal adhesive patches are drug or dietary supplement carriers that have an adhesive that adheres to the oral mucosa and a drug or dietary supplement that is released when the patch is in the subject's oral cavity. Some oral adhesive patches have an adhesive that fixes the patch to the tissue at the time of application, and the extrinsic material contained in the patch begins to permeate through the oral tissue membrane into the bloodstream, thereby providing a benefit to the subject.

[0006] [6] Various mucoadhesive polymers exist that have been used in the development of oral mucoadhesive or bioadhesive patch delivery systems, including chitosan, polyacrylic acid, alginate, polymethacrylic acid, and sodium carboxymethylcellulose. Chitosan, a cationic polymer, is widely used due to its biodegradability and biocompatibility, and exhibits mucoadhesive properties by electrostatically interacting with negatively charged mucin chains. The term bioadhesion means that the drug carrier system is attached to a specific biological site. The biological surface may be epithelial tissue or a mucous film on a tissue surface. When an adhesive is attached to a mucous film, this phenomenon is called mucoadhesive.

[0007] [7] Muco-adhesive patches typically consist of four layers: a base (outer) layer, which is an impermeable backing layer made of a water-insoluble material; an active agent reservoir containing an active agent such as a drug or nutritional supplement; a semipermeable membrane that can function as a rate-limiting barrier; and an adhesive layer. An example of a backing membrane material that is impermeable to saliva / moisture is polyethylene terephthalate / ethylene vinyl acetate (PET / EVA).

[0008] [8] The materials used as the backing layer of a typical muco-adhesive patch are configured to be inert to the active agent and any penetration enhancers present in the active agent reservoir. The impermeable backing layer of known muco-adhesive patches is designed to prevent loss of the active agent due to saliva runoff when the patch is applied in the oral cavity for an extended period, and to allow the active agent to diffuse through oral tissue in a rate-limited and relatively slow manner.

[0009] [9] The adhesion process is complex and involves contact, compaction, and the formation of some kind of bond between the polymer and the mucus. Adhesion of the two materials is achieved by contact between the pressure-sensitive adhesive and the surface (mucosa). Several polymer-related factors such as molecular weight, chain length, degree of crosslinking, degree of hydration, functional groups, charge, and polymer concentration, as well as several environmental and physiological factors such as contact time, mucin turnover rate, and mucus viscosity, influence the degree of mucus adhesion.

[0010]

[10] As described above, the time from application to the manifestation of pharmacological activity of exogenous materials from typical mucosal adhesive patches is very slow due to the relatively slow passive absorption of the exogenous material through intact skin / oral tissue membranes. For example, with commercially available scopolamine transdermal patches, it typically takes 4 hours from application of the patch until circulating plasma concentrations of scopolamine are detected, and an average of 24 hours for drug concentrations to reach their peak. Carvedilol mucosal adhesive patches for tachycardia typically take 8 hours for 95% of the drug to be released into the oral mucosal tissue.

[0011]

[11] Oral tissue is a complex set of tissues that cover the oral cavity. It consists of layers of tissue, including laminar squamous epithelium, basement membrane, and underlying connective tissue. In addition to the dentition, the buccal oral tissue, as well as the sublingual, palatal, and gingival oral tissues, are parts of the oral cavity. The buccal oral tissue consists of the outer epithelium and basement membrane. Non-keratinized laminar squamous epithelium forms the outer buccal epithelium. It is mostly composed of phospholipids and proteins in the form of tonofilaments. The basal layer of the epithelium differentiates into replacement cells that slough off from the outermost tissue surface. Due to its morphology and lipid structure, the epithelium is considered the primary barrier to the penetration of most active drugs in delivery from the cheek.

[0012]

[12] Except for the presence of barrier substances between the surface cells, the surface of the oral epithelium is normally covered with saliva. In addition to its role as a liquid that dilutes and removes surface substances, saliva has more than just a cleansing effect, and mucin in saliva can contribute to enhancing the impermeability of the barrier layer of the oral tissue as a whole.

[0013]

[13] Passive diffusion / translocation transport through oral tissues involves two transport pathways: the paracellular pathway and the transcellular pathway. Penetrating / diffusing agents can utilize both pathways simultaneously, but due to the physicochemical properties of the diffusing agent, one pathway is usually preferred over the other. Since the intercellular spaces and cytoplasm are hydrophilic, lipophilic compounds will have low solubility in this environment. However, tissue cell membranes are inherently rather lipophilic, and hydrophilic solutes will have a low partition coefficient and will not easily permeate the cell membrane. Therefore, the intercellular spaces act as the primary barrier to the permeation of lipophilic compounds, and the cell membrane acts as the primary transport barrier for hydrophilic compounds. Because oral epithelium is layered, a combination of these two pathways may be involved in solute permeation. However, generally, the pathway with the least obstruction to passage prevails.

[0014]

[14] There are many major pathways for the active penetration / diffusion into oral tissues by the action of permeability-enhancing substances. These can act through many mechanisms, including increasing the fluidity of cell membranes, extracting intercellular / intracellular lipids, altering cellular proteins or surface mucins, or dilating blood vessels in the tissue by increasing nitric oxide levels. The greater the degree of action, the greater the permeability capacity of the diffusing substance, the faster the diffusion rate, and the ability of the permeability-enhancing substance to diffuse larger molecules through oral tissues. [Overview of the Initiative] [Problems that the invention aims to solve]

[0015]

[15] As explained above, most oral tissues act as a natural barrier against the rapid penetration of exogenous materials (especially high molecular weight materials), such as nutritional supplements and many medications, through the oral tissues. This is because the transport of these exogenous materials through the oral epithelium usually occurs by passive diffusion, a relatively slow and time-consuming process, and a high degree of adherence to medication by the affected individual is required for them to be even partially effective.

[0016]

[16] It is difficult for users to keep liquid / gel-like medications, such as dietary supplements or drugs, in their mouths for extended periods. Lozenges, chewing gum carriers, and mucoadhesive delivery systems (patches) have been formulated to overcome this limitation on therapeutic exposure time. Both this difficulty and the inherent difficulty of transporting active drugs through oral tissues are reasons why oral administration of active drugs is not a widely used form of administration. [Means for solving the problem]

[0017] overview

[17] According to one embodiment, an oral composition described herein is a composition for oral delivery of an active agent, the composition comprising: a core having at least one active agent, a phase change material, and an exothermic material, and less than 0.5% water.

[0018]

[18] Further described herein by one embodiment is a method for treatment comprising administering an oral composition for oral delivery of an active agent to a subject requiring such delivery, the oral composition comprising: a core having at least one active agent, a phase change material, and an exothermic material, and less than 0.5% water. [Brief explanation of the drawing]

[0019] [Figure 1]

[19] Figure 1 is a flowchart showing a method for administering an active agent using a composition including a thermal energy system (TES) according to one embodiment. [Figure 2]

[20] Figure 2 is a graph showing the melting points of mixtures of light paraffin oil and beeswax at various weight concentrations. [Figure 3A]

[21] Figures 3A and 3B are graphs showing the temperature change over time of a mixture of an exothermic anhydrous salt and water, with Figure 3A being a mixture without a phase change material (PCM). [Figure 3B] Figure 3B shows a mixture containing PCM. [Modes for carrying out the invention]

[0020] Detailed explanation

[22] Unless otherwise indicated, technical terms are used in accordance with their conventional usage. Definitions of common terms in molecular biology can be found in the following: Benjamin Lewin, Genes V, Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al., (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd. in 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc. in 1995 (ISBN 1-56081-569-8).

[0021]

[23] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. Further, all base sizes or amino acid sizes, and all molecular weights or molecular mass values given for nucleic acids or polypeptides or peptides or proteins or portions or fractions thereof are approximate and are provided for illustrative purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The term "comprise" means "include". The abbreviation "e.g." is derived from the Latin "exempli gratia" and is used herein to indicate non-limiting examples. Thus, the abbreviation "e.g." is synonymous with the term "for example".

[0022]

[24] In case of any conflict, the specification including the term explanations shall prevail. Further, all materials, methods, and examples are illustrative and not intended to be limiting.

[0023]

[25] According to one embodiment, what is described herein is a composition for the oral delivery of an active agent, the composition comprising: a core having an active agent, a phase change material, a heat-generating material, and a penetration enhancer, preferably the heat-generating material is in the form of an anhydrous salt, and the core contains less than 0.5% water, said core. Optionally the composition is in the form of chewing gum and further comprises a chewing gum base. Optionally the composition is in the form of a mucoadhesive patch.

[0024]

[26] According to one embodiment, such a composition for oral administration comprises a heat-generating excipient configured to generate heat and increase the temperature in the oral cavity over the delivery period. It is suggested that when the temperature of the administration site rises, the permeability of oral tissues increases, thereby enabling enhanced absorption of the active agent. Optionally the composition is in the form of chewing gum or a mucoadhesive patch.

[0025]

[27] In previous research (AAPS PharmSciTech, Vol. 12, No. 2, June 2011), it was shown that heating of various active agents (buspirone, bupivacaine, antipyrine, and caffeine) used as diffusing agents was demonstrated throughout porcine oral tissues at five different temperatures of 23°C, 30°C, 37°C, 45°C, and 52°C. It was found that the permeation of all diffusing agents tested increased from 1.4-fold to 2.4-fold for every approximately 7°C increase in the experimental temperature. Thus, an exponential relationship was observed between temperature and the permeability of the four diffusing agents tested passing through the oral tissue barrier. Irreversible effects occurred in oral tissues only above 68°C. Therefore, the temperature range tested (23°C to 52°C) can be considered appropriate and safe for oral tissues.

[0026]

[28] Without being bound by theory, it is suggested that heating the oral cavity by administering the compositions disclosed herein increases the temperature of the oral tissues, thereby increasing the energy of the permeators entering the oral tissues and thus enabling permeation. Furthermore, vasodilation of subcutaneous blood vessels as a homeostatic response to the increase in oral tissue temperature also plays an important role in promoting the diffusion and delivery of active agents to the oral tissues. Other advantages of heating the oral cavity may include: a. the release of large amounts of active agents from the compositions; b. increased solubility of the agents in saliva, decreased viscosity of saliva, and increased fluidity of saliva due to heating of saliva; c. increased concentration of active agents in saliva; d. increased exposure of the entire oral tissue to the components of the formulation; e. increased fluidity of tissue membranes; f. increased permeation / diffusion of components into and through tissue membranes; g. increased flow of components from tissues to the bloodstream; h. increased bioavailability of active agents to organs in the body.

[0027]

[29] This specification describes oral delivery compositions of active agents configured to promote penetration into oral tissues by generating heat via a thermal energy system (TES). The TES includes an exothermic material (EM) and a phase change material (PCM). The EM is a material that releases heat upon contact with water / moisture. The PCM is a material that undergoes a phase change from solid to liquid in a given temperature range, preferably 40°C to 48°C, more preferably 44°C to 48°C.

[0028]

[30] If the EM is an anhydrous salt, a hydration reaction occurs when the composition is administered, generating heat within the composition during the period of oral application, which is then transferred to the oral tissues. The composition is configured to generate heat within a specific temperature range by sequentially releasing exothermic energy when an exothermic material (EM), such as an anhydrous salt, is exposed to saliva present in the subject's mouth. The heat generated by the reaction between the anhydrous salt and saliva supplies heat to the oral tissues in the oral cavity, and also causes the PCM incorporated into the composition to absorb the thermal energy released by adjacent activated EM and undergo a phase change (formulated to undergo the phase change within the temperature range generated by the EM), thereby storing thermal energy. Subsequently, as the PCM cools due to the phase change, it gradually releases heat, supplying heat to the oral tissues. This phase change process may occur continuously in a portion of the composition during administration to prolong the heating effect of the TES. This process is repeated / cycled during the oral administration period, acting as a "cascade" thermal energy system that sequentially releases heat in a relatively controlled manner (based on the molar concentration in the formulation) as the EM is gradually hydrated. The presence of PCM in the composition prevents cooling from occurring to a greater extent than in equivalent compositions that do not contain PCM. The longer the time that TES supplies heat to the composition and the oral cavity results in an increased and sustained increase in the diffusion of the active agent during the application period.

[0029]

[31] Furthermore, several embodiments relate to methods for administering active agents, comprising administering a composition comprising the active agent and TES into the oral cavity of a subject requiring it. One embodiment of such a method is described in Method 100, illustrated in Figure 1. Method 100 comprises block 10, which comprises removing the composition from packaging. Preferably, the packaging is airtight packaging. The packaging includes a blister pack with a high-density polyethylene lining (such as a Tyvek® heat-sealed blister pack having individual blister cavities for each piece of gum), which prevents moisture and / or air from passing from the environment outside the packaging into the space containing the composition inside the packaging. Optionally, the composition is packaged in a humidity-controlled environment where the air is dehumidified to prevent the composition from being packaged with moist air. Furthermore, both a pre-coating that completely seals the core portion of the gum and is waterproof, as well as a second final hard coating, serve to prevent the passage of environmental moisture and / or air, even when the gum is removed from the airtight blister package.

[0030]

[32] Method 100 further comprises block 20, which includes exposing the composition to saliva in the oral cavity. If the composition is chewing gum, exposure to saliva is carried out by introducing the composition into the mouth of the subject and beginning to chew the chewing gum. If the composition is a mucous adhesive patch, exposure to saliva is carried out by adhering the mucous adhesive patch to the mucous membrane of the oral cavity, where the side of the patch not facing the tissue is a semipermeable membrane structure. Upon contact with saliva, the EM in the composition is hydrated, thereby generating heat through an exothermic reaction. Adjacent PCM incorporated into the composition absorbs the thermal energy released by the adjacent activated EM and undergoes a phase change (formulated to undergo the phase change within the temperature range generated by the EM), thereby storing thermal energy. The PCM then gradually releases heat as it cools through the phase change, supplying heat to the oral tissue. This phase change process may occur continuously to portions of the composition during administration of the composition in order to prolong the heating effect of the TES of the mucous adhesive patch. The longer the time that TES supplies heat to the composition and oral cavity, the greater and more sustained the increased diffusion of the active agent during the application period.

[0031]

[33] Method 100 further includes block 30, which comprises a solid-to-liquid phase change of the PCM due to the absorption of heat from the composition.

[0032]

[34] Method 100 further includes block 40, which includes a phase change of the PCM from liquid to solid and the release of thermal energy in the composition and oral tissue. This phase change occurs when the local temperature decreases below a certain threshold. Releasing heat in this step results in a longer duration of heat availability of the composition in the oral cavity.

[0033]

[35] After block 40, much of the EM in the composition may be exposed to saliva, thereby hydrating the EM and releasing heat via an exothermic reaction according to block 20, which may result in the continuation of the phase change according to blocks 30 and 40. If the composition is chewing gum, more of the EM in the composition may be exposed to saliva as the subject continues to chew the composition. If the composition is a mucous adhesive patch, more of the EM in the composition may be exposed to saliva as saliva continues to penetrate the mucous adhesive patch, as described below.

[0034]

[36] Method 100 further comprises block 50, which includes the completion of heat release from the EM and PCM, thereby returning the composition to equilibrium at oral temperature. At this point, the composition may be removed from the mouth. In the case of chewing gum, the composition may be removed from the mouth and discarded. In the case of a mucous adhesive patch, the composition may be completely removed from the mouth.

[0035]

[37] Compositions according to embodiments of the present invention comprise one or more active agents. The active agents may optionally be microencapsulated as described below with respect to PCM. The active agents may optionally be contained within food-grade macroporous or microporous granules / particles as described with respect to PCM.

[0036]

[38] As previously stated, both PCM and EM can apply heat to oral tissue for an extended period while the disclosed composition is administered. While many materials can function as PCMs, preferred PCMs have been found to absorb and release thermal energy during melting and re-solidification processes in a temperature range related to the heat released by the EM. These PCMs possess latent heat storage capabilities.

[0037]

[39] According to one embodiment, the PCM used in the composition described herein undergoes a phase change at a temperature of 40°C to 48°C, preferably 44°C to 48°C.

[0038]

[40] According to one embodiment, the PCM is selected from the group consisting of beeswax, glycerol, polyethylene glycol, and paraffin oil. Optionally, beeswax is used as a PCM in combination with an agent that lowers its melting temperature (optionally paraffin oil, glycerol, or polyethylene glycol). Optionally, a combination of beeswax and paraffin oil is used as a PCM. Optionally, beeswax and paraffin oil are used in a ratio of 1:1 to 2:3. Figure 2 is a graph showing the melting points of mixtures of beeswax and light paraffin oil at various ratios. As can be seen, a mixture of beeswax and paraffin oil having about 40% to about 80% beeswax has a melting point of about 32°C to about 62°C, which may be relevant to compositions for oral delivery.

[0039]

[41] According to one embodiment, the PCM is present in the core in an amount of 1% to 10% by weight. The weight ratio of the PCM to the EM is arbitrarily about 1:10.

[0040]

[42] According to one embodiment, PCM is encapsulated using “microencapsulation.” Microencapsulation is an advanced food processing technique in which any compound can be encapsulated within a specific material, creating small spheres ranging in diameter from 1 micron to several hundred microns. The compound or material to be encapsulated is encapsulated by another substance known as the capsule material, wall, or shell material. The capsule material can be either a polymer or a non-polymer, such as cellulose, ethylene glycol, and gelatin. Several techniques are used in microencapsulation. Microencapsulation processes include fluidized bed coating, spray cooling, spray drying, extrusion, and coacervation.

[0041]

[43] Based on the physical and chemical properties of the encapsulated interior, the composition of the shell material, and the microencapsulation method used, various types of capsules can be obtained: simple spheres surrounded by wall material, capsules with irregular interiors, multiple different interiors within a continuous coating of wall material, multi-walled microcapsules, and interior particles embedded within a wall material substrate. Different techniques are used to manufacture microcapsules depending on the type of coating material used, and these techniques result in differences in the properties of the capsules.

[0042]

[44] The selection of a particular technique is made based on the properties of the internal material and the capsule material, and the various properties and morphologies of the desired capsule. Efficient and good encapsulation characterization and optimization can be performed by studying the encapsulation efficiency and various properties such as the morphology, size, hydrophobicity, hygroscopicity, solubility, surface tension, thermal behavior, hydrophobicity, thermal properties, and mechanical properties of the capsule.

[0043]

[45] Microencapsulation coating materials may include silicon dioxide, chitosan; carbohydrates such as starch, sucrose, maltodextrin, modified starch, and cyclodextrin; lipids such as beeswax and diacylglycerol; gums such as acacia gum, gum arabic, agar, guar, and carrageenan; and proteins such as gluten and casein. The coating material or wall / shell material used for microencapsulation must be able to form an aggregated film inside, stabilize and give strength to the capsule, be inert and thus not react with the internal material, not impart any particular taste to the product, be impermeable, and have the ability to release the contents by a specific process at a specific time and place.

[0044]

[46] Spray drying is a technique in which a feed solution, which is a mixture of internal material and wall / shell material, is atomized and formed into a mist in a chamber, and hot air is applied to turn the mist into powder, and a technique in which droplets of a solution / suspension are turned into dry powder by evaporation of the solvent / liquid. Powders of various particle sizes can be produced depending on various factors such as the properties of the feed solution and operating conditions. In spray drying, the internal material, i.e., the material of interest, is trapped in the dry powder.

[0045]

[47] Spray cooling is another microencapsulation technique. Spray cooling is very similar in operation to spray drying, but the main difference is the use of cold air. Here, a mixture of the internal material and wall material is atomized to form a mist inside the chamber, and cold air is blown through it. Because the temperature inside the chamber is low, the tiny droplets solidify, thereby forming microencapsulated powder.

[0046]

[48] ​​Coacervation is another microencapsulation technique. Coacervation is a simple technique that involves forming a homogeneous layer of polymer wall material around an internal material. This is achieved by altering the physicochemical properties of the wall material by changing the temperature, pH, or ionic strength. Here, the internal material and the wall material are mixed to form an immiscible solution. Phase separation is then performed by changing the ionic strength, pH, or temperature to form coacervates, which are tiny droplets consisting of a polymer-rich concentrated phase. These coacervates surround the core material, forming microcapsules. Electrostatic interactions between the two aqueous media cause a transition from liquid to gel, i.e., ionic gelation, leading to the formation of coacervates. This technique is primarily used for encapsulating hydrophilic molecules. Several studies have reported on the successful use of this technique in microencapsulation.

[0047]

[49] Microencapsulation extrusion technology can be used to produce high-density microcapsules. For this method to work, the internal material and the wall material must be immiscible. The core material and the wall material are passed through a concentric nozzle so that the wall material surrounds the core, forming a droplet in which the core is surrounded by the wall material. Solidification is then carried out by either cooling or the use of a suitable gelling bath, in which case the droplet falls and solidifies due to the formation of a composite. The material of capsules formed using this method is relatively larger in size than those formed by other methods, and this technology is limited in the availability of effective wall materials.

[0048]

[50] Encapsulation using emulsification techniques is carried out by dispersing the interior in an organic solvent containing a wall material. The dispersion is then emulsified with oil or water, and an emulsifying stabilizer is added. Internal encapsulation is carried out by the evaporation of the organic solvent, which forms a compact polymer layer around it. This is one of the frequently used encapsulation techniques because the procedure involved is simple.

[0049]

[51] Microencapsulation of PCM may result in: (a) extended shelf life of any or all of the various formulation components; (b) improved thermal stability of PCM; (c) more uniform distribution / dispersion of PCM and thus more uniform thermal activation of the composition; (d) improved controlled release and extended release time of PCM when these formulations are chewed in the oral cavity or released from an impregnated oral mucosal adhesive patch; and (e) improved resistance to the release of the core material required to retain the core material within the capsule shell even when the composition is exposed to stimuli such as heat, pressure or hydration. The diameter size of the microcapsules of the coated material may range from 1 to 200 microns, or further from 1 to 50 microns.

[0050]

[52] According to one embodiment, the PCM may be contained within food-grade macroporous or microporous granules / particles to provide: (a) an extended shelf life of the PCM; (b) improved thermal stability of the PCM; (c) a more uniform distribution / dispersion and thus more uniform heating activation of the composition; (d) easier release of the PCM in the oral cavity with better controlled release and longer release time; and (e) improved release of the PCM as needed. The diameter size of the substantially spherical granules / particles may range from 50 to 200 microns, or further from 1 to 50 microns. Such particles may contain maltodextrin and / or food-grade polystyrene.

[0051]

[53] Preferred EMs include pharmaceutically acceptable salts in anhydrous form that release heat when in contact with water. The EMs used in the compositions may be, but are not limited to, anhydrous salts of magnesium citrate, magnesium sulfate, strontium bromide (SrBr2), strontium chloride (SrCl2), trisodium phosphate (Na3PO4), magnesium chloride (MgCl2), calcium sulfate (CaSO4), and zinc sulfate (ZnSO4). The compositions may contain one or more EMs in various ratios and amounts.

[0052]

[54] Magnesium citrate and magnesium sulfate are preferred anhydrous salts. When these salts are preferably in a completely anhydrous form, they can undergo a relatively rapid hydration reaction within seconds upon exposure to moisture, generating a relatively high energy output (45-90 kilojoules or more per mole). When the composition is brought into contact with water, the amount of heat generated in such a reaction will depend on several factors, including: a. the ease with which EM dissociates and subsequently associates with water molecules, resulting in a relatively robust exothermic chemical reaction; b. the degree to which the composition is maintained in a completely anhydrous state before, during, and after production. Since EM salts containing magnesium citrate and magnesium sulfate are hygroscopic, care should be taken to isolate the EM from moisture during the production and storage of the composition. One effective way to prevent the absorption of water from the air by hygroscopic EM is to coat the core of the composition with a coating that prevents moisture and / or air from passing through the coating, and to package the composition in packaging that prevents or limits exposure to air to the composition. By limiting the oral composition's contact with air and moisture before administration, the maximum amount of heat can be generated during oral administration.

[0053]

[55] According to one embodiment, the core of the composition contains less than 0.5% water.

[0054]

[56] According to one embodiment, EM is encapsulated using microencapsulation. Microencapsulation can be carried out according to the methods described above. EM can be encapsulated by a barrier that limits contact between saliva and EM. For example, in the case of chewing gum, as the composition is chewed, the physical agitation of the chewing gum reduces encapsulation, thereby exposing the EM to saliva. The advantage of encapsulating EM in chewing gum is that the length of time that the EM is in contact with water and generates heat when the chewing gum is chewed by a subject is extended compared to equivalent compositions in which the EM is provided in an unencapsulated form. EM can optionally be contained in food-grade macroporous or microporous granules / particles, as described with respect to PCM.

[0055]

[57] According to one embodiment, the composition comprises a core and one or more coatings. Preferably, the coatings include a barrier which prevents air and / or water vapor from penetrating from the environment outside the barrier into the core of the composition within the barrier.

[0056]

[58] The coating may consist of two layers, where the inner layer is a pre-coat layer, which is in direct contact with the core, and the final coat layer, which covers the pre-coat layer. Optionally, the pre-coat layer completely covers the core and provides a waterproof seal. Optionally, the pre-coat layer contains a wax, oil, or shellac. Optionally, the oil is cocoa butter. Optionally, the wax is beeswax, carnauba wax, candelilla wax, sumac wax, or sunflower wax. Optionally, the pre-coat layer is applied without water using spray drying in a rotary panning apparatus.

[0057]

[59] The final coat layer may contain flavorings, sugar-free sweeteners, and bitterness inhibitors, which are applied using a water spray solution and air-dried using sugar-coated tablet panning or other coating methods. The combined weight of the pre-coat layer and the final coat layer accounts for approximately 20% to 50% of the core's weight.

[0058]

[60] In addition to containing TES, the compositions described herein may also contain a permeation enhancer material (PE) in their core to further improve the permeation / diffusion of the active agent contained in the composition into and through the oral tissue membrane. PE is a chemical substance that promotes penetration into or through poorly permeable biological membranes. This allows for a further increase in the rate of permeation / diffusion of the active agent into and through the oral tissue and subsequently into the body's circulatory system, and an increase in the total amount of permeation / diffusion throughout the application, thereby providing improved / superior topical and / or systemic bioavailability of the active ingredient / agent to the body's tissues, as well as enhanced clinical outcomes and health benefits.

[0059]

[61] According to one embodiment, the penetration enhancer is selected from the group consisting of mannitol, menthol, and essential oils. The essential oil is optionally selected from the group consisting of peppermint oil, sage oil, and eucalyptus oil.

[0060]

[62] An example of a certain class of permeability-enhancing substances that can be incorporated into the compositions of the present invention and coated with various food-grade microencapsulation coatings is essential oil (EO). EO is an oily aromatic liquid extracted from aromatic plant materials and is a natural product consisting of a complex mixture of many aromatic volatile compounds. The main compounds in these mixtures are terpenes, terpenoids, phenylpropanoids, and small amounts of a wide variety of volatile organic compounds. Terpenes are dominant, and phenylpropanoids, if present, are responsible for the characteristic odors and tastes released in the oral cavity when the formulation is heated and / or photoactivated.

[0061]

[63] As penetration enhancers, EOs can increase the delivery of low molecular weight drug compounds to the skin by interacting with intercellular lipids of tissues through physical processes such as extraction, fluidization, increased disorder, and phase separation. EOs and their components can penetrate the bloodstream from skin or oral tissues, and generally they act on membranes temporarily and are readily excreted from the body in urine and feces.

[0062]

[64] The fact that permeation / diffusion / penetration-enhancing materials are important for supporting the transdermal or oral absorption of drugs, dietary supplements, or other oral therapeutic agents by their distribution-enhancing functions, such as lipid breakdown, protein modification, or reduction of the skin's barrier function, allows molecules to pass through tissue layers more quickly. The most important point for safe and effective delivery through oral tissue is the selection and use of permeation / penetration-enhancing materials that relatively temporarily and reversibly reduce the barrier function of oral tissue. Essential oils, as a classification, have a permeation-enhancing activity profile.

[0063]

[65] An example of this classification of permeation / diffusion-promoting substances that can be incorporated into various compositions of the present invention is menthol, the main component of peppermint oil. Menthol (also known as "mint camphor") is an extract of volatile oil derived from the Mentha (mint) genus and is widely available in natural and synthetic forms.

[0064]

[66] Menthol has been shown to increase blood flow to the site of application. A study published in Microvascular Research found that a 4% menthol solution dilated blood vessels and increased blood flow, thereby effectively increasing the permeability / diffusion of various active ingredients across the oral tissue barrier.

[0065]

[67] Another example of a permeation enhancer is eucalyptus oil, which contains 1,8-cineole, a monoterpene cyclic ether, and can promote the penetration / permeation of both lipophilic and hydrophilic compounds. Eucalyptus oil containing polyphenols has been found to be highly effective, causing a nearly 30-fold increase in the drug permeation coefficient. Salvia officinalis (sage oil) has also been shown to be rich in polyphenols, which are antioxidant, antibacterial, anti-inflammatory, and permeation enhancers.

[0066]

[68] According to one embodiment, PE is included in the core of the composition in an amount of 1% to 5% by weight relative to the weight of the core.

[0067]

[69] According to one embodiment, the composition for oral delivery of an active agent is in the form of chewing gum, which may be a synthetic or naturally derived chicle gum base. The synthetic form of the gum base consists of a polymer, a plasticizer, and a resin. The polymer may be, for example, polyvinyl acetate, butadiene-styrene, or polyisobutylene. The chewing gum base is an inert, water-insoluble substance that gives the chewing gum consistency and allows it to be chewed, while maintaining sufficient elasticity to allow the chewing gum to maintain its cohesiveness as a whole while being chewed in the mouth of the subject. The chewing gum base preferably comprises a resin, a polymer / elastomer, and a plasticizer. The resin is responsible for the chewiness of the gum and is generally hydrophobic. The elastomer is a polymer that adds flexibility, and the plasticizer improves the softness and elasticity during chewing.

[0068]

[70] According to one embodiment, the composition is formed using a gum base with a low salt content, preferably 5% by weight ± 2. Preferably, the composition has a salt content of 25% or less.

[0069]

[71] A bitterness inhibitor is a compound that interacts with the molecular pathway of bitterness. According to one embodiment, a bitterness inhibitor is added to the composition to reduce the bitterness of potentially bitter EM. The bitterness inhibitor may optionally be selected from the group consisting of sodium gluconate, adenosine 5'-phosphate, and sodium acetate.

[0070]

[72] Flavorings can be incorporated into the composition. Exemplary flavorings include, but are not limited to, vanilla mint, Turkish coffee, mocha, menthol, mint, strawberry, blueberry, apple, apricot, banana, butterscotch, caramel, cherry, cinnamon, grape, honey, melon, lemon, and cappuccino. Preferably, the flavorings do not contain water.

[0071]

[73] According to one embodiment, the composition for oral delivery of an active drug is in the form of a muco-adhesive patch. The muco-adhesive patch according to one embodiment preferably comprises three parts: a muco-adhesive layer that adheres the patch to oral tissue; a drug reservoir comprising the core described herein, which contains the active drug and TES; and a semipermeable membrane that allows a flow of water / saliva from the oral cavity to come into contact with the drug reservoir. When applied, the muco-adhesive layer adheres to the oral tissue, the semipermeable membrane faces the oral cavity, and the reservoir is located between the muco-adhesive layer and the semipermeable membrane.

[0072]

[74] Muco-adhesive patches include a muco-adhesive layer that adheres the patch to oral tissue, preferably the mucobuccal tissue (inner cheek). A variety of muco-adhesive polymers can be used for the muco-adhesive layer, including, but not limited to, chitosan, polyacrylic acid, alginic acid, polymethacrylic acid, and sodium carboxymethylcellulose. Chitosan, a cationic polymer, is widely used due to its biodegradability and biocompatibility, and exhibits muco-adhesive properties by electrostatically interacting with negatively charged mucin chains. Upon application, the muco-adhesive layer of the patch will be fixed to the tissue, and the extrinsic material contained in the patch will begin to permeate through the oral tissue membrane into the bloodstream.

[0073]

[75] The adhesion process is complex and involves contact, compaction, and the formation of certain bonds between the mucoadhesive layer and the mucus. Mucoadhesive, or bioadhesive, is defined as "a state in which two materials are adhered together," meaning that a drug carrier system is attached to a specific biological site. The adhesion of the two materials is achieved by contact between a pressure-sensitive adhesive and a surface (mucosa). Several polymer-related factors, such as molecular weight, chain length, degree of crosslinking, degree of hydration, functional groups, charge, and polymer concentration, as well as several environmental and physiological factors, such as contact time, mucin rotation rate, and mucus viscosity, influence the degree of mucoadhesive. This is because saliva can seep through the permeable or semi-permeable outer backing layer to the inner layer of the patch containing various compounding materials embedded on the tissue-facing side of the patch.

[0074]

[76] The structural design of the semipermeable membrane layer of the patch can be modified to provide either a permeable or semipermeable distribution / range so as to be able to change the rate of moisture / humidity exposure (slow or rapid introduction of saliva / moisture) from the outer surface of the patch (in contact with saliva) to the inner layer of the patch including the core, and thus change the rate of moisture activation of the EM embedded (optionally encapsulated) inside the inner part of the patch. The semipermeable membrane is made of polyethylene, polypropylene, polycaprolactone, ethylcellulose; and plasticizers such as glycerin, propylene glycol, polyethylene glycol, or triacetin.

[0075]

[77] According to one embodiment, a method for treating a disease, or alternatively, a method as prophylactic or preventative for maintaining optimal health, the method comprising administering an orally administered composition described herein to a subject in need thereof. Various active agents that may be used in the orally administered compositions and diseases that can be treated using the orally administered compositions are described below. An active agent may optionally be a drug or a dietary supplement. A drug is a medicine that, when introduced into the human body or living organism, has a physiological effect and is used to prevent, diagnose, treat or alleviate symptoms of a disease or abnormal condition. A dietary supplement is a product introduced into the human body or living organism that contains nutritional components, which may include vitamins, minerals, herbs, amino acids, enzymes, prebiotics, postbiotics, probiotics, or other nutritional substances, in order to improve nutrition and overall health.

[0076]

[78] According to one embodiment, the oral composition comprises an active agent selected from those listed in Table 1. According to one embodiment, the oral composition can be used in a therapeutic method for treating the indications listed in Table 1. [Table 1]

[0077]

[80] The oral cavity is home to approximately 700 species of microorganisms that form complex, dynamic biofilms, also known as dental plaque.

[0078]

[81] Porphyromonas gingivalis, a Gram-negative anaerobic bacterium found in the oral cavity, is a late colony-forming species of subgingival biofilm and is associated with several destructive periodontal diseases, including periodontitis and peri-implantitis.

[0079]

[82] Furthermore, dental biofilms, and P. gingivalis in particular, have been found to migrate (metastasize) from the oral cavity and disseminate to other organs in the body (especially in individuals with active chronic periodontitis), and are associated with serious systemic diseases such as cardiovascular and respiratory diseases, diabetes, and Alzheimer's disease / dementia (P. gingivalis increases blood-brain barrier permeability and crosses the BBB), and in recent years, P. gingivalis found in the lungs constitutes a high-risk factor for developing serious illness due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is associated with a higher morbidity.

[0080]

[83] To enhance clinical effectiveness across a wide range of applications (before and after dental procedures, preventively for chronic pathogenic diseases such as periodontitis and peri-implantitis, and in response to them), the application of functional chewing gum or oral muco-adhesive patches to treat the oral cavity itself should ideally selectively target specific pathogenic microorganisms associated with the said chronic disease state (without disrupting the healthy commensal microorganisms in the mouth), and should provide both soothing (sedative) and anti-inflammatory effects on oral tissues, both before and after dental procedures.

[0081]

[84] Clinical value may be provided by the use of compositions for oral delivery of active agents as described herein, wherein the compositions are safe and provide biofilm inhibition so that the compositions can provide a sustained reduction in the amount of pathogen P. gingivalis and other similar oral pathogens (such as “Orange and Red Complex”) in the oral cavity for several days or longer after application, by incorporating the active agent within the core of functional chewing gum and oral mucosal adhesive patches for treating the oral cavity.

[0082]

[85] Bacterial members, including early colony-forming species of the gingival cleft, are bacteria with the ability to adhere to the tooth pellicle, are only moderately pathogenic, and are generally considered Gram-positive. The early biofilm base allows access to a bridging community of bacteria known as the “orange complex” (e.g., F. nucleatum), which have been found to cause periodontal disease. Once the “orange complex” or bacteria have established themselves, “red complex” bacteria colonize the plaque / biofilm. “Red complex” bacteria are generally Gram-negative, contain endotoxins (gingipain), and are often described as highly pathogenic (e.g., P. gingivalis).

[0083]

[86] In particular, these “red complex” pathogens (as described above) are called “gateway” oral pathogens that create a systemic single dysbiotic disease state with multiple symptoms. The oral components are the first site of infection where the immune system is alerted and disrupted, creating an inflammatory environment where circulating leukocytes carry these pathogens and related toxic factors such as lipopolysaccharides (LPS) and endotoxins such as gingipain throughout the body via the circulatory system. These affect arterial endothelial cells, infecting arterial walls and nerve tissue, damaging the blood-brain barrier, heart tissue, lungs, and intestines. Therefore, the health of the affected individual must be considered as a systemic system that originates in the oral cavity and, if not properly and effectively controlled, can lead to significant indirect damage to multiple vital organ systems throughout the body.

[0084]

[87] Antibiotics have been and continue to be used as antimicrobial agents to combat the development of chronic oral periodontal disease. Systemic use of these antibiotics has limitations, and even when applied topically in mouthwash or directly to the gingival sulcus via, for example, encapsulated microspheres, their effectiveness is limited and they have historically had a fairly serious and undesirable side effect profile.

[0085]

[88] For example, tetracyclines, including oral minocycline, have been associated with the development of autoimmune syndromes with symptoms such as arthralgia, myalgia, rash, swelling, fever, lymphadenopathy, and general weakness, as well as an increased incidence of oral candidiasis ("thrush"). In clinical trials, the most frequently reported non-dental side effects were headache, infection, flu-like symptoms, and pain. Because tetracycline drugs can cause permanent tooth discoloration during tooth development, they should not be used in children or in pregnant or breastfeeding women.

[0086]

[89] Antibiotic resistance of bacterial cells in biofilms has been reported to be 1,000 to 1,500 times higher than that of free-floating (unbound) bacterial cells in the oral cavity, and this has become an increasing problem in recent years. Antibiotic resistance genes can be transferred between bacterial cells within the biofilm, resulting in antibiotic resistance throughout the biofilm. The widespread use of certain antimicrobial agents such as chlorhexidine to control these oral pathogens is problematic because chlorhexidine has equivalent and non-selective antimicrobial activity against many healthy commensal microorganisms in the oral cavity. Studies have shown that repeated use can lead to altered taste, parotid gland swelling, increased calculus formation, and hypertension. Oral biofilms treated with chlorhexidine were inactivated in just 24 hours and showed a pattern of rapid regrowth to initial bacterial concentrations. Furthermore, based on chlorhexidine's non-selective antimicrobial activity, chlorhexidine treatment caused significant changes in the composition and metabolic activity of the microbiome. In some cases, disease-related traits increased (such as an increase in the abundance of pathogenic strains or a shift to high lactate production).

[0087]

[90] Polyphenols are a type of secondary metabolite abundant in Mediterranean foods and are pharmacologically active natural products with excellent immunomodulatory effects. When they bind to various receptors highly expressed on immune cells (e.g., AhR, RAR, RLR), they act in the immune metabolic pathway through a multimodal approach centered on mitochondria. Firstly, polyphenols activate nutrient sensing via stress response pathways essential for the immune response. Secondly, they regulate the balance of mammalian target of rapamycin (mTOR) / AMP-activated protein kinase (AMPK) in immune cells and are well-tolerated caloric restriction mimetic. Thirdly, polyphenols interfere with the association of NLR family pyrin domain containing 3 (NLRP3) at the endoplasmic reticulum-mitochondrial contact site, inhibiting its activation while improving mitochondrial biosynthesis and autophagosome-lysosome fusion. Finally, polyphenols influence chromatin remodeling and modulate both epigenetic and metabolic reprogramming.

[0088]

[91] Propolis is a natural substance produced by honeybees to build and maintain their hives. This resinous, lipophilic substance is sticky, soft, and flexible when heated, but hardens and becomes brittle when cooled. Propolis is mainly composed of resin (55-60%). Waxes and fatty acids make up about 30-45%, and essential oils and pollen make up about 5-10%. Other substances include minerals, vitamins, polyphenols, and flavonoids. The biological activity of propolis is mostly related to flavonoids and hydroxycinnamic acid.

[0089]

[92] Studies have shown that it is difficult to standardize the chemical composition and flavonoid content of propolis. This is because it depends on the environmental conditions of the collection site, the origin, the type of plant pollen, and the type of bee that produced it. Depending on the location, the chemical composition of propolis includes chrysin, galangin, pinosembrin, and pinovaskin. These are flavonoids that do not have a B-ring substituent. The main component of temperate propolis is caffeic acid phenethyl ester. Similarly, the chemical composition of propolis originating from tropical regions includes prenylated phenylpropanoids (e.g., artepillin C), while propolis found in the Pacific and African regions contains geranylflavanone as a characteristic compound.

[0090]

[93] Therefore, in order to overcome the inherent variability of propolis sources obtained in nature, it would be advantageous in the present invention to incorporate reproducible (batch-to-batch and seasonal) ethanolic extracts of propolis (EEP) into preferred chewing gum formulations or oral mucosal adhesive patches for treating the oral cavity itself.

[0091]

[94] Propolis ethanol extract (EEP) shows high efficacy against Bacteroides and Peptostreptococcus strains. Propolis extract also showed excellent performance in in vitro tests against yeast, exhibiting high levels of antiviral activity against herpes simplex virus-1 (HSV-1). Propolis extract showed high anti-HSV-1 activity when the virus was pre-treated with these drugs before infection. Anti-HIV-1 activity was observed in propolis samples from several geographical regions.

[0092]

[95] Propolis has been reported to be a potent anti-inflammatory agent. In recent years, in vitro and in vivo studies have been conducted on the effects of propolis on inflammation. Caffeate phenethyl ester (CAPE), a major component of propolis derived from beehives, has been demonstrated to have remarkable anti-inflammatory, antibacterial, antiviral, antifungal, antioxidant, and anticancer properties.

[0093]

[96] Studies have shown that a topical mouth rinse containing propolis in an alcoholic aqueous solution heals surgical wounds in the cheeks; therefore, it plays a role in epithelial repair after tooth extraction and exerts an anti-inflammatory effect against orofacial pain. Propolis contained in toothpaste has been found to improve oral health and show an inhibitory effect on plaque formation, which is considered to be the main cause of the progression of most oral diseases.

[0094]

[97] In vitro studies have shown that propolis extract (EEP) induces the death of P. gingivalis cells by rapidly increasing the membrane permeability of bacterial cells, and that its antimicrobial activity against P. gingivalis is maintained even after extensive heat treatment, demonstrating a high level of heat resistance, a useful property for use in the present invention.

[0095]

[98] Neohesperidin dihydrochalcone (NHDC), a sugarless sweetener and flavor enhancer, is a precursor of anthocyanins, contains polyphenols, and has been reported to have various biological activities, including antioxidant and hepatitis-suppressing effects. However, its anti-inflammatory function and mechanism of action remain largely unknown. DHCA, a metabolite of NHDC, significantly downregulated the secretion of pro-inflammatory cytokines. In contrast, NHDC showed only a slight effect, suggesting that biological metabolism from NHDC to DHCA is necessary for anti-inflammatory function. However, both NHDC and DHCA rescued the suppression of LPS-induced oxidative phosphorylation, a characteristic of anti-inflammatory M2 macrophages. 3T3-L1 adipocytes showed a decrease in fat deposition in the presence of DHCA, while sugar-containing NHDC showed only a slight increase in fat deposition. In high-fat diet-induced obese mice, treatment with NHDC successfully downregulated body weight gain in a dose-dependent manner. Furthermore, M2 polarized bone marrow-derived macrophages (BMDMs) from NHDC-fed mice secreted large amounts of the anti-inflammatory cytokine IL-10. These results suggest that NHDC and its physiological metabolite, DHCA, may have the potential to suppress inflammatory responses and obesity. The inventors observed that in an orally administered composition containing NHDC, when released by chewing gum, it strongly binds to oral tissues, including the tongue, and is slowly released over time (up to several hours). As a result, the sweetness lingers in the mouth for a long time, making even plain water taste sweet.

[0096]

[99] High-purity stevia is a natural sugar substitute made from the leaves of the stevia plant. It is about 100 to 300 times sweeter than table sugar, but contains no carbohydrates, calories, or artificial ingredients, and does not raise blood sugar levels.

[0097]

[0100] Xylitol is a sugar alcohol that resembles sugar in appearance and taste, but is lower in calories and does not raise blood sugar levels. Xylitol intake has been shown to reduce the number of Streptococcus mutans (S. mutans) and Streptococcus sobrinus (S. sobrinus) in saliva, but not the number of Streptococcus sanguinis (S. sanguinis) and Streptococcus mitis (S. mitis). Therefore, habitual xylitol intake reduces the amount of cariogenic streptococci without affecting beneficial streptococci in the oral cavity. Thus, all of these can also be incorporated into the composition of the present invention. Xylitol can be used in particular as a final hard coating on the outside of functional chewing gum.

[0098]

[0101] Phloretin, a flavor enhancer, is a dihydrochalcone abundant in polyphenols found in various plants, including apples, strawberries, kumquats, pears, honeybush, and sweet tea. Numerous studies have revealed the multifaceted pharmacological effects of phloretin, including anticancer, anti-inflammatory, anti-diabetic, neuroprotective, and antibacterial properties. These activities have been demonstrated in both in vitro and in vivo experimental settings. Phloretin exhibits various pharmacological effects, including antibacterial, anticancer, and cell and organ protective properties, both in vitro and in vivo. The molecular basis of the anti-inflammatory mechanism that gives rise to these pharmacological effects arises from inhibiting the signaling pathways of inflammatory mediators that support the suppression of inflammation in immune cells, obesity-induced inflammation, arthritis, endothelial, myocardial, liver, kidney, and lung injuries, and inflammation in the intestines, skin, and nervous system. Phloretin dose-dependently inhibited the proliferation and survival rate of S. mutans. Furthermore, this reduced the expression of gtfB and gtfC genes, which correlated with a decrease in extracellular polysaccharide (EPS) / bacteria and WIG / WSG ratios. Inhibition of the expression of the comED and luxS genes, which are involved in stress tolerance, was associated with a decrease in the acid-producing and acidifying abilities of S. mutans. Phloretin exhibits antibacterial properties against S. mutans, regulating acid production and resistance and reducing biofilm formation.

[0099]

[0102] Peppermint oil has been found to possess antibacterial, antimicrobial, and antifungal properties. Because it can suppress oral biofilms and treat periodontal disease, it is one of the most widely used essential oils. Mentha, derived from peppermint oil, is also a vasoactive agent that causes vasodilation in tissues, making it a powerful tissue permeability enhancer.

[0100]

[0103] Green tea polyphenols, particularly (-)-epigallocatechin gallate (EGCg), the main component of tea polyphenols, completely inhibited the proliferation and adhesion of P. gingivalis to buccal epithelial cells at concentrations of 250-500 micrograms / ml. Among polyphenol compounds, (-)-epicatechin gallate (ECg) and (-)-gallocatechin gallate (GCg) were the second most effective in inhibiting these activities after EGCg. On the other hand, the activity of (+)-catechin (C(+)), (-)-epicatechin (EC), (+)-gallocatechin (GC), and (-)-epigallocatechin (EGC) was very low. These results indicate that the inhibitory effect on the adhesion of P. gingivalis to buccal epithelial cells is due to the presence of a galloyl moiety that esterifies with the 3-OH group of the catechin moiety in the polyphenol compounds.

[0101]

[0104] Curcumin (CUM), also known as diferuloylmethane, is the main polyphenol substance found in the rhizome of Curcuma longa. CUM has been shown to have multifaceted functions (anti-inflammatory, antioxidant, neuroprotective, immunomodulatory, antitoxin, anti-apoptotic, anti-diabetic (reduces insulin resistance), anti-infertility, antimicrobial, anti-allergic, anti-dermatological, antidepressant, cardioprotective, etc.) and does not cause major side effects even when administered in large quantities. Curcumin inhibits the growth of periodontal pathogens (Aggregatibacter actinomycetemcomitans, F. nucleatum, P. gingivalis, etc.) under both floating and biofilm conditions.

[0102]

[0105] Spirulina is a type of cyanobacteria, often called blue-green algae, and is a powerful antioxidant rich in polyphenols. Its use reduces pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and the inflammatory transcription factor NF-κB in gingival tissue, promotes bone formation-related factors (new bone growth around the teeth) in periodontitis (periodontal disease), and upregulates the BMP-2 / Smad pathway.

[0103]

[0106] Coconut oil is a natural product derived from coconuts that contains polyphenols with many benefits, including antibacterial, anti-inflammatory, and antioxidant properties. Dental plaque, the main cause of periodontitis, contains colonies of pathogenic microorganisms. The development of inflammation in periodontal tissue stimulates the release of inflammatory mediators such as TNF-α and TGF-β. Treatment of periodontitis can be carried out by starting with initial treatment, usually accompanied by additional treatments such as topical drug delivery.

[0104]

[0107] L-carnosine can counteract various factors closely associated with age-related cognitive decline and the risk of developing dementia, including neuroinflammation, oxidative stress, and deficiencies in neurotrophic factors. It exerts neuroprotective effects through the regulation of the HO-1 / Hsp72 system and by mitigating neuronal damage caused by oxidative stress. It possesses biochemical properties such as antioxidant activity, divalent metal ion chelating activity, muscle proton buffering activity, anti-crosslinking activity, and reactive carbonyl scavenging activity.

[0105]

[0108] L-histidine has been shown to protect against age-related brain diseases such as cerebral infarction, cerebral ischemia, cerebral edema, sciatic nerve lesions, and neuropathic pain. It improves neurogenesis. Furthermore, it upregulated the protein expression levels of both neuronal cell markers (β-tubulin-III and neurofilamentous heavy protein) and the antioxidant enzymes glutathione peroxidase-1 and superoxide dismutase-1. Conversely, it downregulated the protein expression levels of amyloid-β (1-42) and cleavage caspase-3. mRNA levels of the pro-inflammatory cytokines interleukin (IL)-8, IL-1β, and tumor necrosis factor α were also downregulated and can be used in the formulations of the present invention.

[0106]

[0109] Astaxanthin rescued the number of surviving pyramidal neurons in the hippocampus. Lipid peroxidation (malondialdehyde concentration) decreased, and antioxidant capacity (amounts of reduced glutathione and superoxide dismutase) in the hippocampus (the part of the brain responsible for learning and memory) increased.

[0107]

[0110] Magnesium L-threonate promotes synaptic plasticity and increases synaptic density in the hippocampus, a brain region crucial for memory formation, thereby slowing cognitive decline and brain aging. It has been shown to have various benefits, including improved relaxation, increased concentration, and improved sleep quality. It is effective for cognitive and mental health conditions such as brain fog, mood disorders, migraines, and cognitive decline.

[0108]

[0111] PQQ is pyrroloquinoline quinone. Also known as methoxatin or pyrroloquinoline quinone disodium salt, it is a powerful antioxidant. It is a compound produced by bacteria and found in fruits and vegetables. In bacteria, PQQ aids in the digestion of alcohol and sugar (which produces energy). This energy helps the bacteria survive and multiply. While animals and plants do not utilize PQQ in the same way as bacteria, it is a growth factor that aids in the growth of plants and animals. It also appears to help with stress tolerance. PQQ supplements are often used for energy, memory, concentration enhancement, and overall brain health and may be included in the compositions of this invention.

[0109]

[0112] Studies have shown that phytochemicals present in cardamom seeds, which are rich in polyphenols, can improve cognitive function, enhance mood, and protect brain cells from oxidative damage and inflammation. They can also reduce the accumulation of amyloid-beta plaques, a type of neurotoxin associated with Alzheimer's disease and neurodegeneration, and their form can be used in the formulations of the present invention.

[0110]

[0113] Boron is associated with proper brain function. Assessments of human cognitive and psychomotor functions have shown that boron deficiency impairs performance on tasks involving motor speed and dexterity, attention, and short-term memory, and boron can be included in the composition according to the present invention.

[0111]

[0114] The bark and leaves of the ginkgo biloba root are rich in ginkgolide compounds, which help promote the elevation of acetylcholine in key brain regions responsible for decision-making and short-term memory recall. These compounds are also beneficial for cerebral blood circulation and can be included in the composition according to the present invention.

[0112]

[0115] Hyperzine A has been shown to increase the bioavailability of acetylcholine by inhibiting acetylcholinesterase, an enzyme that breaks down acetylcholine. This fosters an ideal environment for forming new neural connections and improving memory retention, and can be incorporated into compositions according to the present invention.

[0113]

[0116] Pomegranate seed oil has been shown to help improve cognitive function in individuals with multiple sclerosis who are experiencing disease-related cognitive impairment. Consumption of anthocyanin-rich cherry juice for 12 weeks improved memory and cognitive function in elderly individuals with mild to moderate dementia and can be incorporated into the composition according to the present invention.

[0114]

[0117] Gotu kola is thought to support memory function, promote mental clarity, promote healthy stress levels, and support healthy cardiovascular function, and can be included in the composition according to the present invention.

[0115]

[0118] Aloe vera not only improves the oxidative state of the hippocampus and cerebral cortex, but also enhances motor and memory abilities. Aloe has unique advantages as an effective drug for reducing oxidative damage, reducing inflammation, increasing vasodilation, therapeutic efficacy in treating tumors and neurodegenerative diseases, and maintaining general brain health and memory. Aloe has also been shown to have cholinergic and cognitive-enhancing properties. Currently, aloe is used as an alternative medicine for diabetes, asthma, epilepsy, liver disease, HIV, cancer, and osteoarthritis, and can be included in the compositions according to the present invention.

[0116]

[0119] Vitamin D is an important calcium-regulating hormone with diverse functions in many tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function, and that vitamin D deficiency may accelerate age-related cognitive decline, which can be incorporated into the compositions according to the present invention.

[0117]

[0120] Niacinamide protects brain cells from stress and injury. Deficiency in this vitamin causes a decline in brain function, manifesting as memory impairment and dementia. Niacinamide intake is likely to be beneficial for brain health. Niacin promotes the growth and development of brain cells (neurons). In fact, brain fog and even psychiatric symptoms have been associated with niacinamide deficiency and can be included in compositions according to the present invention.

[0118]

[0121] Vitamin B12 deficiency is associated with memory impairment, particularly in older adults. One study involving individuals with early-stage dementia showed that vitamin B12 may help slow cognitive decline. This is because it is important for producing serotonin and dopamine, neurotransmitters that enhance mood. Consequently, vitamin B12 may be useful in preventing and treating depression and anxiety. It can also improve concentration and memory and can be included in compositions according to the present invention.

[0119]

[0122] Folic acid (folate) aids in the production of DNA and RNA, the formation of neurotransmitters, and the development of the nervous system during pregnancy. Folate is also known to be beneficial for depression, mental fatigue, and irritability because it can be quickly broken down to provide energy to the body, and can therefore be included in the composition according to the present invention.

[0120]

[0123] Zinc promotes antioxidant activity, neurogenesis, and immune system responses. From neonatal brain development to the maintenance and control of adult brain function, zinc is a crucial homeostatic component of the central nervous system. It is present in high concentrations in the amygdala, auditory brainstem, cerebral cortex, and hippocampus. Zinc (Zn) functions as a neurotransmitter and second messenger in the brain, controls long-term potentiation in the hippocampus, enhances neuronal viability, and promotes learning and memory, and can be included in compositions according to the present invention.

[0121]

[0124] Alpha-lipoic acid (ALA) is a potent antioxidant that may alleviate age-related cognitive impairment and neurodegenerative diseases. Clinical randomized controlled trials have demonstrated the cognitive function-improving effects of lipoic acid in Alzheimer's disease, and it can be included in the composition according to the present invention.

[0122]

[0125] Alpha-GPC is naturally produced in the body as a precursor to acetylcholine, one of the important neurotransmitters in the brain's neural network. As a supplement, this compound quickly crosses the blood-brain barrier and helps promote acetylcholine synthesis. Furthermore, because alpha-GPC promotes the development of cell membranes in the cerebral cortex, or "gray matter," and improves mental processing, it can be included in compositions according to the present invention.

[0123]

[0126] Bacopa monnieri is a herb commonly used in traditional Ayurvedic medicine for its beneficial effects on memory and concentration. Studies have shown that the bacoside compounds in this potent plant cross the blood-brain barrier and, similar to hyperzine A, help increase acetylcholine levels by inhibiting its breakdown by acetylcholinesterase. Thus, bacopa monnieri can help generate new neural pathways and can be included in compositions according to the present invention.

[0124]

[0127] Marigolds are rich in lutein and zeaxanthin, which can help enhance memory and cognitive function. Marigold extract also possesses antioxidant and anti-inflammatory properties, which would protect the brain from stress and aging, and therefore can be included in the composition according to the present invention.

[0125]

[0128] The amino acid tryptophan is important for cognitive processes because it is involved in serotonin production. Low levels of this amino acid can impair cognition, including the memory of events or experiences, and therefore it can be included in the composition according to the present invention.

[0126]

[0129] The oral composition of the present invention may incorporate components / agents / drugs that can be used to treat obesity, stress, insulin resistance / type 2 diabetes, cardiovascular disease, chronic kidney disease, rheumatoid arthritis, metabolic syndrome, gut microbiota abnormalities, and Crohn's disease.

[0127]

[0130] Some examples of substances that may be used in the formulations of the present invention to treat or prevent obesity, insulin resistance / type 2 diabetes, intestinal metabolic disorders, metabolic syndrome, and Crohn's disease include (but are not limited to): a. Inosine, as one of the important metabolites of purines, and the function of its transmembrane transporter ENT1, which promotes the thermogenesis program and energy expenditure (EE) of brown adipose tissue (BAT), offer new hope for weight loss in BAT-centered obesity treatment, according to recent findings. b. Berberine improves the physiological stimulation of glucose via the insulin-like growth factor-1 (IGF-1) cascade, thereby inducing insulin secretion in the body, reducing insulin resistance, and improving insulin sensitivity of liver tissue, muscle tissue, and fat. c. Naringin supplementation improved impaired glucose tolerance and insulin resistance in high-fat diet model mice and increased glucose uptake by skeletal muscle cells in an AMPK-dependent manner. Naringin has anti-inflammatory and antioxidant benefits in diabetic nephropathy rats, as evidenced by its downregulation of IL-1, the inflammatory cytokine TNF, and IL-6, and its upregulation of the antioxidants SOD, GSH, and CAT. It is also very effective for weight loss; supplementing with naringin resulted in approximately a 14% reduction in calorie intake and approximately a 50% reduction in total fat percentage. Furthermore, naringin significantly reduced perigonadal adipose tissue volume even after weight control. d. Rosmarinic acid is a potent polyphenol that has been found to act like insulin to lower overall blood glucose levels. e. Green coffee extract can lower blood glucose levels and prevent fat accumulation. Green coffee also appears to help lower hypertension in some individuals. f. Fenugreek can enhance insulin sensitivity by enhancing insulin action at the cellular level, lowering HbA1c levels by utilizing glucose in peripheral tissues, and maintaining blood glucose levels.A study in a group that took fenugreek as a dietary supplement showed a significant decrease in fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and low-density lipoprotein cholesterol (LDL cholesterol), but a significant increase in serum insulin. g. Ephedra use promotes weight loss in selected populations. In healthy overweight and obese populations, ephedra reduced body weight, fasting glucose levels, and insulin levels. These findings indicate that ephedra reduces the risk of impaired glucose tolerance and obesity. h. 7-ketoDHEA has shown effects that improve metabolic disorders associated with body weight and insulin resistance. For example, one study evaluated whether 7-ketoDHEA reduces abdominal fat and improves insulin activity in older adults. The results showed that 7-ketoDHEA supplementation reduced fat and lowered insulin levels. i. Vitamin C does not directly lead to fat oxidation or a reduction in body fat. However, it is correlated with body weight and waist circumference. According to one study, vitamin C and body size are inversely correlated, meaning that lower plasma ascorbic acid levels are associated with higher body mass index (BMI). Possible beneficial effects of ascorbic acid on obesity-related mechanisms include: (1) regulating lipolysis in adipocytes, (2) regulating glucocorticoid release from the adrenal glands, (3) inhibiting glucose metabolism and leptin secretion in isolated adipocytes, (4) improving hyperglycemia and reducing glycation in obese diabetic models, and (5) reducing inflammatory responses. Perhaps all of these characteristics are related to the excellent antioxidant properties of this vitamin. j. Alpha-lipoic acid.

[0128]

[0131] According to one embodiment, the topical application time of the oral composition preferably needs to be in the range of 5 to 20 minutes for the total exposure time (TET). The oral delivery composition according to this embodiment diffuses and penetrates into the oral tissue in this relatively short time, supplying a relatively large amount of active drug to the subject. Such administration has great clinical value and health benefits for the user, as patient adherence to medication can be a problem for many users and is a major factor that needs to be considered and overcome.

[0129]

[0132] The following examples are provided to illustrate specific features and / or embodiments. These examples should not be construed as limiting the disclosure to the features or embodiments described. [Examples]

[0130]

[0133] Example 1: Hydration of EM with and without PCM

[0134] Experiments were conducted to measure the heat of hydration of anhydrous salts with and without PCM.

[0131]

[0135] To test for anhydrous salts without PCM, 18 g of anhydrous magnesium citrate was combined with 8 g of anhydrous magnesium sulfate (totaling 26 g), and this mixture was then combined with 74 g of distilled water. To test for anhydrous salts with PCM, the same concentration of anhydrous salt was added to the same volume of water, along with 2.6 g of PCM in the form of paraffin oil:beeswax in a 1:1 weight ratio mixture. The ratio of PCM to anhydrous salt was 1:10. The temperature of the mixture was measured over time and can be seen in Figure 3A (without PCM) and Figure 3B (with PCM).

[0132]

[0136] As shown in Figure 3A, the anhydrous mixture of EM alone (without PCM) rapidly reached its peak temperature in about 2 minutes, rapidly decreased (cooled) by 5°C in the first 5 minutes, and then decreased a total of 12°C in the first 10 minutes. In comparison with Figure 3B, the exact same anhydrous mixture of EM with added PCM rapidly reached its peak temperature, gradually decreased by 2°C in the first 5 minutes, and then decreased a total of only 5°C in the first 10 minutes. This particular combination of EM with PCM improved the heat retention of the solution by 2.5 times in the first 5 minutes of the hydration reaction and by 3.0 times in the first 10 minutes of the hydration reaction. This data indicates that an intraoral delivery composition containing a core with EM and PCM can maintain intraoral heat for a longer period than an equivalent composition with EM but without PCM.

[0133]

[0137] Example 2A: Chewing gum composition containing an active agent, PCM, and EM

[0138] A chewing gum formulation was prepared for delivering an active agent via oral delivery. The core was prepared using the components listed in Table 2. This composition was proposed for use in the treatment or prevention of gingivitis, periodontitis, peri-implantitis, oral candidiasis, halitosis, and dental caries. The core was prepared to contain less than 0.5% water. [Table 2]

[0134]

[0140] The amount of gum base used was 38%, while other components of the gum accounted for 62%. The gum base was a low-ash gum base with an ash content of 5% by weight ± 2. The gum base contained synthetic polymers / elastomers, plasticizers, and resins.

[0135]

[0141] Cores prepared from the components listed in Table 2 can be coated with a water-free precoat using one or any mixture of beeswax, carnauba wax, candelilla wax, sumac wax, sunflower wax, and cocoa butter, applied via a dragee panning process. A final coating containing a mixture of xylitol, flavoring, and a bitterness inhibitor is applied using a water-spray-drying dragee panning process. The final coating contains water. The weight ratio of core to coating was 6:4 or 7:3 overall.

[0136]

[0142] These core compositions applied heat to the oral cavity while the subject chewed and maintained the elasticity of the chewing gum for at least 10 minutes.

[0137]

[0143] Example 2B: Chewing gum composition containing an active agent, PCM, and EM

[0144] A chewing gum composition was prepared for delivering an active agent via oral delivery. The core was prepared using the components listed in Table 3. This composition was suggested for use in the treatment of mild to moderate cognitive impairment, early Alzheimer's disease, early frontotemporal dementia, and for improving mental agility and ability.

[0138]

[0145] The core was prepared to contain less than 0.5% water. [Table 3]

[0139]

[0147] The amount of gum base used was 37.5%, while other components of the gum accounted for 62.5%. The gum base was a low-ash gum base with an ash content of 5% ± 2. The gum base contained synthetic polymers / elastomers, plasticizers, and resins.

[0140]

[0148] Cores prepared from the components listed in Table 3 are coated with a water-free precoat using a mixture of beeswax, carnauba wax, candelilla wax, sumac wax, sunflower wax, and cocoa butter, or each wax individually, applied via the sugar-coated tablet panning process. A final coating containing a mixture of xylitol, flavoring, and a bitterness inhibitor is applied using a water-spray-dried sugar-coated tablet panning process. The final coating contains water. The weight ratio of the core to the coating is 6:4 to 7:3 overall.

[0141]

[0149] These compositions applied heat to the oral cavity for 5-10 minutes while the subjects chewed, and maintained the elasticity of the chewing gum during and after chewing.

[0142]

[0150] Example 3A: Chewing gum composition containing an active agent, PCM, and EM

[0151] A composition similar to that of Example 2A was prepared, but using a gum base with an ash content of 35% ± 2, a low amount of active agent (11.25% of core weight), a low amount of anhydrous salt (12.5% ​​of core weight), and a low amount of PCM (1.25% of core weight). The amount of gum base in this core was 75%. This composition provided less calorific value than the composition of Example 2A because it had a lower content of EM in the form of anhydrous salt and a lower content of PCM. This chewing gum maintained its elasticity.

[0143]

[0152] Example 3B: Chewing gum composition containing an active agent, PCM, and EM

[0153] A composition similar to that of Example 3A was prepared, but with a lower amount of active agent (9.55% of core weight), a higher amount of anhydrous salt (25% of core weight), and a higher amount of PCM (2.5% of core weight). The amount of gum base in this core was 63%. This composition provided less calorific value than the composition of Example 2A because it had a lower content of EM in the form of anhydrous salt and a lower content of PCM. This chewing gum maintained its elasticity.

[0144]

[0154] Example 3C: Chewing gum composition containing an active agent, PCM, and EM.

[0155] A composition similar to that in Example 3B was prepared, but with a higher concentration of the active agent (16.5% of the core weight). The amount of gum base in this core was 56%. This composition failed to maintain elasticity, exhibited properties similar to a molten, soft polymer, and could not maintain cohesive force.

[0145]

[0156] Without being constrained by theory, it is suggested that compositions like the one described in Example 3C did not maintain elasticity due to the high ash content of the gum base. In the compositions of Examples 2A and 2B, the low ash content of the gum base before the addition of additional components allowed for the addition of relatively large amounts of the active agent, PCM, and especially EM in the form of anhydrous salts, while maintaining the elasticity of the chewing gum. It is suggested that a gum base with an ash content of less than 10% should be used as a starting material to enable high addition of EM and active agents in chewing gum formulations. Formulations like those in Examples 2A and 2B can be enriched with high amounts of active substance (30% or more) and EM (15-20%).

[0146]

[0157] Described herein, according to one embodiment, is an oral delivery composition for an active agent comprising a core, the core having at least one active agent, a phase change material (PCM), and an exothermic material, and containing less than 0.5% water. The exothermic material may optionally be in the form of an anhydrous, pharmaceutically acceptable or food-grade salt. The exothermic material may optionally be in the form of an anhydrous salt selected from the group consisting of magnesium citrate, magnesium sulfate, strontium bromide (SrBr2), strontium chloride (SrCl2), trisodium phosphate (Na3PO4), magnesium chloride (MgCl2), calcium sulfate (CaSO4), and zinc sulfate (ZnSO4). The exothermic material may optionally be in the form of an anhydrous salt selected from the group consisting of magnesium citrate and magnesium sulfate. The core of the composition may optionally contain 10% to 25% of the exothermic material. The active agent may optionally be selected from the group consisting of drugs and nutritional supplements. The active ingredients are optionally selected from the following group: propolis, propolis extract, caffeine, naringin, green tea extract, green tea polyphenols, chitosan, ephedra, green coffee extract, cinnamon, berberine, vitamin D, aloe vera, ginger, sage oil, fenugreek, 7-keto-DHEA, folic acid, vitamin B12, niacinamide, alpha-lipoic acid, vitamin C, zinc, curcumin, phloretin, peppermint oil, menthol, L-carnosine, L-histidine, astaxanthin, L- Magnesium threonate, cardamom, boron, inosine, mannitol, PQQ, rosmarinic acid, ginkgo biloba, hyperzine A, pomegranate seed oil, anthocyanins, alpha-GPC, Bacopa monnieri, gotu kola, marigold, caffeate phenethyl ester (CAPE), neohesperidin dihydrochalcone (NHDC), stevia, xylitol, (-)-epigallocatechin gallate (EGCg), (-)-gallocatechin gallate (GCg), spirulina, coconut oil, tryptophan, and mannitol. Optionally, the core of the composition contains more than 25% by weight of the active agent. Optionally, the core of the composition contains 30% to 40% by weight of the active agent. Optionally, the PCM undergoes a solid-to-liquid phase change at a temperature of 40°C to 48°C, and optionally at a temperature of 44°C to 48°C. Optionally, PCM is present in the core of the composition in an amount of 1% to 10% by weight. Optionally, PCM is present in the core of the composition in an amount of 2% by weight. Optionally, PCM is selected from the group consisting of beeswax, glycerol, polyethylene glycol, and paraffin oil.Optionally, the PCM includes beeswax and paraffin oil. Optionally, the beeswax and paraffin oil are present in a ratio of 1:1 to 2:3. Optionally, the composition further includes a permeation enhancer. Optionally, the permeation enhancer is selected from the group consisting of mannitol, menthol, and essential oils. Optionally, the essential oil is selected from the group consisting of peppermint oil, sage oil, and eucalyptus oil. Optionally, the permeation enhancer is present in the core of the composition in an amount of 1% to 5% by weight. Optionally, the composition further includes components selected from the group consisting of sweeteners, bitterness inhibitors, and fragrances. Optionally, one or more of the PCM, exothermic materials, and active agents are microencapsulated. Optionally, the composition includes at least one coating layer surrounding the core. Optionally, the coating includes a pre-coating layer that functions as a moisture barrier. Optionally, the pre-coating layer includes beeswax, carnauba wax, candelilla wax, sumac wax, sunflower wax, or cocoa butter. Optionally, the composition further includes a final coating layer. The weight ratio of the core to the composition is optionally 6:4 to 7:3. The composition is optionally in the form of gum and further comprises a gum base. The gum base optionally contains 5% ± 2% ash by weight. The salt content of the composition is optionally 25% by weight or less. The composition is optionally in the form of a mucous adhesive patch. The composition optionally further comprises a mucous adhesive layer and a semipermeable membrane layer surrounding the core.

[0147]

[0158] Further described herein is a method for administering an active agent to a subject according to one embodiment, the method comprising: introducing the active agent into the oral cavity of a subject using a composition comprising a core, the core comprising at least one active agent, a phase change material (PCM), and an exothermic material, and less than 0.5% water; and bringing the composition into contact with saliva to generate heat in the oral cavity of the subject.

[0148]

[0159] Further described herein, according to one embodiment, is a method for treating or preventing a disease or symptom, or for optimizing health, the method comprising: administering an active agent to a subject in need via an oral route using a composition comprising the core, the core comprising at least one active agent, a phase change material (PCM), and an exothermic material, and less than 0.5% water. Diseases or symptoms may be arbitrarily selected from the following group: periodontal disease (periodontitis, peri-implantitis), recurrent aphthous stomatitis, oral candidiasis, dental caries, bad breath, cardiovascular disease, respiratory disease, diabetes, Alzheimer's disease, frontotemporal dementia, dementia, Parkinson's disease, microbial diseases, biofilm formation, inflammation, neuroinflammation, cognitive decline, cerebral infarction, cerebral ischemia, cerebral edema, sciatic nerve lesions, neuropathic pain, mood disorders, improvement of mental capacity / sensitivity, memory recall, obesity, stress, insulin resistance / type II diabetes, chronic kidney disease, rheumatoid arthritis, metabolic syndrome, intestinal flora abnormalities, and Crohn's disease.

[0149]

[0160] Given the many possible embodiments to which the disclosed principles of the present invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be considered as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. Accordingly, the inventors claim as an invention everything contained within the scope and spirit of these claims.

Claims

1. An oral composition for delivering an active agent into the oral cavity, comprising a core having at least one active agent, a phase change material (PCM), and an exothermic material, and containing less than 0.5% water.

2. The composition according to claim 1, wherein the heat-generating material is in the form of a salt that is pharmaceutically acceptable or food-grade anhydrous.

3. The exothermic materials are magnesium citrate, magnesium sulfate, and strontium bromide (SrBr). ２ ), strontium chloride (SrCl ２ ), trisodium phosphate (Na ３ PO ４ ), magnesium chloride (MgCl ２ ), calcium sulfate (CaSO4) ４ ), and zinc sulfate (ZnSO ４ The composition according to claim 2, which is a form of an anhydrous salt selected from the group consisting of ).

4. The composition according to claim 3, wherein the heat-generating material is in the form of an anhydrous salt selected from the group consisting of magnesium citrate and magnesium sulfate.

5. The composition according to claim 1, wherein the core of the composition comprises 10% to 25% of a heat-generating material.

6. The composition according to claim 1, wherein the active agent is selected from the group consisting of drugs and nutritional supplements.

7. The active ingredients are propolis, propolis extract, caffeine, naringin, green tea extract, green tea polyphenols, chitosan, ephedra, green coffee extract, cinnamon, berberine, vitamin D, aloe vera, ginger, sage oil, fenugreek, 7-keto-DHEA, folic acid, vitamin B12, niacinamide, alpha-lipoic acid, vitamin C, zinc, curcumin, phloretin, peppermint oil, menthol, L-carnosine, L-histidine, astaxanthin, magnesium L-threonate, cardamom, and rhombic acid. The composition according to claim 1, selected from the group consisting of: inosine, mannitol, PQQ, rosmarinic acid, ginkgo biloba, hyperzine A, pomegranate seed oil, anthocyanin, alpha-GPC, Bacopa monnieri, gotu kola, marigold, caffeate phenethyl ester (CAPE), neohesperidin dihydrochalcone (NHDC), stevia, xylitol, (-)-epigallocatechin gallate (EGCG), (-)-gallocatechin gallate (GCg), spirulina, coconut oil, tryptophan, and mannitol.

8. The composition according to claim 1, wherein the core of the composition comprises more than 25% by weight of the active agent.

9. The composition according to claim 8, wherein the core of the composition comprises 30% to 40% by weight of an active agent.

10. The composition according to claim 1, wherein the PCM undergoes a phase change from solid to liquid at a temperature of 40°C to 48°C.

11. The composition according to claim 10, wherein the PCM undergoes a phase change from solid to liquid at a temperature of 44°C to 48°C.

12. The composition according to claim 1, wherein the PCM is present in the core of the composition in an amount of 1% to 10% by weight.

13. The composition according to claim 12, wherein the PCM is present in the core of the composition in an amount of 2% by weight.

14. The composition according to claim 1, wherein the PCM is selected from the group consisting of beeswax, glycerol, polyethylene glycol, and paraffin oil.

15. The PCM is the composition according to claim 14, comprising beeswax and paraffin oil.

16. The composition according to claim 15, wherein beeswax and paraffin oil are present in a ratio of 1:1 to 2:

3.

17. The composition according to claim 1, further comprising a permeation enhancer.

18. The composition according to claim 17, wherein the permeation enhancer is selected from the group consisting of mannitol, menthol, and essential oils.

19. The composition according to claim 18, wherein the essential oil is selected from the group consisting of peppermint oil, sage oil, and eucalyptus oil.

20. The composition according to claim 17, wherein the permeation enhancer is present in the core of the composition in an amount of 1% to 5% by weight.

21. The composition according to claim 1, further comprising a component selected from the group consisting of sweeteners, bitterness inhibitors, and flavorings.

22. The composition according to claim 1, wherein one or more of the PCM, the heat-generating material, and the active agent are microencapsulated.

23. The composition according to claim 1, further comprising at least one coating layer surrounding the core.

24. The composition according to claim 23, wherein the coating includes a pre-coating layer that functions as a moisture barrier.

25. The composition according to claim 24, wherein the pre-coating layer comprises beeswax, carnauba wax, candelilla wax, sumac wax, sunflower wax, or cocoa butter.

26. The composition according to claim 24, further comprising a final coating layer.

27. The composition according to claim 23, wherein the weight ratio of the core to the composition is 6:4 to 7:

3.

28. The composition according to claim 1, which is in the form of gum and further comprises a gum base.

29. The composition according to claim 28, wherein the gum base contains 5% by weight ± 2% ash.

30. The composition according to claim 1, wherein the salt content of the composition is 25% by weight or less.

31. A method for administering an active agent to a subject, comprising introducing an active agent into the oral cavity of a subject using a composition comprising a core, the core comprising at least one active agent, a phase change material (PCM), and an exothermic material, and containing less than 0.5% water, and generating heat in the oral cavity of the subject by bringing the composition into contact with saliva.

32. A method for treating or preventing a subject's disease or symptoms, or for optimizing the subject's health, comprising administering an active agent to a subject in need of it via an oral route using a composition comprising the core, the core comprising at least one active agent, a phase change material (PCM), and an exothermic material, and less than 0.5% water.

33. A method for treating a disease or symptom according to claim 32, wherein the disease or symptom is selected from the group consisting of periodontal disease (periodontitis, peri-implantitis), recurrent aphthous stomatitis, oral candidiasis, dental caries, bad breath, cardiovascular disease, respiratory disease, diabetes, Alzheimer's disease, frontotemporal dementia, dementia, Parkinson's disease, microbial disease, biofilm formation, inflammation, neuroinflammation, cognitive decline, cerebral infarction, cerebral ischemia, cerebral edema, sciatic nerve lesions, neuropathic pain, mood disorders, improvement of mental capacity / sensitivity, memory recall, obesity, stress, insulin resistance / type II diabetes, chronic kidney disease, rheumatoid arthritis, metabolic syndrome, intestinal microbiota abnormalities, and Crohn's disease.

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