Self-microemulsifying multi-deliverable system

Abstract

Compositions in the form of oil-based solutions are described that form oil-in-water (OIW) microemulsions in the aqueous environment of the GI tract when taken orally via hard or soft capsules. The microemulsions formed by the oil-based solutions within the GI tract can rapidly deliver oil-soluble and alcohol-soluble (including alcohol-soluble PEG derivative-assisted) deliverables to the bloodstream through the tissues that form the GI tract. The in-situ formed microemulsions produced by ingestion of the encapsulated oil-based solutions contain oil-phase microemulsion droplets of monolayer surfactant-bound particles suspended in the aqueous continuous phase of the GI tract. The oil-based solutions can also form water-core liposomes suspended in the aqueous continuous phase of the GI tract in situ.

Description

[0001] Citation to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 923,028, filed on October 18, 2019, entitled “Self-emulsifying delivery system,” which is incorporated herein by reference in its entirety. Background Art

[0003] Nutritional supplements typically enter the bloodstream in a variety of ways. Supplements taken orally are absorbed at different rates due to different factors. For example, the average absorption rate of oral solid supplements is about 10% to 20%. Oral gel capsules can increase this to about 30%, transdermal patches can increase it to about 45%, and conventional oral (sublingual) administration can increase it to about 50%. Injections provide about 90% to 100% absorption in the bloodstream, but are not commonly used for nutritional supplements.

[0004] Emulsion is a mixture of two or more insoluble liquids. Therefore, two or more liquids will not form a solution, and there is an identifiable interface between the combined liquids. Emulsions can be macroemulsions, pseudoemulsions, nanoemulsions or microemulsions. Emulsions can be used for parenteral delivery, ocular delivery, transdermal delivery, oral delivery, etc. Emulsions include particles of a continuous (carrier) phase. The particles of the emulsion can be combined by liposomes (double layers), micelles (monolayers) or monolayer surfactants, wherein the oil of the particles is associated with the surfactant system, but does not necessarily form an oil core.

[0005] Figure 1A and Figure 1B Liposome 100 is shown having a double wall (bilayer) of phospholipids formed by a hydrophilic outer wall 120 and a hydrophilic inner wall 125. The interior of the double wall 110 is hydrophobic. The hydrophilic inner wall 125 forms a capsule interior 130 to form what may be referred to as a "water-core" liposome. Liposomes may be thought of as small liquid-filled capsules in which the capsule wall is formed by two layers of phospholipids, thus having a double wall. Since phospholipids constitute the outer membrane of living cells, liposome 100 may also be thought of as having a permeable membrane wall similar to that of a cell, but without the nucleus or other components of a living cell within the capsule interior 130. The outer wall 120 and inner wall 125 of a representative liposome 100 are polar and thus water-soluble, while the interior of the double wall 110 is non-polar and thus oil-soluble.

[0006] The liposome 100 exists as a hydrophilic continuous phase and carries a hydrophilic liquid within the capsule interior 130 formed by the bilayer membrane. A relatively small amount of hydrophobic liquid can be carried inside the double wall 110 of the liposome 100. A common phospholipid used to form liposomes is phosphatidylcholine (PC) (a substance found in lecithin). In a hydrophobic (non-polar) continuous phase, the opposite may occur, resulting in a bilayer structure with a hydrophobic or "oil-core". Liposomes like this can be called "reverse liposomes" because they have an "oil" instead of a "water" core.

[0007] When liposomes are introduced into the body, it is known that liposomes deliver their internal contents to living cells by one of the following four methods: adsorption, endocytosis, lipid exchange and fusion. In adsorption, the outer wall of the liposome adheres to the living cell and releases its contents into the living cell through the outer wall of the living cell. In endocytosis, the living cell swallows the liposome, thereby bringing the entire liposome into the cell. Then, the cell dissolves the outer wall of the liposome and releases the liposome contents into the interior of the living cell. In lipid exchange, the liposome opens near the living cell, and the living cell absorbs the liposome contents at a local high concentration. In fusion, the outer wall of the liposome becomes part of the outer wall of the living cell, thereby carrying the contents of the liposome into the enlarged living cell. If the liposome can be sufficiently close to the cell and is appropriately constructed to interact with the outer wall of the living cell, these pathways allow the internal contents of the liposome to be potentially 100% transferred to the interior of the living cell.

[0008] Figure 2 A side view of the plan view of the phospholipid double wall (bilayer) that forms a liposome. The phospholipids have a polar, hydrophilic "head" and a less polar, relatively hydrophobic "tail." In this representative example, the heads form the top and bottom of the bilayer, and the tails form the interior middle. As mentioned earlier, some oil-soluble substances may reside between the top and bottom layers of the interior region occupied by the tails.

[0009] Figure 3Represents micelle 300, which has a single wall (monolayer) of phospholipids forming a hydrophilic exterior 320 and a hydrophobic interior 310, and therefore lacks the hydrophilic vesicle interior of a liposome. Therefore, micelles lack a double layer relative to liposomes and do not provide a vesicle interior that can contain a water-soluble hydrophilic core component. The phospholipid tails in the interior of micelle 300 are closely spaced and may be compressed against each other. Therefore, any hydrophobic components retained in micelle 400 are dispersed in the tails of the phospholipids. This is comparable to the situation where oil-soluble compounds reside between the inner and outer layers that form the bilayer of the liposome. Micelles 400 can be considered as the outer wall of the liposome without providing an inner wall inside the hydrophilic vesicle. Polyethylene glycol-modified vitamin E (e.g., tocopherol polyethylene glycol succinate 1000 (TPGS)) can also be used to form micelles in water, and since TPGS has a water-soluble head and an oil-soluble tail, it is performed in a manner similar to phospholipids. In the nonpolar continuous phase, the reverse situation can occur, resulting in a monolayer structure with a hydrophilic interior. Such a structure can be called a "reverse micelle".

[0010] Figure 4 A monolayer of surfactant-bound particles 400 is shown, wherein an associated oil component 450 is associated with a hydrophobic tail 460 of the surfactant. In this representative example, the surfactant has formed a round shape, thereby surrounding the associated oil component 450, and thus is close to a relatively large swollen micelle with a different oil core, but the association of the associated oil component 450 with the hydrophobic tail 460 of the surfactant does not require such surrounding. When a monolayer of surfactant surrounds the oil, thereby forming an oil core, the resulting surfactant and oil droplets are considered to be the suspended particle components of a microemulsion (if formed without pressure or shear), and are therefore thermodynamically stable. In a polar continuous phase, the hydrophilic polar head 470 of the surfactant will form a hydrophilic exterior and a hydrophobic interior, thereby forming a hydrophobic oil-soluble core. In a hydrophobic (non-polar) continuous phase, the reverse situation can occur, resulting in a monolayer structure with a hydrophilic (polar) water core. Structures like this can be called "inverse emulsions" or "inverse microemulsions."

[0011] Conventional self-emulsifying and self-microemulsifying delivery systems (SEDS or SMEDS) are mixtures of oil, surfactant, co-surfactant and desired deliverables. SMEDS components are encapsulated in hard or soft gel capsules and swallowed. When released into the aqueous gastrointestinal fluid of the stomach, the capsule dissolves to release the components of the SMEDS. Then, it is believed that these components form microemulsion droplets (surfactant and oil particles) in situ, and the microemulsion has the aqueous gastrointestinal fluid of the gastrointestinal (GI) tract as a continuous phase or carrier phase. Therefore, when dissolved, the capsule is considered to form an oil-in-water (OIW) microemulsion in the aqueous environment of the stomach.

[0012] If an OIW microemulsion is formed in the stomach, the oil-soluble substance deliverable is loaded in the oil of the surfactant and oil particles, thereby allowing the oil-soluble substance deliverable to be delivered to the tissues of the GI tract. Thus, the system is intended to increase the transfer of the oil-soluble substance deliverable to the bloodstream, even if the deliverable is substantially insoluble in the aqueous gastric environment.

[0013] Curcuminoids are extracted from turmeric powder, which is a product of the Curcuma longa plant. There are three types of curcuminoids: curcumin, demethoxycurcumin and bisdemethoxycurcumin. Curcumin is a solid alcohol-soluble substance that is insoluble in water and is therefore poorly absorbed into the GI tract. The solubility of solid curcumin in water buffered to pH 5.0 is reported to be 11 ng / mL, and the bioavailability of the solid curcumin powder subsequently administered orally in rats is reported to be 1%. Therefore, for solid powders, no quantifiable serum levels in humans have been reported until a large oral dose of 3.6 grams of solid powder is swallowed. It can be seen from this that individuals may need to swallow at least 3.6 grams of curcumin powder every day to have the desired pharmacological effect.

[0014] When swallowed orally, free curcumin is known to exist at very low levels in vivo, while curcumin metabolites (curcumin-glucuronide and curcumin-sulfate) are mainly found due to conjugation of free curcumin during absorption through the intestine, with curcumin-glucuronide being the major product of the two metabolites. However, it has been reported that curcumin-glucuronide has a weaker effect on gene expression in a human hepatoma cell line (HepG2) than free curcumin.

[0015] Curcumin has been reported to possess desirable biological activities including anti-inflammatory, antiviral, anticancer, antioxidant and antidepressant capabilities. Curcumin has also been reported to possess the unusual ability to modulate CB1 and CB2 receptors, as does the cannabinoids, as a non-cannabinoid. A readily available source of curcumin powder is CURCUMIN C3 COMPLEX TM , available from Sabinsa Corporation, East Windsor, NJ; however, curcumin may also be obtained from other sources.

[0016] β-caryophyllene is a liquid, oil-soluble substance that is insoluble in water and is known to have low bioavailability in aqueous systems such as the GI tract. β-caryophyllene is a terpene (bicyclic sesquiterpene) found in essential oils of plants including cloves, hops, black pepper, rosemary and cannabis. It has anti-inflammatory properties, as a non-cannabinoid to activate endocannabinoid CB2 receptors, provide an unusual ability to increase mitochondrial function and potentially reduce neurodegenerative lesions. β-caryophyllene may provide inflammation-reducing activity associated with cannabidiol (CBD), but with stronger analgesic activity.

[0017] Boswellia serrata (frankincense, mastic) is a solid, alcohol-soluble substance that is insoluble in water and is known to have very low bioavailability in aqueous systems such as the GI tract. Boswellia serrata is a polyphenol (pentacyclic triterpenoid) extracted from the Boswellia serrata tree and is reported to reduce inflammation, especially in cases of joint and intestinal inflammation, due to blocking the function of leukotrienes. The extract contains bioactive boswellic acids.

[0018] Quercetin is a solid, alcohol-soluble substance that is insoluble in water and is known to have extremely low bioavailability in aqueous systems such as the GI tract. Quercetin is a plant-derived polyphenol from the flavonoid group and is found in many fruits, vegetables, leaves, and grains. When administered IV, quercetin acts as an antioxidant by scavenging (inactivating) free radicals such as oxygen free radicals and as an activator of estrogen receptors. However, the bioavailability of quercetin in humans is low and highly variable (0-50%), and after oral ingestion of foods or supplements containing quercetin, quercetin is rapidly cleared from the body with an elimination half-life of 1-2 hours. After dietary intake, quercetin undergoes rapid and extensive metabolism, which makes it unlikely that the biological effects observed in IV administration studies are applicable to routine oral administration.

[0019] Berberine hydrochloride is a solid, alcohol-soluble substance that is slightly soluble in water and is known to have low bioavailability in aqueous systems such as the GI tract. Berberine is an acid salt of the protoberberine group derived from benzylisoquinoline alkaloids (isoquinoline alkaloids), which are found in plants such as Berberis, goldenseal, goldthread, turmeric, and others. The extract is believed to provide benefits in reducing insulin resistance, promoting glycolysis, and providing blood sugar control.

[0020] Milk thistle extract is a solid, alcohol-soluble substance that is insoluble in water and is known to have low bioavailability in aqueous systems such as the GI tract. Milk thistle extract is reported to have an antioxidant effect attributed to the flavonoid silymarin and to help remove heavy metals, alcohols and pesticides from the liver. In addition to increasing liver glutathione levels, the antioxidant effect is believed to protect the outside of the cells from oxidative damage and potential cell mutations that can be caused by oxidative damage. Milk thistle extract is an extract of the milk thistle plant containing at least 50% silymarin by weight, and preferably at least 70% silymarin by weight. Silymarin is the main active ingredient in milk thistle extract, in pure solid form, and when the milk thistle extract is swallowed orally, silymarin is believed to have an absorption rate of from 20% to up to 50%.

[0021] Artemisinin is a solid alcohol-soluble substance with low solubility in both oil and water and associated poor bioavailability unless chemically modified. Artemisinin is a sesquiterpene lactone containing a peroxy bridge and is derived from the Asian plant Artemisia annua. Artemisinin is reported to have antiparasitic and antimalarial activities as well as potential anticancer and antiviral activities.

[0022] Andrographis is a solid alcohol-soluble substance with poor solubility in water. Andrographis is a diterpene lactone reported to have antibacterial, anti-inflammatory and antioxidant activities.

[0023] Luteolin is a solid alcohol-soluble substance that is slightly soluble in water. Luteolin is a flavonoid found in celery, broccoli, green pepper, parsley, thyme, dandelion, perilla, chamomile tea, carrots, olive oil, peppermint, rosemary, navel orange and oregano. Plants rich in luteolin have been used in traditional Chinese medicine to treat various diseases, such as hypertension, inflammatory lesions and cancer.

[0024] Resveratrol is a solid alcohol-soluble substance that is insoluble in water. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol produced by several plants in response to injury or when the plant is attacked by pathogens (such as bacteria or fungi). Sources of resveratrol in food include grape skin, blueberries, raspberries and mulberries. Resveratrol exists in two geometric isomers: cis-(Z) and trans-(E). Trans-resveratrol and cis-resveratrol isomers can be free or bound to glucose. Although 70% of orally administered resveratrol is absorbed by the body, the bioavailability is only about 0.5% because resveratrol is extensively metabolized into its glucuronide conjugates by the liver and intestine before reaching the bloodstream. Due to the low bioavailability, animal models have shown that 200 to 500 milligrams (mg) of resveratrol are needed per kilogram of diet to affect cell signaling pathways important for mitochondrial biogenesis.

[0025] Diindolylmethane (DIM) is a solid, alcohol-soluble substance that is insoluble in water. DIM is an amine derived from indole-3-carbinol and is found in cruciferous vegetables such as broccoli, Brussels sprouts, cabbage, and kale. DIM is reported to induce antioxidant response elements (AREs).

[0026] Hesperidin is a solid alcohol-soluble substance that is insoluble in water. Hesperidin is a polyphenolic flavanone commonly obtained from citrus fruits and has been reported to have positive effects on vascular conditions, including poor blood circulation. Although the specific mechanism is currently unknown, it is believed that hesperidin may work by reducing vascular inflammation.

[0027] Cannabinoids are a class of compounds that act on cannabinoid receptors in cells, thereby altering the release of neurotransmitters. Cannabinoids include endocannabinoids that occur naturally in animals, phytocannabinoids found in plants of the Cannabis genus and some other plants, and synthetic cannabinoids that are synthesized. Type 1 cannabinoid receptors are found primarily in the brain and are not present in the part of the brainstem responsible for respiratory and cardiovascular function. Type 2 cannabinoid receptors are found primarily in the immune system and appear to be responsible for the anti-inflammatory effects and potential other therapeutic effects of cannabinoids.

[0028] Phytocannabinoids are isolated from plants of the genus Cannabis, which is believed to include three species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Cannabis plants containing less than 0.3% tetrahydrocannabinol (THC) by weight are often referred to as "industrial hemp", while plants containing more than 0.3% THC by weight are often referred to as "marijuana". At least 113 different phytocannabinoids have been isolated from plants of the genus Cannabis. Phytocannabinoids are isolated in their "A" or acidic form and then decarboxylated (usually by heating) to their more biologically active decarboxylated form.

[0029] THC is the best-known cannabinoid because it binds to the type 1 receptor and is thought to have psychoactive effects. Cannabidiol (CBD) is becoming a more common non-psychoactive cannabinoid because it acts on both type 1 and type 2 receptors and is known to reduce pain and inflammation, and calm some neurological responses, such as those associated with Dravet syndrome in children. In addition, CBD may combat cognitive impairment associated with THC use, including short-term memory loss, and may have additional antipsychotic effects in addition to its use as an antioxidant. Cannabigerol (CBG) is another non-psychoactive cannabinoid that may have similar effects to CBD. Cannabichromene (CBC), cannabinol (CBN), and cannabitriol (CBT) are other cannabinoids that are being studied for potential bioactivity.

[0030] Cannabis extract is an oil-soluble substance extracted from the cannabis plant and is insoluble in water, so it is a phytocannabinoid. Preferred cannabis extracts include cannabidiol (CBD), tetrahydrocannabinol (THC) and other cannabinoids (including cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin (THCV), cannabidiol (CBDV) and cannabicycler (CBC)). Preferred cannabis extracts contain at least 30% CBD and / or THC by weight, and more preferred cannabis extracts contain at least 60% CBD and / or THC by weight. The most preferred cannabis extracts contain at least 80% CBD and / or THC by weight. "Industrial hemp oil" is a cannabis extract with a concentration of less than 0.3% tetrahydrocannabinol (THC) and a relatively high concentration of cannabidiol (CBD)-therefore lacking psychoactive effects.

[0031] Oral delivery of cannabis extracts with conventional delivery systems may produce negligible blood concentrations 20 minutes after administration and may not provide effective bloodstream concentrations, which are believed to be about 0.4 ng / mL and higher in the bloodstream. In fact, for individuals with low absorption, effective bloodstream concentrations may not be achieved, or may not be achieved at all, after 90 minutes of oral administration with conventional oil delivery systems without ingesting undesirably large amounts of the conventional oral delivery system. Thus, of the cannabinoids ingested orally with conventional oil delivery systems, the vast majority of the ingested cannabinoids may be excreted and never utilized.

[0032] While research on the health benefits of cannabinoids is still ongoing, pharmacological benefits have been demonstrated or may be demonstrated in the previously mentioned Dravet syndrome in children, Parkinson's disease, schizophrenia, anxiety disorders, and inhibiting the development of some cancer cells. Because the human endocannabinoid system is involved in basic life functions, including appetite, immune response, reproduction, and pain management, the effects of cannabinoids on the human body may be diverse. The ability of cannabinoids to prevent overactivation of these functions may reduce the progression or prevent diseases based on overactivation of these functions.

[0033] Terpenes are liquid, oil-soluble extracts that are insoluble in water. Terpenes can be extracted from plants and some insects, including conifers, flowers, citrus fruits, and insects such as termites and swallowtail butterfly. From a molecular point of view, all terpenes have isoprene functional groups and are different types of organic molecules. In addition to their historical use as spices, terpenes also provide a basis for bioactive substances including vitamin A, vitamin D and steroids. Terpenes include compounds such as limonene, pinene, linalool and the previously discussed beta caryophyllene. Oral delivery of terpenes with conventional delivery systems can produce negligible blood concentrations and cannot provide effective blood flow concentrations.

[0034] Zinc is a solid mineral that is usually available as a water-soluble salt, such as zinc gluconate, zinc citrate, zinc acetate, zinc picolinate, zinc sulfate, etc. Zinc is considered an essential nutrient, so the body cannot produce or store it. Zinc plays a variety of roles in gene expression, enzyme reactions, protein and DNA synthesis, and is a key component of a healthy immune system, especially in fighting viral infections.

[0035] Although each of the above-mentioned plant extracts is claimed to have potential health benefits, the problem of obtaining any actual therapeutic benefit from its consumption is the lack of bioavailability. As an example, in order for curcumin to show any potentially useful blood concentration, a person must eat more than 3 grams of curcumin per day, and in fact, in order to obtain the therapeutic dose required for health benefits, a larger amount of curcumin may need to be taken. Although 3+ grams of curcumin per day is technically digestible, few people would consider consuming such a large amount. In addition, curcumin is not the most difficult to deliver among these plant extracts. For example, without chemical modification, artemisinin is essentially undeliverable with conventional delivery systems.

[0036] Among these deliverables that are potentially beneficial to human health, for example, curcumin is a deliverable targeted for delivery via self-microemulsifying delivery systems (SMEDS), which otherwise require very high doses of unpalatable curcumin due to its water insolubility and, therefore, very poor bioavailability. Therefore, conventional SMEDS attempt to deliver curcumin to the bloodstream while circumventing its water insolubility, and multiple grams of raw curcumin must be eaten / tasted daily.

[0037] Although conventional SMEDS have been tried for curcumin, these conventional systems have the following disadvantages, including limited deliverable selection, low solubility of deliverables in SMEDS delivery components, and poor emulsion formation. The low solubility of deliverables in SMEDS delivery components together with poor emulsion formation result in relatively poor delivery of deliverables to the bloodstream, usually no more than conventional oil delivery methods. Poor emulsion formation results in the formation of unstable and / or relatively large oil core particles greater than 100nm in the GI tract. For example, particles with an average diameter of 100nm are believed to be delivered to the bloodstream by the GI tract at only about 40%, while particles with an average diameter of 75nm are believed to be delivered to the bloodstream by the GI tract at about 60%. The low solubility of deliverables in SMEDS delivery components results in relatively few deliverables in any emulsion formed in the GI tract. If the deliverable is not part of the emulsion formed in situ, the deliverable is delivered conventionally, rather than by SMEDS.

[0038] The self-microemulsifying delivery systems and methods of the present invention overcome at least one disadvantage associated with conventional SMEDS. Summary of the invention

[0039] In one aspect, the present invention provides a composition for delivering a deliverable to the gastrointestinal tract, the composition comprising an outer capsule enclosing an oil-based solution; wherein the oil-based solution comprises an emulsion system and a deliverable, wherein the emulsion system comprises a surfactant system, an emulsified oil system, and a resin system, and wherein the deliverable is selected from the group consisting of an oil-soluble substance, an alcohol-soluble substance, and a combination thereof.

[0040] In another aspect of the invention, there is a method for preparing a composition for delivering a deliverable to the gastrointestinal tract, the method comprising heating a solution of alcohol and water to a low temperature of 65°C to 78°C, wherein the solution of alcohol and water has a ratio of alcohol to water of 80:20 to 97:3 by volume to form a heated solvent solution; combining an alcohol-soluble substance deliverable with the heated solvent solution to form a heated deliverable mixture; combining a surfactant system and a resin system with the heated deliverable mixture; raising the heated deliverable mixture to a temperature above 78°C to form a reduced solution; and combining an emulsified oil system with the concentrated solution to form an oil-based solution.

[0041] In another aspect of the present invention, there is an ingestible and edible composition for relieving pain, the composition comprising an encapsulated oil-based solution comprising 2% to 3% by weight phospholipids, 24% to 30% by weight polyethylene glycol derivatives, 8% to 13% by weight turmeric oleoresin, 1% to 2.5% by weight propolis, 12% to 18% by weight emulsified oil, 23% to 31% by weight turmeric oil, 5% to 9% by weight beta caryophyllene, 1.5% to 4% by weight industrial hemp oil, 1% to 3% by weight piperine, 4% to 4% by weight curcumin, and 2% to 4% by weight Boswellia serrata.

[0042] In another aspect of the present invention, there is an ingestible and edible composition for balancing the microbial load in a mammal, the composition comprising an encapsulated oil-based solution comprising 3.2% to 5% by weight of phospholipids, 26.3% to 30% by weight of a polyethylene glycol derivative, 3% to 7% by weight of turmeric oleoresin, 2.6% to 4% by weight of propolis, 18.2% to 23% by weight of emulsified oil, 11% to 20% turmeric oil by weight, 1% to 5% cinnamon oil by weight, 1% to 5% peppermint oil by weight, 0.2% to 1.3% industrial hemp oil by weight, 0.3% to 2% berberine hydrochloride by weight, 2% to 5% milk thistle extract by weight, 3% to 7% artemisinin by weight, 0.3% to 2% andrographis paniculata by weight, 2% to 6% boswellia serrata by weight, and 2% to 4% quercetin by weight.

[0043] In another aspect of the present invention, there is an ingestible and edible composition for controlling inflammation, the composition comprising an encapsulated oil-based solution comprising 1% to 3% phospholipids by weight, 25% to 34% polyethylene glycol derivatives by weight, 6% to 10% turmeric oleoresin by weight, 8% to 13% associated oils by weight, 27% to 35% turmeric oil by weight, 2% to 6% cinnamon oil by weight, 7% to 10% spearmint oil by weight, 2% to 5% berberine hydrochloride by weight, 2% to 5% milk thistle extract by weight, 2% to 5% resveratrol by weight, 2% to 5% hesperetin by weight, and 2% to 5% quercetin by weight.

[0044] In another aspect of the present invention, there is an ingestible and edible composition for supplementing dietary zinc in a mammal, the composition comprising an encapsulated oil-based solution comprising 1% to 3% by weight phospholipids, 25% to 34% by weight of a polyethylene glycol derivative, 7% to 10% by weight of propolis, 22% to 30% by weight of associated oils, 10% to 15% by weight of turmeric oil, 10% to 15% by weight of spearmint oil, 3% to 5% by weight of zinc acetate, 2% to 5% by weight of luteolin, 2% to 5% by weight of hesperetin, and 2% to 5% by weight of quercetin.

[0045] The scope of the present invention is defined solely by the appended claims and shall not be affected by the statements in this summary. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The invention may be better understood with reference to the following drawings and description. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

[0047] Figure 1A and Figure 1B It refers to a liposome having a phospholipid double wall (bilayer) formed of a hydrophilic outer wall and a hydrophilic inner wall.

[0048] Figure 2 Represents a planar side view of the phospholipid double wall (bilayer) that forms a liposome.

[0049] Figure 3 It refers to micelles having a single wall (monolayer) of phospholipids forming a hydrophilic exterior and a hydrophobic interior, which lack the hydrophilic vesicle interior of liposomes.

[0050] Figure 4 Represents a monolayer of surfactant-bound particles in which the associated oil component is associated with the hydrophobic tail of the surfactant.

[0051] Figure 5 A method of preparing a composition comprising an encapsulated oil-based solution is presented.

[0052] Figure 6 Results of LC / MS / MS plasma curcumin analysis at time intervals of 0, 10, 20, 40, 60, 90, 120, 180 and 480 (commercially available only) minutes are provided.

[0053] Figure 7 Results of LC / MS / MS plasma curcumin-glucuronide analysis at time intervals of 0, 10, 20, 40, 60, 90, 120, 180 and 480 (commercially available only) minutes are presented. DETAILED DESCRIPTION

[0054] Compositions in the form of oil-based solutions are described that form oil-in-water (OIW) microemulsions in the aqueous environment of the GI tract when taken orally via hard or soft capsules. Microemulsions formed by oil-based solutions within the GI tract can rapidly deliver oil-soluble and alcohol-soluble (including alcohol-soluble PEG derivative-assisted) deliverables to the bloodstream through the tissues that form the GI tract. In situ-formed microemulsions resulting from administration of encapsulated oil-based solutions contain oil-phase microemulsion droplets of monolayer surfactant-bound particles suspended in an aqueous continuous phase of the GI tract. Oil-based solutions can also form in situ water-core liposomes suspended in an aqueous continuous phase of the GI tract.

[0055] The outer capsule containing the oil-based solution can be of the "hard shell" or "soft shell" type. Useful hard shell capsules are made from aqueous solutions of gelling agents, such as animal proteins (primarily gelatin) or plant polysaccharides or their derivatives (such as carrageenan and modified forms of starch and cellulose). Other additional ingredients are gelling agents (such as glycerol or sorbitol) to reduce the hardness of the capsule, colorants, preservatives, disintegrants, lubricants and surface treatment agents. Examples of outer hard shell capsules include Nutra Pak capsules available from NutraPakUSA, East Rutherford, NJ, or QUALICAPS available from Qualicaps, Inc., Whitsett, NC TM Useful soft shell capsules are typically a combination of gelatin, water, an opacifier, and a plasticizer such as glycerol or sorbitol. The main source of gelatin is collagen, found in the skin and bones of animals, and is usually derived from cattle or pigs. Vegetarian capsules are primarily made of hydroxypropyl methylcellulose (HPMC) and, as an alternative, polyethylene oxide (PEO). Examples of external soft shell capsules are available from NutraPak USA or Soft Gel Technologies, Inc., Los Angeles, CA. In either case, the choice of hard shell capsule material or soft shell capsule material will not adversely affect the encapsulated oil-based solution released into the GI tract.

[0056] In an oil-based solution encapsulated by an external capsule, a solid deliverable is dissolved in the liquid of the oil-based solution. When the resulting solution is placed in an aqueous environment (e.g., the GI tract), it is considered to form a microemulsion droplet having an oil-based core, a resin intermediate layer that encapsulates the core, and an external surfactant monolayer that encapsulates the intermediate layer. While dissolving each other, the different solubilities of these layered structures are considered to enable the accommodation of a wide variety of deliverables, including deliverables that are alcohol-soluble and / or oil-soluble. When introduced into the GI tract, the composition provides improved deliverable solubility and bloodstream uptake compared to conventional SMEDS.

[0057] The emulsion system of the oil-based solution through encapsulation that forms SMEDS comprises surfactant system, emulsified oil system and resin system.Except the microemulsion droplet in aqueous continuous phase (for example GI tract), the emulsion system can also be designed to produce water-core liposome.No matter the specific composition used in the emulsion system, one or more deliverables are included and dissolved in the oil-based solution through encapsulation.Therefore, surfactant system, emulsified oil system, resin system and deliverable form oil-based solution.Think that this is contrasted with conventional SMEDS system, in conventional SMEDS system, deliverable will not dissolve completely in emulsion formation component or will dissolve poorly or conventional emulsion system is water-based rather than oil-based.

[0058] When released into the aqueous environment of the GI tract, the oil-based solution forms microemulsion droplets and optionally forms liposomes, which contain the deliverable and have an average droplet diameter of 10 to 100 nanometers (nm), and preferably an average droplet diameter of 10 to 80 nanometers. More preferably, the formed microemulsion droplets and any contained liposomes have an average particle size of 10 nm to 60 nm. Therefore, for the formed microemulsion droplets (containing any deliverable) and any formed liposomes (containing the water-soluble deliverable), these average droplet diameters are observed in an aqueous environment.

[0059] The surfactant system of the emulsion system comprises a phospholipid such as phosphatidylcholine (PC) and a polyethylene glycol derivative such as tocopherol polyethylene glycol succinate (TPGS). Additional surfactants may be included in the surfactant system if they are compatible with the formation of the desired unilamellar surfactant-bound particles that form the microemulsion droplets and optionally the water-core liposomes.

[0060] The phospholipids of the surfactant system are glycerophospholipids preferably separated from lecithin. Since the phospholipids are preferably lecithin isolates, the isolate preferably comprises 80% (w / w) of the specified phospholipids, and the remaining components are one or more additional phospholipids separated from lecithin or other lecithin isolates. Preferably, the phospholipid lecithin isolate comprises phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide phosphoethanolamine (Cer-PE), ceramide phosphorylcholine (SPH) and combinations thereof, wherein PC, PE and combinations thereof are more preferred.

[0061] The polyethylene glycol derivative of the surfactant system can be a polyethylene glycol-modified vitamin E, such as tocopheryl polyethylene glycol succinate 1000 (TPGS), polysorbate 40, polysorbate 60 or polysorbate 80. Preferably, the polyethylene glycol derivative is TPGS, polysorbate 40 or polysorbate 80. More preferably, the polyethylene glycol derivative is TPGS or polysorbate 40. TPGS, polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 are generally considered to be interchangeable. However, polysorbate 20 is less preferred because it is less likely to form a desired microemulsion in combination with phospholipids.

[0062] Preferably, the surfactant system constitutes 27% to 35% by weight of the oil-based solution containing one or more deliverables that form an OIW microemulsion when released into the GI tract. The phospholipids preferably constitute 1% to 5% of the oil-based solution, while the polyethylene glycol derivative preferably constitutes 26% to 30% of the oil-based solution. Thus, the preferred ratio of phospholipids to polyethylene glycol derivatives in the oil-based solution is 1:5 to 1:30.

[0063] The emulsified oil system of the emulsion system comprises an associated oil, and the associated oil comprises at least one of medium chain triglycerides (MCT), citrus oil and a combination thereof. By "associated", it is meant that the oil can be kept in a phospholipid / polyethylene glycol derivative monolayer. MCT oil is a triglyceride, and its fatty acid has an aliphatic tail of 6-12 carbon atoms. Preferred MCT oils include caproic acid (caproic acid, hexanoic acid), caprylic acid (caprylic acid, octanoic acid), capric acid (capricacid, decanoic acid), lauric acid (dodecanoic acid) and a combination thereof. More preferred MCT oils include caprylic acid, capric acid and a combination thereof. Preferred citrus oils include orange oil, lemon oil and a combination thereof.

[0064] In addition to the associated oil, the emulsified oil system preferably also comprises a terpene oil (eg turmeric oil, cinnamon oil, peppermint oil, spearmint oil) or a mixture of terpene oils.

[0065] Preferably, the emulsified oil system constitutes 38% to 55% by weight of the oil-based solution containing one or more deliverables that form an OIW microemulsion when released into the GI tract. The associated oil preferably constitutes 8% to 28% of the oil-based solution. When included, the terpene oil or terpene oil mixture preferably constitutes 18% to 46% of the oil-based solution. Therefore, when the terpene oil or terpene oil mixture is included, the preferred ratio of the associated oil to the terpene oil or terpene oil mixture in the oil-based solution is 1:1.7 to 1:5.5.

[0066] The resin system of the emulsion system comprises at least one resin selected from the group consisting of turmeric oleoresin, propolis, astaxanthin oleoresin, rosin, ginger oleoresin and combinations thereof. The resins of the resin system may be solid or semi-solid with some viscous oily liquid content and are insoluble in water. Although the resin system may contain some oil, there is sufficient solid content so that it is not considered a liquid, at most as having a tightly bound liquid oil component. One or more resins of the resin system are part of the emulsion system; however, they may also provide biological activity.

[0067] Turmeric oleoresin is an oil-soluble substance and is extracted from the turmeric plant, but in relation to the curcuminoids which are "hard" solids, turmeric oleoresin is a viscous, waxy paste which may contain an oil component. Turmeric oleoresin contains 37%-55% curcuminoids by weight and up to 25% volatile oils by weight. Turmeric oleoresin is isolated as one of the three recovered fractions from the processing of turmeric rhizomes. Since turmeric oleoresin includes curcuminoids, the oleoresin can provide the biological activity of curcumin.

[0068] To obtain the turmeric oleoresin, the turmeric rhizome is typically dried and ground into a powder. The powder is then extracted with a solvent (some combination of acetone, dichloromethane, 1,2-dichloromethane, methanol, ethanol, isopropanol, and hexane) to provide a solid waxy component, namely, turmeric oleoresin, turmeric oil, and solvent-dissolved solid curcumin. Thus, while the oleoresin contains some oil, it is the oil that is captured in or with the solids because the turmeric light oil or "turmeric essential oil" is removed during the extraction process. As previously discussed, the recovered turmeric "light" oil or turmeric "essential" oil can form part of the emulsified oil system of the oil-based solution. Also as previously discussed, the solvent is removed from the extraction solvent in which the curcumin is dissolved to produce the curcumin powder.

[0069] Propolis is a resinous substance containing polyphenols of the flavonoid class, produced by bees from tree buds, and used by bees to fill cracks or seal hives. Propolis usually contains about 50% resin, 30% wax, 10% oil, 10% pollen and organic matter. Due to the variety of ingredients, propolis may be considered as a complex mixture with water-soluble, alcohol-soluble and oil-soluble components when extracted. Preferably, the propolis ethanol extract can be used as a resin "propolis" to form a resin system or a part of a resin system of an oil-based solution; however, other propolis extracts can be used in a resin system. More preferably, the propolis extract used in the resin system contains at least 50%, most preferably at least 60% extracted propolis by weight. Propolis helps to improve the immune system, reduce inflammation, promote blood circulation and other benefits.

[0070] Astaxanthin oleoresin is a waxy solid alcohol-soluble substance that is insoluble in water. Astaxanthin oleoresin can be extracted from algae, plants and animals. Astaxanthin is a terpene known to have antioxidant properties, for example providing the red color to prawns, lobsters and salmon. Astaxanthin cannot be synthesized by mammals and therefore must be provided through the diet.

[0071] Preferably, the resin system constitutes 3% to 18% by weight of an oil-based solution containing one or more deliverables which form an OIW microemulsion when released into the GI tract. When used, turmeric oleoresin preferably constitutes 3% to 14% of the oil-based solution, while when used, propolis preferably constitutes 1% to 10% of the oil-based solution. When used in combination, the ratio of propolis to turmeric oleoresin is preferably 1:1.7 to 1:5.

[0072] The ratio of the resin system to the surfactant system to the emulsified oil system is preferably 1:2-4:3.5-6 by weight, including a deviation of up to 20% (by weight), and more preferably a deviation of up to 10%, so (1:2-4:3.5-6)±20% (by weight) or (1:2-4:3.5-6)±10% (by weight) is more preferred.

[0073] The oil-based solution may optionally contain other ingredients or "adjuvants" that are chemically compatible with the oil-soluble or alcohol-soluble deliverable and emulsion systems and that do not substantially interfere with microemulsion or liposome formation. Such adjuvants may include preservatives, antioxidants, electrolytes, fillers, and pigments. Other adjuvants may be used.

[0074] The deliverable can be in liquid and / or solid form, and can be an alcohol-soluble substance, an oil-soluble substance or a water-soluble substance. Preferably, at least one solid deliverable is included. More preferably, the oil-based solution includes at least two deliverables, which include at least one alcohol-soluble and at least one oil-soluble deliverable. Compared with conventional SMEDS, the advantage of the emulsion system is the following ability of the emulsion system: dissolving a variety of different alcohol-soluble substances and oil-soluble substances, thereby allowing both alcohol-soluble and oil-soluble deliverables to be delivered to the GI tract in essence at the same time. In addition to the OIW microemulsion, the following ability of the emulsion system considered is additionally beneficial: water-core liposomes are also formed, and therefore water-soluble deliverables are delivered simultaneously with alcohol-soluble substances and / or oil-soluble deliverables by liposomes.

[0075] Useful alcohol-soluble substances that can be delivered include curcumin, Boswellia serrata, quercetin, berberine hydrochloride, milk thistle extract, artemisinin, andrographolide, luteolin, resveratrol, diindolylmethane, and hesperetin. Other alcohol-soluble substances can be used with the emulsion system that do not interfere with microemulsion formation and can be dissolved in oil-based solutions.

[0076] Useful oil-soluble materials that can be delivered include beta caryophyllene and cannabis extract.Other oil-soluble materials can be used with the emulsion system that do not interfere with microemulsion formation and can be dissolved in the oil-based solution.

[0077] Useful water-soluble deliverables include mineral salts such as zinc, magnesium and calcium.Other water-soluble materials can be used with the emulsion system which do not interfere with microemulsion formation and which are soluble in oil-based solutions due to the non-polar character of the counterions associated with the minerals.

[0078] Based on the specific deliverable selected for inclusion in the oil-based solution, one gram of oil-based solution can dissolve 50mg to 200mg of deliverable, preferably 100mg to 200mg of deliverable, and more preferably 120mg to 180mg of deliverable, which forms an OIW microemulsion when released into the GI tract. Therefore, the encapsulated oil-based solution contains 10% to 20% deliverable by weight, preferably 12% to 18% deliverable by weight. Although higher deliverable loadings can be used, the solubility of solid phase deliverables is not very feasible, and insoluble deliverables will be significantly reduced to no bioavailability. Therefore, in the oil-based solution, insoluble oil-soluble substances or alcohol-soluble substances deliverables are included, which will provide almost no to no increase in the bioavailability of insoluble deliverables, waste deliverables and may increase liver burden.

[0079] The ratio of deliverable to emulsion system is preferably 1:4-8 (by weight), including deviations of up to 20% (by weight), and more preferably up to 10% (by weight), so (1:4-8) ± 20% (by weight) or (1:4-8) ± 10% (by weight) is more preferred. A relatively large amount of deliverable is dissolved in the emulsion system compared to conventional systems, where about 2%-3% of the dissolved deliverable is expected, which is a significant and unexpected improvement, possibly due to the layered structure identified in the formed microemulsion droplets.

[0080] In addition to the monolayer surfactant-bound particles that form microemulsions in the GI tract, another identified benefit of oil-based solutions is the ability to form water-core liposomes. Thus, the zinc and other salts described previously are believed to be delivered via liposomes formed in situ. In addition to the surfactant-bound particle microemulsions in the GI tract, the ability of the emulsion system to form water-core liposomes is believed to provide the ability to deliver alcohol-soluble substances, oil-soluble substances, and water-soluble deliverables to the tissues of the GI tract in parallel. The ability of oil-based solutions to provide such a diverse array of different deliverables with significantly increased bioavailability to the bloodstream of mammals in a single capsule is another significant and unexpected benefit.

[0081] Figure 5A method of making a composition comprising an encapsulated oil-based solution is shown 500. The oil-based solution may optionally contain a water-soluble deliverable.

[0082] In 510, the solvent solution of alcohol and water is heated to form a heated solvent solution 512. The heated solvent solution 512 preferably comprises ethanol and water. However, other alcohols that are compatible with the subsequent OIW microemulsion formation in the GI tract and the desired deliverables may also be used. The ratio of alcohol to water in the heated solvent solution 512 is preferably 80:20 to 97:3 (by volume), more preferably 90:10 to 95:5 (by volume). The heated solvent solution 512 is preferably heated to a temperature of 65° C. to 78° C., more preferably 68° C. to 75° C.

[0083] At 520, the alcohol soluble substance deliverable and / or optional water soluble deliverable are combined with the heated solvent solution 512 with stirring to form a heated deliverable mixture 522. Depending on the solubility of the deliverable, some deliverables will completely dissolve during the addition process, while other deliverables may not. For example, a deliverable having the solubility characteristics of berberine is unlikely to completely dissolve at this stage.

[0084] At 530 , the surfactant and resin system of the emulsion system are combined with the heated deliverable mixture 522 with continued agitation to form a solution 532 .

[0085] At 540, the temperature of solution 532 is raised to above 78°C (which is the boiling point of ethanol). Preferably, the temperature of solution 532 is then raised to above 100°C (which is the boiling point of water). Preferably, the temperature of solution 532 does not exceed 120°C. Heating and stirring are continued until the ethanol and water are substantially removed to form a concentrated solution 542.

[0086] At 550 , the emulsified oil system of the emulsion system including any oil-soluble material deliverables is combined with the concentrated solution 542 to form an oil-based solution 552 .

[0087] At 560, the oil-based solution 552 is allowed to cool to room temperature with stirring.

[0088] At 570, the oil-based solution 552 is encapsulated with an outer capsule.

[0089] The following examples are provided to illustrate one or more preferred embodiments of the present invention.Many variations of the following examples may be made within the scope of the present invention.

[0090] Example

[0091] Example 1: Formation of an oil-based solution containing oil-soluble substances, alcohol-soluble substances and / or water-soluble deliverables, which forms an OIW microemulsion when released into the GI tract

[0092] Desired alcohol soluble substances and / or water soluble deliverables are added to the heated water / alcohol solution to at least partially dissolve the deliverables and form a heated deliverable mixture. The surfactant and resin system of the emulsion system are then added to form a solution. The solution temperature is then raised to above 100°C. An emulsified oil system (comprising any oil soluble deliverable) is then added to the solution. The solution is then allowed to cool to room temperature. Stirring is utilized until the solution cools to room temperature. The resulting oil-based solution is then placed in an external capsule to form any orally administrable SMEDS.

[0093] Example 2 : An oil-based solution for pain relief containing a deliverable that forms an OIW microemulsion when released into the GI tract

[0094] The following substances are combined using the general method of Example 1: 2% to 3% by weight of phospholipids, 24% to 30% by weight of polyethylene glycol derivatives, 8% to 13% by weight of turmeric oleoresin, 1% to 2.5% by weight of propolis, 12% to 18% by weight of associated oils, 23% to 31% by weight of turmeric oil, 5% to 9% by weight of beta caryophyllene, 1.5% to 4% by weight of cannabis extract ("industrial hemp oil"), 3% to 4% by weight of curcumin extract (curcumin preferably constitutes greater than 90% by weight), and 2% to 4% by weight of Boswellia serrata. The composition may optionally contain 1% to 3% by weight of piperine.

[0095] Example 3 : Oil-based solutions containing deliverables for balancing microbial load in mammals that form OIW microemulsions when released into the GI tract

[0096] The general method of Example 1 was used to combine the following substances: 3.2% to 5% by weight phospholipids, 26.3% to 30% by weight polyethylene glycol derivatives, 3% to 7% by weight turmeric oleoresin, 2.6% to 4% by weight propolis, 18.2% to 23% by weight associated oils, 11% to 20% by weight turmeric oil, 1% to 5% by weight cinnamon oil, 1% to 5% by weight peppermint oil, 0.2% to 1.3% by weight cannabis extract (industrial hemp oil), 0.3% to 2% by weight berberine hydrochloride, 2% to 5% by weight milk thistle extract, 3% to 7% by weight artemisinin, 0.3% to 2% by weight andrographis paniculata, 2% to 6% by weight Boswellia serrata, and 2% to 4% by weight quercetin.

[0097] Example 4 : An oil-based solution containing a deliverable that forms an OIW microemulsion when released into the GI tract for controlling inflammation

[0098] The general method of Example 1 was used to combine the following: 1% to 3% by weight phospholipids, 25% to 34% by weight polyethylene glycol derivatives, 6% to 10% by weight turmeric oleoresin, 8% to 13% by weight associated oils, 27% to 35% by weight turmeric oil, 2% to 6% by weight cinnamon oil, 7% to 10% by weight spearmint oil, 2% to 5% by weight berberine hydrochloride, 2% to 5% by weight milk thistle extract, 2% to 5% by weight resveratrol, 2% to 5% by weight hesperetin, and 2% to 5% by weight quercetin.

[0099] Example 5 : An oil-based solution for dietary zinc supplementation containing a deliverable that forms an OIW microemulsion when released into the GI tract

[0100] The general method of Example 1 was used to combine the following substances: 1% to 3% by weight phospholipids, 25% to 34% by weight polyethylene glycol derivatives, 7% to 10% by weight propolis, 22% to 30% by weight associated oils, 10% to 15% by weight turmeric oil, 10% to 15% by weight spearmint oil, 3% to 5% by weight zinc acetate, 2% to 5% by weight luteolin, 2% to 5% by weight hesperetin, and 2% to 5% by weight quercetin.

[0101] Example 6 : Comparative blood uptake of curcumin delivered orally via capsules

[0102] For the delivery and bioavailability of curcumin, an oil-based solution delivery system generally conforming to Example 2 was compared to a commercially available, purportedly encapsulated emulsion delivery system. The commercial product is indicated on its label as a cellulose soft gel capsule containing sunflower lecithin and 400 mg of curcumin powder. The commercial product is believed to also contain TPGS and turmeric oil. The commercial product may or may not contain additional ingredients.

[0103] Analysis of the commercially available product determined that a single capsule contained approximately 1 mL of liquid containing 266 mg of curcumin, 76 mg of demethoxycurcumin, and 38 mg of bisdemethoxycurcumin. The same analysis of the encapsulated oil-based solution capsules confirmed that each hard capsule shell contained approximately 1 mL of liquid containing 50 mg of curcumin, 10 mg of demethoxycurcumin, and 2 mg of bisdemethoxycurcumin.

[0104] In order to provide the same amount of curcumin for accurate ingestion performance and bioavailability comparison, the following steps were taken. Since each capsule is known to contain about 266 mg of curcumin, the liquid contents of one commercially available capsule and about half of the liquid contents of a second commercially available capsule are taken to provide a dose of about 400 mg of curcumin. Therefore, one "dose" of the commercially available product contains about 400 mg of curcumin and has a total packaged volume of about 1.5 mL. For the oil-based solution capsules, since each capsule is known to contain about 50 mg of curcumin, 8 capsules are taken to provide about 400 mg of curcumin. Therefore, one "dose" of the oil-based solution contains about 400 mg of curcumin and has a total packaged volume of about 6 mL.

[0105] Human subjects orally ingested a dose of either the commercial product or the oil-based solution while fasting. For each, venous blood samples were collected from human subjects before and after dosing (taking capsules) at different time intervals, approximately 3 hours for the oil-based mixture and approximately 8 hours for the commercial product. Therefore, a baseline blood sample was collected before taking any dose. The collected blood samples were subjected to plasma separation by centrifuge, and the resulting plasma samples were stored at -25°C until analysis. The resulting plasma samples were analyzed for curcumin and its metabolites (curcumin-glucuronide and curcumin-sulfate) using LC / MS / MS.

[0106] Figure 6 Results of LC / MS / MS plasma curcumin analysis at time intervals of 0, 10, 20, 40, 60, 90, 120, 180 and 480 (commercially available only) minutes are provided. The analysis is performed directly on curcumin without prior enzymatic cleavage of glucuronides. The time after the subject took a dose (dose consumption) when the blood sample was collected is represented on the X-axis, while the nanograms (ng) of curcumin per milliliter (mL) determined for the plasma sample is represented on the Y-axis.

[0107] As can be seen from the figure, the commercially available product did not provide measurable plasma free curcumin concentrations within 8 hours. In contrast, the oil-based solution provided a maximum free curcumin plasma concentration of 3.14 ng / mL 20 minutes after administration and maintained measurable free curcumin plasma concentrations for the next 2 hours. We believe that the therapeutically effective dose of free curcumin is approximately 1 ng / mL, which is maintained by the oil-based solution from about 10 minutes until about 2 hours after administration.

[0108] Since the commercial product does not produce a measurable free curcumin concentration in plasma, it is not possible to compare the uptake performance of the oil-based solution with the commercial product in terms of free curcumin bloodstream delivery and bioavailability. Thus, the commercial product is unable to deliver unmetabolized curcumin to the bloodstream of human subjects, while the oil-based solution delivers a significant amount of unmetabolized (and therefore "free") curcumin to the bloodstream. Similar results would be expected in other mammals.

[0109] Figure 7 Results of LC / MS / MS plasma curcumin-glucuronide analysis at time intervals of 0, 10, 20, 40, 60, 90, 120, 180 and 480 (commercially available only) minutes are provided. The analysis was performed directly on curcumin-glucuronide. The time after the subject took a dose when the blood sample was collected is represented on the X-axis, and the nanograms (ng) of curcumin-glucuronide per milliliter (mL) determined for the plasma sample is represented on the Y-axis. Direct bloodstream delivery of free curcumin was determined Figure 4 The analysis is different. Figure 5 The analysis determined the concentrations of the main metabolites of curcumin produced in the bloodstream in response to a dose of an oil-based solution and a commercial product.

[0110] The oil-based solution provided a peak concentration of curcumin-glucuronide of about 800 ng / mL at about 1.5 hours after taking the capsule, and maintained plasma concentrations above 300 mg / mL for 10 to 180 minutes after taking the capsule. The commercially available product provided a peak concentration of curcumin-glucuronide of about 68 ng / mL at about 1.5 hours after taking the capsule, did not produce meaningful measured concentrations until about 40 minutes after taking the capsule, and provided concentrations of about 60 ng / mL between 3 and 8 hours.

[0111] Comparison of peak performance of metabolized curcumin delivery shows that the delivery provided by the oil-based solution is about 12 times higher than that provided by the commercial product, and therefore more than one order of magnitude higher. From the perspective of time after taking, both the oil-based solution and the commercial product provide peak blood flow concentrations of curcumin-glucuronide about 1.5 hours after taking a dose. The substantial timing difference between the oil-based solution and the commercial product is that the plasma concentration of curcumin-glucuronide provided by the oil-based solution drops relatively quickly after the peak, compared with the significantly lower but longer-lasting blood flow curcumin-glucuronide concentration provided by the commercial product. The constant, low curcumin-glucuronide concentration provided by the commercial product indicates that the 68ng / mL plasma concentration of metabolized curcumin-glucuronide is unlikely to be a byproduct of a curcumin dose with no therapeutic effect.

[0112] Area under the curve (AUC) calculations were performed to determine the total curcumin-glucuronide produced from the oil-based solution compared to the commercial product. The AUC value provides a measure of the cumulative amount of curcumin-glucuronide in the bloodstream, thereby measuring the total exposure over a period of time. The cumulative amount refers to the total bloodstream available curcumin-glucuronide metabolized from curcumin up to the selected time.

[0113] The plasma curcumin-glucuronide concentration value of the commercial product was used as a control (denominator), while the plasma curcumin-glucuronide concentration value of the oil-based solution was used as the numerator to determine the AUC bioavailability value. This was possible because both capsules contained approximately 400 mg of curcumin. Therefore, the AUC value reflects how many times more curcumin-glucuronide is produced in the bloodstream by the oil-based solution relative to the commercial product at the selected time.

[0114] Table I below provides the calculated results 3 hours after capsule ingestion, with estimates made due to slight variations in the timing of blood sample draws.

[0115] Table I

[0116]

[0117] In the time period of 10 to 60 minutes after administration, substantial and rapid generation of metabolized curcumin in the bloodstream was seen for the oil-based solution relative to the commercial product, with the oil-based solution generating 78 times more metabolized curcumin in the bloodstream after 20 minutes. After 60 minutes, the delivery difference declined, with the oil-based solution delivering an average of about 17 times more compared to the commercial product. Taken together, these results suggest that the commercial product is unable to form a microemulsion in the GI tract or at least is unable to form a microemulsion that can deliver curcumin to the bloodstream more effectively than taking powdered curcumin.

[0118] In order to provide a clear and more consistent understanding of the specification and claims of the present application, the following definitions are provided.

[0119] Oil-soluble substances are substances that are insoluble in water, and they are dissolved in medium chain triglyceride (MCT) oil with more than 50 mg / mL, preferably more than 100 mg / mL. Oil-soluble substances are usually soluble in MCT oil at room temperature, and are easily soluble or very soluble in MCT oil at a temperature of more than 70 degrees Celsius. The term "usually soluble in MCT oil at room temperature" is used because some high-purity oil-soluble substances are soluble in MCT oil in small amounts at room temperature, but are easily soluble or very soluble in MCT oil above 70 degrees Celsius, and once dissolved in MCT oil at high temperatures, they will remain dissolved at room temperature. Oil-soluble substances neither include water nor are they water. Therefore, there may be technically soluble liquids and solids in oil, but because they are also soluble in water or are not fully soluble in MCT oil, they are not "oil-soluble substances".

[0120] Alcohol-soluble substances are substances that are insoluble in water and have greater solubility in ethanol than in medium chain triglyceride (MCT) oil. For example, the non-derivatized hormone DHEA is soluble in ethanol to up to about 150 mg / mL, so it is easily soluble, and its solubility in MCT oil is only about 10 mg / mL at most, so it can only be dissolved in small amounts. Alcohol-soluble substances neither include water nor are they water. Therefore, there may be technically soluble liquids and solids in alcohol, but because they are also soluble in water or more soluble in MCT oil or equally soluble in MCT oil than in ethanol, they are not "alcohol-soluble substances".

[0121] Phosphatidylcholine (PC) molecules are a subset of a larger group of phospholipids and are commonly used to form liposomes in water. When placed in water without other ingredients, PC forms liposomes. In the presence of oil, applying sufficient shear forces to PC liposomes in water can produce monolayer structures, including micelles. PC has a water-soluble head, while the tail is much less water-soluble than the head. PC is a neutral lipid, but carries an electric dipole moment of about 10D between the head and the tail, making the molecule itself polar.

[0122] Tocopheryl polyethylene glycol succinate 1000 (TPGS) is generally considered a surfactant, with a nonpolar, oil-soluble "vitamin E" tail and a polar, water-soluble polyethylene glycol head. TPGS is a member of the polyethylene glycol derivative family that also includes polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0123] Room temperature and pressure refer to 20 to 28 degrees Celsius at about 100 kPa.

[0124] A solid is a substance that is not a liquid or a gas at room temperature and pressure. A solid substance can have one of many forms, including a monolithic solid, a powder, a gel, a wax, or a paste.

[0125] A liquid is a substance that is not a solid or a gas at room temperature and pressure. A liquid is an incompressible substance that takes the shape of its container as it flows.

[0126] Solutions lack a discernible interface between the dissolved molecules and the solvent. In a solution, the dissolved molecules are in direct contact with the solvent.

[0127] Dissolved means that the deliverable is in the droplet solution. When dissolved, the separation of the deliverable (thus, liquid separation or solid formation) does not cause the droplet average particle size to exceed 200nm (as determined by DLS and discussed further below or by the formation of deliverable precipitate crystals visible to the naked eye). Therefore, if the average particle size exceeds 200nm or precipitate crystals are formed visible to the naked eye, the deliverable will not dissolve in the droplet solution. If the deliverable is not dissolved in the solution, it is insoluble in the solution. In many aspects, solubility can be considered as a continuum that depends on concentration. For example, the following descriptive terms can be used to represent the solubility of a solute in a solvent at 25 degrees Celsius (grams of solids / mL of solvent):

[0128] Description level 1 part solvent / 1 part solute Very soluble Less than 1 Soluble 1 to 10 Soluble 10 to 30 A small amount of soluble 30 to 100 Slightly soluble 100 to 1000 Very slightly soluble 1000 to 10,000 Insoluble More than 10,000

[0129] Separation occurs when a previously dissolved solid or liquid leaves solution and is no longer in direct contact with the solvent of the solution. Separation of a solid from a solvent occurs by recrystallization, precipitation, etc. Separation of a liquid from a solvent occurs by partitioning and forming a visible meniscus between the solvent and the separated liquid.

[0130] An emulsion is a mixture of two or more immiscible liquids. Thus, one of the liquids carries droplets of the second liquid. The droplets of the second liquid can be said to be dispersed in a continuous phase of the first liquid. An interfacial layer, a separation layer or a boundary layer exists between the carrier liquid (continuous phase) and the droplets of the second liquid. Emulsions can be macroemulsions, pseudoemulsions, microemulsions or nanoemulsions. The main difference between macroemulsions, microemulsions and nanoemulsions is the average diameter of the droplets dispersed in the continuous phase and the stability of the emulsion over time. Pseudoemulsions differ in the presence of solids in the emulsion.

[0131] Droplets or liquid particles are formed from the hydrophobic "oil" phase of the microemulsion and are carried by the hydrophilic continuous phase. The exterior of the droplets is defined by a boundary layer that surrounds the volume of each liquid droplet. The boundary layer of the droplets defines the outer surface of the droplets that form the dispersed oil phase of the microemulsion. The continuous phase of the microemulsion is located outside the droplet boundary layer and thus carries the droplets.

[0132] A microemulsion is a thermodynamically stable dispersion of oil in water, with oil being defined as any water-insoluble liquid. Microemulsions are formed by simple mixing of the different components. Therefore, microemulsions form spontaneously without the need for high shear forces. Unlike macroemulsions, microemulsions do not scatter light substantially. The IUPAC definition of a microemulsion is "an isotropic and thermodynamically stable system made of water, oil, and a surfactant, with a dispersed domain diameter of about 1 to 100 nm, typically 10 to 50 nm". Therefore, the droplets of a microemulsion are about three orders of magnitude smaller than those of a macroemulsion and are thermodynamically stable.

[0133] The visually transparent microemulsion has an average particle size of 200 nm or less and has no precipitated solid crystals visible to the naked eye.

[0134] The continuous phase refers to the portion of the microemulsion that carries the droplets containing the deliverable. For example, the oil-in-water (OIW) microemulsions described herein (non-polar droplets in a polar continuous phase) have oil droplets containing the deliverable to be delivered, which are carried in a polar "water" continuous phase. Although the terms "water" and "oil" are used, "water" can be any liquid that is more polar than "oil" (e.g., a polar oil), and "oil" can be any liquid that is less polar than "water". Therefore, the terms "polar continuous phase" and "water continuous phase" are synonymous unless water is specifically discussed as one of the components of the microemulsion.

[0135] The average droplet diameter is determined by dynamic light scattering, sometimes referred to as photon correlation spectroscopy. The determination is carried out between 20 and 25 degrees Celsius. An example of an instrument suitable for average droplet diameter determination is available from ParticleSizing Systems, Port Richey, FL's Nicomp 380ZLS particle size analyzer. DLS can determine the diameter of the droplets in the liquid by measuring the light intensity scattered from the droplets to the detector over time. When the droplets move due to Brownian motion, the light scattered from more than two droplets produces positive interference or negative interference at the detector. By calculating the autocorrelation function of the light intensity and assuming that the droplets are distributed, it can be determined that the droplet size is from 1nm to 5 microns (μm). The instrument can also measure the Zeta potential of the droplets.

[0136] Ingestible means capable of being ingested by a living mammal through the mouth, while edible means suitable for consumption, thus contrasting with unpalatable or poisonous. Edible also means that the composition has less than the permitted amount of viable aerobic microorganisms and meets the American Herbal Products Association (AHPA) guidelines for metals, adulteration, toxins, residual solvents, and pesticides.

[0137] Where range values ​​are provided, it is to be understood that each intermediate value between the upper and lower limits of the range and between any other descriptive values ​​or intermediate values ​​within the range (unless the context clearly specifies otherwise, to one tenth of the lower limit unit) is encompassed in the present invention. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also encompassed in the present invention, but are subject to any specifically excluded limitations within the range. Where the range includes one or two limitations, the present invention also includes the range excluding any one or two of the limitations contained therein.

[0138] While various aspects of the invention have been described, it will be apparent to those of ordinary skill in the art that other aspects and implementations are possible within the scope of the invention.

[0139] Accordingly, the invention is not to be restricted except by the attached claims and their equivalents.

Claims

1. A composition for delivering a deliverable to the gastrointestinal tract, the composition comprising an outer capsule filled with only an oil-based solution, in, The oil-based solution comprises an emulsion system and a deliverable; Wherein, the emulsion system comprises a surfactant system, an emulsified oil system and a resin system, Wherein, the deliverable substance is selected from oil-soluble substances, alcohol-soluble substances and combinations thereof, wherein the alcohol is ethanol, and the alcohol-soluble deliverable substance is selected from curcumin, Boswellia serrata, quercetin, berberine hydrochloride, milk thistle extract, artemisinin, andrographolide, luteolin, resveratrol, diindolylmethane, hesperetin and combinations thereof; wherein the surfactant system accounts for 27% to 35% by weight of the oil-based solution, and the surfactant system comprises phospholipids and polyethylene glycol derivatives; wherein the emulsified oil system comprises an associative oil selected from the group consisting of medium chain triglycerides, citrus oils, and combinations thereof, and the emulsified oil system accounts for 38% to 55% by weight of the oil-based solution; and wherein the resin system comprises a resin selected from turmeric oleoresin, and the resin system accounts for 3% to 18% by weight of the oil-based solution; wherein, in the oil-based solution, the ratio of the resin system to the surfactant system to the emulsified oil system is (1:2 to 4:3.5 to 6) ± 20% by weight; Furthermore, the composition is configured to form an oil-in-water microemulsion in the aqueous gastrointestinal tract of a mammal, the oil-in-water microemulsion comprising a monolayer of surfactant-bound particles.

2. The composition according to claim 1, wherein The oil-in-water microemulsion is thermodynamically stable.

3. The composition of claim 1, further configured to form liposomes in the aqueous gastrointestinal tract of a mammal, wherein: The liposomes are water-core liposomes containing a water-soluble deliverable.

4. The composition according to claim 1, wherein The monolayer surfactant-bound particles are a layered structure having an oil-based inner core, a resinous middle layer encapsulating the inner core, and an outer surfactant monolayer encapsulating the middle layer.

5. The composition according to claim 1, wherein The monolayer of surfactant-bound particles has an average droplet diameter of 10 to 100 nanometers.

6. The composition according to claim 1, wherein The monolayer of surfactant-bound particles has an average droplet diameter of 10 to 80 nanometers.

7. The composition of claim 1, wherein The monolayer of surfactant-bound particles has an average droplet diameter of 10 to 60 nanometers.

8. The composition of claim 1, wherein The phospholipids are glycerophospholipids separated from phosphatidylcholine.

9. The composition of claim 8, wherein The phospholipid is selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide phosphoethanolamine (Cer-PE), ceramide phosphorylcholine (SPH) and combinations thereof.

10. The composition according to claim 8, wherein The phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine and a combination thereof.

11. The composition according to claim 8, wherein At least 80% by weight of the phospholipids are phosphatidylcholine.

12. The composition of claim 1, wherein The polyethylene glycol derivative is selected from tocopherol polyethylene glycol succinate 1000, polysorbate 40, polysorbate 60, polysorbate 80 and a combination thereof.

13. The composition of claim 1, wherein The polyethylene glycol derivative is selected from tocopherol polyethylene glycol succinate 1000, polysorbate 40 and a combination thereof.

14. The composition of claim 1, wherein In the oil-based solution, the ratio of the phospholipid to the polyethylene glycol derivative is 1:5 to 1:

30.

15. The composition of claim 1, wherein The medium chain triglyceride is selected from hexanoic acid, caprylic acid, capric acid, lauric acid (dodecanoic acid) and a combination thereof.

16. The composition of claim 1, wherein The medium chain triglycerides are selected from caprylic acid, capric acid and combinations thereof.

17. The composition of claim 1, wherein The citrus oil is selected from the group consisting of orange oil, lemon oil and combinations thereof.

18. The composition of claim 1, wherein The emulsified oil system further comprises a terpene oil.

19. The composition of claim 18, wherein The terpene oil is selected from turmeric oil, cinnamon oil, peppermint oil, spearmint oil and a mixture of these terpene oils.

20. The composition of claim 18, wherein The terpene oil is turmeric oil.

21. The composition of claim 1, wherein In the oil-based solution, the emulsified oil system comprises associated oil and terpene oil in a ratio of 1:1.7 to 1:5.

5.

22. The composition of claim 1, wherein The resin system consists essentially of turmeric oleoresin.

23. The composition of claim 1, wherein The resin system consists essentially of propolis.

24. The composition of claim 1, wherein The resin system consists essentially of turmeric oleoresin and propolis.

25. The composition of claim 24, wherein In the oil-based solution, the ratio of the propolis to the turmeric oleoresin is 1:1.7 to 1:

5.

26. The composition of claim 1, wherein The deliverable is selected from the group consisting of curcumin, Boswellia serrata, quercetin, berberine hydrochloride, milk thistle extract, artemisinin, andrographolide, luteolin, resveratrol, diindolylmethane, hesperidin, beta-caryophyllene, cannabis extract, and combinations thereof.

27. The composition of claim 1, wherein The oil-soluble substance deliverable is selected from the group consisting of beta caryophyllene, cannabis extract and combinations thereof.

28. The composition of claim 26, wherein The deliverable further comprises a water-soluble deliverable that is soluble in the oil-based solution.

29. The composition of claim 28, wherein The water-soluble deliverable is a mineral salt.

30. The composition of claim 28, wherein The water-soluble deliverable is selected from the group consisting of zinc salts, magnesium salts, calcium salts, and combinations thereof.

31. The composition of claim 1, wherein The oil-based solution is configured to dissolve 50 mg to 200 mg of the deliverable per gram of the oil-based solution.

32. The composition of claim 1, wherein The oil-based solution contains 10% to 20% by weight of the deliverable.

33. The composition of claim 1, wherein The ratio of the deliverable to the emulsion is (1:4-8) ± 20% by weight.

34. The composition of any one of claims 1 to 33, wherein The oil-based solution is configured to deliver the deliverable through the gastrointestinal tract of a mammal and provide a measurable plasma concentration of the deliverable in an unmetabolized form within 20 minutes after the mammal orally administers the composition on an empty stomach, wherein the deliverable is selected from the alcohol-soluble substance, the oil-soluble substance, and a combination thereof.

35. An ingestible and edible composition for relieving pain, the composition comprising an encapsulated oil-based solution comprising 2% to 3% by weight phospholipids, 24% to 30% by weight polyethylene glycol derivatives, 8% to 13% by weight turmeric oleoresin, 1% to 2.5% by weight propolis, 12% to 18% by weight emulsified oil, 23% to 31% by weight turmeric oil, 5% to 9% by weight beta caryophyllene, 1.5% to 4% by weight industrial hemp oil, 1% to 3% by weight piperine, 4% to 4% by weight curcumin, and 2% to 4% by weight Boswellia serrata.

36. An ingestible and edible composition for balancing the microbial load in a mammal, the composition comprising an encapsulated oil-based solution comprising 3.2% to 5% by weight of phospholipids, 26.3% to 30% by weight of a polyethylene glycol derivative, 3% to 7% by weight of turmeric oleoresin, 2.6% to 4% by weight of propolis, 18.2% to 23% by weight of emulsified oil, 11% by weight of % to 20% turmeric oil, 1% to 5% cinnamon oil, 1% to 5% peppermint oil, 0.2% to 1.3% industrial hemp oil, 0.3% to 2% berberine hydrochloride, 2% to 5% milk thistle extract, 3% to 7% artemisinin, 0.3% to 2% andrographis paniculata, 2% to 6% boswellia serrata, and 2% to 4% quercetin.

37. An ingestible and edible composition for controlling inflammation, the composition comprising an encapsulated oil-based solution comprising 1% to 3% phospholipids by weight, 25% to 34% polyethylene glycol derivatives by weight, 6% to 10% turmeric oleoresin by weight, 8% to 13% associated oils by weight, 27% to 35% turmeric oil by weight, 2% to 6% cinnamon oil, 7% to 10% spearmint oil by weight, 2% to 5% berberine hydrochloride by weight, 2% to 5% milk thistle extract by weight, 2% to 5% resveratrol by weight, 2% to 5% hesperetin by weight, and 2% to 5% quercetin by weight.

38. An ingestible and edible composition for supplementing dietary zinc in a mammal, the composition comprising an encapsulated oil-based solution comprising: 1% to 3% by weight phospholipids, 25% to 34% by weight polyethylene glycol derivatives, 7% to 10% by weight propolis, 22% to 30% by weight associated oils, 10% to 15% by weight turmeric oil, 10% to 15% by weight spearmint oil, 3% to 5% by weight zinc acetate, 2% to 5% by weight luteolin, 2% to 5% by weight hesperetin, and 2% to 5% by weight quercetin.

39. A method of forming an oil-based solution for inclusion in a composition for delivering a deliverable to the gastrointestinal tract as described in any one of claims 1-34, the method comprising: heating a solution of alcohol and water to a low temperature of 65° C. to 78° C., wherein the solution of alcohol and water has a ratio of alcohol to water of 80:20 to 97:3 by volume to form a heated solvent solution; combining an alcohol-soluble substance deliverable with the heated solvent solution to form a heated deliverable mixture; combining a surfactant system and a resin system with the heated deliverable mixture; raising the heated deliverable mixture to a temperature above 78° C. to form a concentrated solution; An emulsified oil system is combined with the concentrated solution to form an oil-based solution.

40. The method of claim 39, further comprising encapsulating the oil-based solution in an external capsule.

41. The method of claim 39, wherein: The alcohol is ethanol.

42. The method of claim 39, wherein: The ratio of alcohol to water is 90:10 to 95:5 by volume, and the low temperature is 68°C to 75°C.

43. The method of claim 39, wherein: Combining the alcohol-soluble material deliverable with the heated solvent solution further comprises combining a water-soluble deliverable with the heated solvent solution.

44. The method of claim 39, further comprising heating the concentrated solution to a temperature greater than 100°C but not greater than 120°C prior to combining the emulsified oil system with the concentrated solution.

45. The method of claim 39, wherein: Combining the emulsified oil system with the concentrated solution further comprises combining an oil-soluble material deliverable with the concentrated solution.

46. ​​The method of claim 39, wherein: The surfactant system comprises a phospholipid and a polyethylene glycol derivative.

47. The method of claim 46, wherein: The phospholipids are glycerophospholipids separated from phosphatidylcholine.

48. The method of claim 47, wherein: The phospholipid is selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide phosphoethanolamine (Cer-PE), ceramide phosphorylcholine (SPH) and combinations thereof.

49. The method of claim 47, wherein: The phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine and a combination thereof.

50. The method of claim 47, wherein: At least 80% by weight of the phospholipids are phosphatidylcholine.

51. The method of claim 46, wherein: The polyethylene glycol derivative is selected from tocopherol polyethylene glycol succinate 1000, polysorbate 40, polysorbate 60, polysorbate 80 and a combination thereof.

52. The method of claim 46, wherein: The polyethylene glycol derivative is selected from tocopherol polyethylene glycol succinate 1000, polysorbate 40 and a combination thereof.

53. The method of claim 39, wherein: The surfactant system comprises 27% to 35% by weight of the oil-based solution.

54. The method of claim 46, wherein: In the oil-based solution, the ratio of the phospholipid to the polyethylene glycol derivative is 1:5 to 1:

30.

55. The method of claim 39, wherein: The emulsified oil system comprises an associative oil selected from the group consisting of medium chain triglycerides, citrus oils, and combinations thereof.

56. The method of claim 55, wherein: The medium chain triglyceride is selected from hexanoic acid, caprylic acid, capric acid, lauric acid (dodecanoic acid) and a combination thereof.

57. The method of claim 55, wherein: The medium chain triglycerides are selected from caprylic acid, capric acid and combinations thereof.

58. The method of claim 55, wherein: The citrus oil is selected from the group consisting of orange oil, lemon oil and combinations thereof.

59. The method of claim 55, wherein: The emulsified oil system further comprises a terpene oil.

60. The method of claim 59, wherein: The terpene oil is selected from turmeric oil, cinnamon oil, peppermint oil, spearmint oil and a mixture of these terpene oils.

61. The method of claim 59, wherein: The terpene oil is turmeric oil.

62. The method of claim 39, wherein: The emulsified oil system comprises 38% to 55% of the oil-based solution.

63. The method of claim 39, wherein: In the oil-based solution, the emulsified oil system comprises associated oil and terpene oil in a ratio of 1:1.7 to 1:5.

5.

64. The method of claim 39, wherein: The resin system comprises a resin selected from the group consisting of turmeric oleoresin, propolis, astaxanthin oleoresin, rosin, ginger oleoresin, and combinations thereof.

65. The method of claim 39, wherein: The resin system consists essentially of turmeric oleoresin.

66. The method of claim 39, wherein: The resin system consists essentially of propolis.

67. The method of claim 39, wherein: The resin system consists essentially of turmeric oleoresin and propolis.

68. The method of claim 39, wherein: The resin system comprises 3% to 18% by weight of the oil-based solution.

69. The method of claim 67, wherein: In the oil-based solution, the ratio of the propolis to the turmeric oleoresin is 1:1.7 to 1:

5.

70. The method of claim 39, wherein: In the oil-based solution, the ratio of the resin system to the surfactant system to the emulsified oil system is (1:2-4:3.5-6)±20% by weight.

71. The method of any one of claims 39-70, wherein: The alcohol-soluble substance that can be delivered is selected from curcumin, Boswellia serrata, quercetin, berberine hydrochloride, milk thistle extract, artemisinin, andrographolide, luteolin, resveratrol, diindolylmethane, hesperetin and combinations thereof.

72. The method of claim 45, wherein: The oil-soluble substance deliverable is selected from the group consisting of beta-caryophyllene, cannabis extract and combinations thereof.

73. The method of claim 43, wherein: The water-soluble deliverables are mineral salts that are soluble in the oil-based solution.

74. The method of claim 43, wherein: The water-soluble deliverable is selected from the group consisting of zinc salts, magnesium salts, calcium salts, and combinations thereof.

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