Composition

Abstract

Microemulsions are described in which hydrophobic liquid droplets are distributed in a continuous hydrophilic liquid phase. The microemulsions described can be considered modified oil-in-water (MOIW) microemulsions in which both the "oil" and "water" phases of the microemulsion are modified. The oil phase droplets of the MOIW microemulsion are modified with alcohol, which can solubilize oil-soluble species, including cannabis extracts and terpenes. The polar continuous "water" phase of the MOIW microemulsion is modified with a sugar or sugar alcohol.

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 896,820, filed September 6, 2019, entitled "Microemulsion Delivery System for Cannabis Extracts and Terpenes," which is incorporated by reference in its entirety. [Background technology]

[0002] Cannabinoids are compounds that act on cannabinoid receptors in cells, altering the release of neurotransmitters. Cannabinoids include endocannabinoids, which are naturally produced in animals; phytocannabinoids, which are found in cannabis and some other plants; and synthetic cannabinoids. Type 1 cannabinoid receptors are found primarily in the brain and are absent from the brainstem, which is responsible for respiratory and cardiovascular function. Type 2 cannabinoid receptors are found primarily in the immune system and appear to be responsible for anti-inflammatory and possibly other therapeutic effects.

[0003] Phytocannabinoids are isolated from plants in the Cannabis genus, which is considered to include three species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Cannabis plants containing less than 0.3% tetrahydrocannabinol (THC) by weight are commonly referred to as "hemp," while plants containing 0.3% or more THC by weight are commonly referred to as marijuana. At least 113 different phytocannabinoids can be isolated from Cannabis plants. Phytocannabinoids are isolated in their "A" or acidic form and then decarboxylated, often by heat, to a more biologically active decarboxylated form.

[0004] THC is the most well-known cannabinoid and is considered psychoactive because it binds to type 1 receptors. Cannabidiol (CBD) is a more commonly known non-psychoactive cannabinoid because it acts on type 1 and type 2 receptors and is known to reduce pain and inflammation and calm several neurological responses, such as those associated with Dravet syndrome in children. Additionally, CBD can counter cognitive impairments associated with THC use, including short-term memory loss, and may have additional antipsychotic effects in addition to acting as an antioxidant. Cannabigerol (CBG) is another non-psychoactive cannabinoid that may have effects similar to CBD. Cannabichromene (CBC), cannabinol (CBN), and cannabiditriol (CBT) are other cannabinoids being studied for their potential biological activity.

[0005] While research into the health benefits of cannabinoids remains ongoing, their pharmacological utility has been demonstrated or is likely to be demonstrated for the aforementioned childhood Dravet syndrome, Parkinson's disease, schizophrenia, anxiety disorders, and the suppression of the development of some cancer cells. Because the human endocannabinoid system is involved in fundamental life functions, including appetite, immune response, reproduction, and pain management, the effects of cannabinoids on the human body are likely to be diverse. The ability of cannabinoids to block overactivation of these functions may reduce or prevent the progression of diseases based on overactivation of these functions.

[0006] Terpenes are extracted from plants such as conifers, flowers, and citrus fruits, as well as from some insects such as termites and swallowtail butterflies. From a molecular perspective, all terpenes contain an isoprene functional group and are a diverse class of organic molecules. In addition to their historical use as fragrances, terpenes provide the basis for biologically active substances, including vitamin A and steroids. Terpenes include compounds such as limonene, pinene, linalool, and beta-caryophyllene. Beta-caryophyllene, for example, has uses as a fragrance and anti-inflammatory agent.

[0007] Oral delivery of cannabinoids and terpenes using conventional delivery systems may result in negligible blood levels 20 minutes after administration, and do not provide effective bloodstream concentrations, which are considered to be about 0.4 ng / mL or higher of cannabinoids in the bloodstream. In fact, for individuals with low absorption who do not consume undesirably large amounts of conventional oral delivery systems, effective bloodstream concentrations may not be achieved, or may not be achieved at all, 90 minutes after administration with conventional oral delivery systems. Thus, of the cannabinoids or terpenes consumed with conventional oral delivery systems, the majority of the consumed cannabinoids or terpenes may be excreted and never used.

[0008] An emulsion is a mixture of two or more liquids that do not solubilize. Therefore, the two or more liquids do not form a solution, and a discernible interface exists between the combined liquids. Emulsions can be macroemulsions, pseudoemulsions, nanoemulsions, or microemulsions. Emulsions can be used for parenteral, ocular, transdermal, oral, and other delivery systems.

[0009] 1A depicts an exemplary nanoemulsion droplet 100 having a single wall of phospholipids (monolayer) forming a hydrophilic exterior 120 and a hydrophobic interior 110. The monolayer wall of the nanoemulsion droplet 100 is formed from a single layer of phospholipids. The exterior wall 120 is water-soluble due to phosphate functional groups, while the interior 110 is lipid-soluble due to alkyl functional groups. FIG. 1B depicts a plurality of nanoemulsion droplets 100 in a continuous phase 150.

[0010] FIG. 2A depicts a microemulsion droplet 200 having a single wall of phospholipids (monolayer) forming a hydrophilic exterior 220 and a hydrophobic interior 210. Similar to the nanoemulsion droplet 100, the monolayer wall of the microemulsion droplet 200 is formed from a single layer of phospholipids. Compared to the depicted nanoemulsion droplet 100, the microemulsion droplet 200 is substantially smaller in diameter, which is often the case with microemulsions. In fact, the diameter of the microemulsion droplet 200 is reduced when the nonpolar tails 230 of the monolayer phospholipids are "squished" against each other, thus forming a more "solid" internal hydrophobic barrier than is the case with the nanoemulsion droplet 100 depicted in FIG. 1. FIG. 2B depicts multiple microemulsion droplets 200 in a continuous phase 250. Also depicted in the continuous phase 250 are several individual phospholipid molecules 260 that are not incorporated into the microemulsion droplet 200.

[0011] Transdermal creams are typically "pseudoemulsions" with solid granules of the delivery product that are not completely solubilized within the emulsion droplets that form the cream. In contrast to the larger droplets of macroemulsions and pseudoemulsions, the smaller droplets of nanoemulsions and microemulsions offer the potential for better delivery performance than previously available from macroemulsions and pseudoemulsions, either for transdermal or oral absorption.

[0012] Although high-energy mixing in the form of pressure (including shear), temperature, and combinations thereof used to form nanoemulsions can provide the smaller droplets of microemulsions, such nanoemulsions are not thermally stable and therefore not shelf-stable microemulsions, but rather resemble macroemulsions in that the nanoemulsion components eventually separate into immiscible polar and nonpolar liquids. Thus, as depicted in Figures 1 and 2, nanoemulsion droplets tend to be larger than microemulsion droplets because they continuously expand in diameter after formation until the aggregated droplets separate from the continuous phase. Summary of the Invention [Problem to be solved by the invention]

[0013] Traditionally, macroemulsions, nanoemulsions, and microemulsions have been used to deliver either oil-soluble or water-soluble products. Cannabis extracts and terpenes are oil-soluble, but when solubilized in oil, they are absorbed relatively slowly and inconsistently through the digestive tract. However, traditional oil-in-water (OIW) emulsions containing cannabis extracts and some terpenes, regardless of emulsion form, generally form oil droplets that easily dissociate from the aqueous phase of the emulsion, with higher concentrations of cannabis extract in the oil droplets. This dissociation of oil droplets from the aqueous phase of traditional oil-in-water emulsions results in significant losses in the blood uptake rate and total blood delivery of cannabinoids and terpenes when delivered by traditional oil-in-water emulsions. This is thought to be due to the fact that when the oil droplets of the emulsion dissociate from the aqueous phase, the resulting dissociated emulsion becomes a mixture of oil, water, and some residual emulsion, resulting in a slow and inconsistent delivery, as the dissociated oil has a delivery profile roughly similar to that of the oil alone. Thus, traditional oil-in-water emulsions containing cannabis extracts and some terpenes tend to suffer from the same bloodstream uptake drawbacks as oil-only formulations, because the oil phase has dissociated from the water phase by the time the traditional emulsion is consumed.

[0014] There is a continuing need for simple and efficient materials and methods for oral delivery systems, so as to deliver cannabinoids and terpenes to the bloodstream quickly and at higher concentrations per consumed amount.Traditional oil mixtures have traditionally suffered from extremely slow, low and inconsistent uptake due to GI absorption pathways.Traditional oil-in-water emulsion systems have inherent drawbacks, including poor stability to cooling and heating, particularly in terms of maintaining the desired average droplet size in emulsion, preventing oil and water components from phase separation, and preventing the dissociation of the product and / or oil from emulsion, which are important for effective oral delivery to the bloodstream.In addition to these drawbacks that lead to slow, insufficient and inconsistent uptake of product into the bloodstream, traditional emulsion systems also have the drawback of requiring too large a volume of emulsion compared to the mass or volume of the product.

[0015] The microemulsions and methods of the present invention overcome at least one of the drawbacks associated with conventional oral delivery systems by enabling convenient, rapid, efficient, and reproducible oral delivery of cannabinoids and terpenes to the bloodstream. [Means for solving the problem]

[0016] In one aspect, the present invention provides a composition comprising an oil-soluble species and a modified oil-in-water microemulsion comprising a modified oil phase and a modified polar continuous phase, wherein the oil-soluble species is solubilized in the modified oil phase, the modified oil phase comprises a phospholipid, a polyethylene glycol derivative, an oil, and an alcohol, and the modified polar continuous phase comprises a sugar or sugar alcohol, and water.

[0017] In another aspect of the invention, there is a method of forming a modified oil-in-water microemulsion containing an oil-soluble species, the method comprising combining a phospholipid, a polyethylene glycol derivative, an oil, and an alcohol to form an alcohol-lipid mixture; combining a sugar or sugar alcohol and water to form a modified polar continuous phase; and combining the oil-soluble species with the alcohol-lipid mixture and the modified polar continuous phase at atmospheric pressure to form the modified oil-in-water microemulsion.

[0018] In another aspect of the invention, there is provided a method of delivering an oil-soluble species to the bloodstream of a human subject, comprising: intraorally administering a modified oil-in-water microemulsion to the human subject; and delivering the oil-soluble species to the bloodstream of the human subject, wherein within 20 minutes of administering the modified oil-in-water microemulsion to the human subject, about 1 mL of the modified oil-in-water microemulsion provides the human subject with a blood concentration of the oil-soluble species of 0.3 to 1.5 ng / mL.

[0019] Other compositions, methods, features, and advantages of the present invention will be or become apparent to one of ordinary skill in the art upon examination of the following figures and detailed description. It is intended that all such additional compositions, methods, features, and advantages be included within this specification, be within the scope of the present invention, and be protected by the following claims. The present invention may be better understood with reference to the following drawings and description, in which the components are not necessarily to scale and are not intended to accurately represent molecules or their interactions, emphasis instead being placed upon illustrating the principles of the invention. [Brief explanation of the drawings]

[0020] [Figure 1A] 1 depicts nanoemulsion droplets with a single wall of phospholipids (monolayer) forming a hydrophilic exterior and a hydrophobic interior. [Figure 1B] 1 depicts a plurality of nanoemulsion droplets in a continuous phase. [Figure 2A]1 depicts a microemulsion droplet with a single wall of phospholipids (monolayer) forming a hydrophilic exterior and a hydrophobic interior. [Figure 2B] 1 depicts a plurality of microemulsion droplets displayed in a continuous phase. [Figure 3] 1 illustrates a method for making MOIW microemulsions containing oil-soluble species. [Figure 4] Provides CBD blood uptake rate and concentration analysis results in graphical form. [Figure 5] Provides cumulative AUC values ​​determined from bloodstream concentration analysis in graphical format. DETAILED DESCRIPTION OF THE INVENTION

[0021] Microemulsions are described where hydrophobic liquid droplets are distributed in a continuous hydrophilic liquid phase. Compared to conventional oil-in-water (OIW) microemulsions, the described microemulsions can be considered modified oil-in-water (MOIW) microemulsions, in which both the "oil" and "water" phases of the microemulsion are modified. The oil phase droplets of MOIW microemulsions are modified with alcohol, allowing for better delivery of oil-soluble species to the bloodstream than oil blends or the oil phase of conventional oil-in-water (OIW) microemulsions. The polar continuous "water" phase of MOIW microemulsions is modified with sugars or sugar alcohols. Preferably, the modified polar continuous phase of MOIW microemulsions is primarily a sugar or sugar alcohol phase. The modified oil phase droplets are dispersed in the modified polar continuous phase of MOIW microemulsions.

[0022] MOIW microemulsions can provide for the uptake of oil-soluble species into the mammalian bloodstream through the oral and gastric mucosa and transdermally through the skin. MOIW microemulsions can orally deliver effective concentrations of oil-soluble species into the bloodstream of an individual more rapidly, such as within 20 minutes of administration, than the oil phase of conventional OIW microemulsions, even when the individual has low absorption. Furthermore, of the introduced oil-soluble species, MOIW microemulsions can deliver a significantly higher proportion of the introduced oil-soluble species into the bloodstream of an individual than the oil phase of conventional OIW microemulsions.

[0023] The denatured polar continuous phase is believed to enable the denatured oil phase droplets of the microemulsion to incorporate and retain a high alcohol content. Thus, the denatured polar continuous phase is believed to force the alcohol into the oil and oil-soluble species residing inside the monolayer wall formed from the phospholipid and polyethylene glycol derivative, and thus into the hydrophobic core of the denatured oil droplets, while the denatured polar continuous phase containing the sugar or sugar alcohol and water residing outside the monolayer.

[0024] Unlike the water-continuous phase of conventional OIW emulsions, the sugar or sugar alcohol of the modified polar continuous phase does not readily form an azeotrope with the alcohol, and therefore has a reduced ability to extract alcohol from the oil droplets compared to water. The hydrophobic portion of the monolayer wall formed from the phospholipid tails and combined with the polyethylene glycol derivative in the described ratio is also believed to reduce alcohol loss from the oil droplets compared to conventional OIW emulsions.

[0025] The high alcohol content of the modified oil phase droplets, provided by the combination of the modified polar continuous phase and the hydrophobic monolayer, is believed to increase the solubility of oil-soluble species in the modified oil droplets of the MOIW microemulsion compared to conventional OIW emulsions. This enhanced solubility of oil-soluble species in the modified oil droplets of the MOIW is believed to reduce dissociation (e.g., recrystallization, precipitation, etc., and therefore separation) of oil-soluble species from the oil droplets of the MOIW microemulsion during storage, thereby making the MOIW microemulsion a storage-stable microemulsion that is preferably visually transparent. In addition, the enhanced solubility of oil-soluble species in the modified oil droplets of the MOIW is believed to deliver a greater amount of oil-soluble species to the bloodstream per unit volume of the MOIW microemulsion compared to conventional OIW emulsions.

[0026] In MOIW microemulsions, the modified oil phase droplets containing the oil-soluble species have an average droplet diameter of 1 to 100 nanometers, with a preferred average droplet diameter of 5 to 50 nanometers. More preferably, the modified oil phase droplets of MOIW microemulsions have an average droplet diameter of 10 to 30 nanometers.

[0027] The oil-soluble species of the MOIW microemulsion can be delivered transmucosally (e.g., orally, intranasally, vaginally, or rectally) or transdermally via the MOIW microemulsion. Preferably, the MOIW microemulsion containing the oil-soluble species is ingestible and edible.

[0028] The MOIW microemulsion preferably comprises a ratio of phospholipid, oil, polyethylene glycol derivative, alcohol, sugar or sugar alcohol, and water of 1:2:0.6-3.3:4:7-9:2-3.5 by weight, with a deviation of up to 20% by weight, and a deviation of up to 10% by weight being more preferred, and thus 1:2:0.6-3.3:4:7-9:2-3.5±20% by weight or 1:2:0.6-3.3:4:7-9:2-3.5±10% by weight being preferred.

[0029] The oil-soluble species is preferably included in the MOIW microemulsion in a ratio of oil to oil-soluble species of 1:0.05-0.4 by weight, with a ratio of oil to oil-soluble species of 1:0.1-0.3 by weight being preferred, with a deviation of up to 10% by weight, and a deviation of up to 5% by weight being more preferred, thus 1:0.05-0.3±10% by weight or 1:0.05-0.3±5% by weight being preferred.

[0030] 3 depicts a method 300 of making a MOIW microemulsion 336 that includes an oil-soluble species 311. In addition to the oil-soluble species 311, the microemulsion 336 may include additional deliverables that are soluble in water or oil.

[0031] In 310, oil-soluble species 311 are combined with an alcohol-lipid mixture 312 comprising a polyethylene glycol derivative, a phospholipid, an oil, and an alcohol. In 320, the alcohol-lipid mixture 312 comprising oil-soluble species 311 is combined with a modified polar continuous phase 322 comprising a sugar or sugar alcohol, and water. The alcohol-lipid mixture 312 comprising oil-soluble species 311 can be considered a modified oil phase dispersed in the modified polar continuous phase 322, which can be considered a modified water phase.

[0032] In 330, a microemulsion 336 containing oil-soluble species 311 is formed by mixing at atmospheric pressure. Unlike nanoemulsions, microemulsions 336 can be formed at atmospheric pressure without the need for high pressure and / or shear energy. Microemulsions 336 can be formed using high pressure and / or shear, as used in forming nanoemulsions, but unlike nanoemulsions, which begin the dissociation process after formation, even if the dissociation is very slow, microemulsions 336 are thermally stable at room temperature and pressure after formation, and the result is ultimately a microemulsion 336. Thus, the formation of microemulsion 336 avoids the undesirable use of high pressure and / or shear during formation and is storage stable after formation.

[0033] Although method 300 depicts oil-soluble species 311 being first combined with alcohol-lipid mixture 312, alcohol-lipid mixture 312 and polar continuous phase 322 can be combined first, and then oil-soluble species 311 added to form microemulsion 336 (not shown). Reorganization of this step is possible because the modified oil phase and modified polar continuous phase "self-assemble" droplets containing the oil-soluble species to form microemulsion 336 at atmospheric pressure.

[0034] The oil-soluble species 311 is a liquid at room temperature and pressure; however, at high purity, such as greater than 55% by weight, the oil-soluble species 311 may be or include a crystalline solid. Once solubilized in oil, the oil-soluble species 311 will remain solubilized in oil at room temperature and pressure. The oil-soluble species 311 preferably includes a cannabis extract and / or terpenes.

[0035] The oil-soluble species 311 are solubilized in the droplets of the microemulsion 336 and thus in the alcohol-lipid mixture 312. The alcohol-lipid mixture 312 is preferably configured such that the oil-soluble species 311 are more soluble in the alcohol-lipid mixture 312 than in the oil of the microemulsion 336 alone.

[0036] Preferably, the oil-soluble species 311 comprises 1% to 6% by weight of the microemulsion 336. However, to provide a visually clear emulsion with the widest range of oil-soluble species, a weight percentage of 1% to 4% of the oil-soluble species 311 is preferred, with a weight percentage of 1% to 3% being more preferred. When the oil-soluble species 311 is substantially terpenes, a higher weight percentage within the 1% to 6% range can be used than when the oil-soluble species is substantially cannabis extract, while still maintaining a visually clear emulsion. These stated weight percentages for the oil-soluble species 311 refer to oil-soluble species 311 solubilized in the droplets of the microemulsion 336, not suspended in the emulsion liquid or otherwise dissociated from the droplets. An example of this situation is discussed in conjunction with Example 3 below, where commercially purchased products have inaccurate oil-soluble species content on the label, or approximately 70% of the oil-soluble species in the product have dissociated from the emulsion.

[0037] Cannabis extract is an oily extract from plants of the Cannabis genus.Preferred cannabis extracts include cannabidiol (CBD), tetrahydrocannabinol (THC), and other cannabinoids, including cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), and cannabichromene (CBC).Preferred cannabis extracts contain at least 30% by weight of CBD and / or THC, while more preferred cannabis extracts contain at least 60% by weight of CBD and / or THC.Most preferred cannabis extracts contain at least 80% by weight of CBD and / or THC.

[0038] Preferred terpenes include monoterpenes (incorporating two isoprene units and having the molecular formula C 10 H 16 ), monoterpenoids, diterpenes (incorporating four isoprene units and often having the molecular formula C 20 H 32Preferred terpenes for inclusion in microemulsion 336 include limonene, pinene, linalool, beta-caryophyllene, retinol, phytol, myrcene, humulene, ocimene, terpinolene, geraniol, and geranylgeraniol.

[0039] The alcohol-lipid mixture 312 may optionally include an alcohol-soluble deliverable that is solid at room temperature and pressure. Thus, unlike the oil-soluble species 311, which are liquid at room temperature and pressure or are heated and solubilized in oil, as described above, the alcohol-soluble deliverable is solid at room temperature and pressure. Preferably, the alcohol-soluble deliverable is less soluble in oil than the oil-soluble species 311. Such an alcohol-soluble deliverable is solubilized in the denatured oil phase droplets of the microemulsion, and thus in the alcohol-lipid mixture 312 with the oil-soluble species 311.

[0040] The alcohol-soluble delivery materials include several plant sterols, several polyphenols, and several antimicrobial agents. Preferred plant sterols include Tribulus terrestris and Yohimbe. Preferred polyphenols include resveratrol, pterostilbene, curcumin, boswellia, and quercetin. Preferred antimicrobial agents include artemisinin, monolaurin, and Panax notoginseng. Preferably, these alcohol-soluble delivery materials are incorporated into the alcohol-lipid mixture 312 of the microemulsion 336 as solids in powder form.

[0041] The modified polar continuous phase 322 may include a species or species of water-soluble deliverables that are more soluble in water than the oil-soluble species 311. Such water-soluble deliverables are solubilized in the modified polar continuous phase 322 of the microemulsion 336, and thus in the carrier liquid of the microemulsion 336.

[0042] The combined phospholipid and polyethylene glycol derivative form the boundary between the denatured polar continuous phase and the interior of the denatured oil phase droplets of the microemulsion 336. To maintain the desired alcohol concentration within the droplets, it is therefore important to reduce the loss of alcohol to the denatured polar continuous phase and the associated dissociation of oil-soluble species from the droplets, phospholipid, polyethylene glycol derivative, as well as the ratio between the two, as previously discussed.

[0043] The phospholipids in the alcohol-lipid mixture 312 are preferably glycerophospholipids isolated from lecithin. Because the phospholipids are preferably lecithin isolates, the designated isolates preferably contain 80% (w / w) of the designated phospholipids, with the remaining constituents being one or more additional phospholipids isolated from lecithin or other lecithin isolates. Preferred phospholipid lecithin isolates include phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide phosphorylethanolamine (Cer-PE), ceramide phosphorylcholine (SPH), and combinations thereof, with PC, PE, and combinations thereof being more preferred. However, not all phospholipid lecithin isolates are surprisingly interchangeable in forming storage-stable and visually clear MOIW microemulsions, as phosphatidylserine (PS) and phosphoric acid (PA) isolates are not useful when both storage-stable and visually clear MOIW microemulsions are desired. When the oil-soluble species 311 is a cannabis extract, the phospholipid is preferably PC.

[0044] The phospholipids may be present in 2% to 10% by weight of the microemulsion 336. Preferably, the phospholipids comprise 4% to 10% by weight of the microemulsion 336. When the oil-soluble species is a cannabis extract, the phospholipids comprise 4% to 8% by weight of the microemulsion 336.

[0045] The polyethylene glycol derivative of the alcohol-lipid mixture 312 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 60, or polysorbate 80. More preferably, the polyethylene glycol derivative is TPGS or polysorbate 80. When the oil-soluble species is a cannabis extract, the preferred polyethylene glycol derivative is TPGS.

[0046] The polyethylene glycol derivative may be present in 5% to 15% by weight of the microemulsion 336. Preferably, the polyethylene glycol derivative comprises 6% to 12% by weight of the microemulsion 336. When the oil-soluble species is a cannabis extract, the polyethylene glycol derivative comprises 9% to 11% by weight of the microemulsion 336.

[0047] TPGS, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80 are often considered interchangeable surfactants. This was determined not to be the case in the formation of the described microemulsion 336 when a storage-stable and visually clear microemulsion was desired.

[0048] When used in conjunction with phospholipids, TPGS produced storage-stable, visually clear microemulsions at ratios of phospholipid to TPGS of about 1:0.4 to 1:4 by weight, with preferred storage-stable MOIW microemulsions formed at ratios of 1:1.6 to 1:4 by weight. When used in conjunction with phospholipids, polysorbate 20 did not produce storage-stable, visually clear microemulsions. When used in conjunction with phospholipids, polysorbate 40 produced storage-stable, visually clear microemulsions at ratios of PC to polysorbate 40 of about 1:2 to 1:3 by weight, with preferred storage-stable MOIW microemulsions formed at ratios of about 1:3 by weight. When used in conjunction with phospholipids, polysorbate 60 provides storage-stable, visually clear microemulsions at ratios of phospholipid to polysorbate 60 of about 1:2 to 1:4 by weight, with preferred storage-stable MOIW microemulsions formed at ratios of 1:2 to 1:3 by weight. When used in conjunction with phospholipids, polysorbate 80 provides storage-stable, visually clear microemulsions at ratios of phospholipid to polysorbate 80 of about 1:0.4 to 1:4 by weight, with preferred storage-stable MOIW microemulsions formed at ratios of 1:0.6 to 1:4 by weight.

[0049] These results demonstrate that polyethylene glycol derivatives are surprisingly not interchangeable in forming storage-stable, visually clear MOIW microemulsions. In fact, polysorbate 20 is not useful. Moreover, TPGS and polysorbate 80 are preferred polyethylene glycol derivatives in combination with phospholipids, as they provide the desired storage-stable, visually clear microemulsions over the widest range of oil-soluble species concentrations.

[0050] The alcohol-lipid mixture 312 preferably includes at least one oil held within the phospholipid / polyethylene glycol derivative monolayer. The oil can be MCT oil, citrus oil, or a combination thereof. MCT oil is a triglyceride in which the fatty acid has an aliphatic end of 6 to 12 carbon atoms. Preferred MCT oils include caproic acid (hexanoic acid), caprylic acid (octanoic acid), capric acid (decanoic acid), lauric acid (dodecanoic acid), and combinations thereof. More preferred MCT oils include caprylic acid, capric acid, and combinations thereof. Preferred citrus oils include orange oil, lemon oil, and combinations thereof. When the oil-soluble species is a cannabis extract, the oil is preferably a combination of caprylic acid and capric acid.

[0051] The oil may be present in the microemulsion 336 at 5% to 15% by weight. Preferably, the oil comprises 7% to 13% by weight of the microemulsion 336. When the oil-soluble species is a cannabis extract, the oil comprises 9% to 11% by weight of the microemulsion 336.

[0052] The microemulsion 336 includes at least one alcohol. The preferred alcohol is food grade, as the microemulsion 336 is preferably edible. Preferably, the alcohol is ethanol, with USP Food Grade 190 tested (95% ethanol, 5% water) ethanol being more preferred. As discussed further below, an alcohol water content greater than 10% is less preferred, as the additional water should be considered in conjunction with the total water content of the microemulsion 336 to inhibit dissociation of oil-soluble species from the denatured oil phase droplets.

[0053] The alcohol may be present in the microemulsion 336 at 5% to 25% by weight. Preferably, the alcohol comprises 10% to 23% by weight of the microemulsion 336. When the oil-soluble species is a cannabis extract, the alcohol comprises 16% to 22% by weight of the microemulsion 336.

[0054] The modified oil phase droplets of microemulsion 336 can be considered to have a high alcohol content and therefore have an oil to alcohol weight ratio of 1:1.5 to 1:4, preferably 1:1.5 to 1:3, by weight.

[0055] The modified polar continuous phase 322 comprises a sugar or sugar alcohol and water. By "sugar or sugar alcohol" is meant a sugar or sugar alcohol preferably containing 3 to 12 carbon atoms that is liquid at room temperature or soluble in water at room temperature. Preferred sugars include sucrose, cane sugar, and pure maple syrup, the latter being preferred due to its tree resin content. Preferred sugar alcohols have 3 to 6 carbon atoms and include glycerol (glycerin).

[0056] Although additional sugar alcohols, including xylitol, erythritol, mannitol, and sorbitol, can be expected to be useful in forming microemulsions 336, not all sugar alcohols are surprisingly interchangeable in forming shelf-stable and visually clear MOIW microemulsions, as xylitol, erythritol, mannitol, and sorbitol are not useful when both shelf-stable and visually clear microemulsions are desired. Thus, preferred sugars or sugar alcohols include sucrose, cane sugar, pure maple syrup, glycerol, and combinations thereof. More preferred sugars or sugar alcohols include pure maple syrup, glycerol, and combinations thereof. Currently, the most preferred sugar or sugar alcohol is glycerol.

[0057] When the sugar or sugar alcohol is glycerol, the ratio of glycerol to water is 2:1 to 4.5:1 by weight, preferably 3:1 to 4.5:1 by weight. When the sugar or sugar alcohol is pure maple syrup, sucrose, or cane sugar, and water is present in the syrup or used to solubilize the sucrose or cane sugar, this additional water becomes part of the water component of the microemulsion 336 and is therefore included as water in the weight ratio of sugar or sugar alcohol to water.

[0058] When the sugar or sugar alcohol is glycerol and the total water content of the microemulsion 336 is >10%-25%, the glycerol may be present in the microemulsion 336 at 30%-55%, preferably 30%-50%, by weight. When the total water content of the microemulsion 336 is >10%-20%, the glycerol may be present in the microemulsion 336 at 30%-50%, preferably 30%-45%, by weight. When the oil-soluble species is a cannabis extract, the glycerol may comprise 35%-45% of the microemulsion 336 by weight.

[0059] The water of the polar continuous phase 332 is present in the microemulsion 336 at >10% to 25% by weight. Preferably, the water is present in the microemulsion 336 at >10% to 20% by weight. More preferably, the water may be present in the microemulsion 336 at 11% to 16% by weight. When the oil-soluble species is a cannabis extract, the water may be present in the microemulsion 336 at 12% to 15% by weight. A water content of 10% or less by weight in the microemulsion 336 may result in dissociation of the oil-soluble species from the droplets and, therefore, a non-storage stable MOIW microemulsion.

[0060] The microemulsion 336 may optionally contain other ingredients or "adjuvants" that are chemically compatible with the oil-soluble species and do not substantially interfere with the separation between the modified oil and aqueous phases of the microemulsion. Such adjuvants may include hydrophilic or lipophilic gelling agents, thickeners, preservatives, antioxidants, electrolytes, fragrances, fillers, and pigments. Other adjuvants may be used in the microemulsion.

[0061] The following examples are provided to illustrate one or more preferred embodiments of the invention. Many variations can be made to the following examples that remain within the scope of the invention. [Example]

[0062] Example 1: Formulation of MOIW microemulsions containing cannabis extract as the oil-soluble species MOIW microemulsions with a total volume of 1 mL were prepared. Each MOIW microemulsion contained approximately 10 mg of cannabis extract containing approximately 80% CBD by weight. The MOIW microemulsions also contained 30 mg to 100 mg of PC, 150 mg to 250 mg of ethanol, 300 mg to 550 mg of glycerin, and 50 mg to 150 mg of medium-chain triglycerides. TPGS was included to provide the desired physical structure in the MOIW microemulsion. In addition to these components, the MOIW microemulsions contained sufficient water to provide a total emulsion volume of 1 mL.

[0063] Example 2: Method for making MOIW microemulsions containing cannabis extract Approximately 10 mg of CBD from a cannabis extract containing approximately 80% CBD by weight was combined in MCT oil, which was then combined with TPGS, PC, glycerin, and ethanol in water, and the combination was then mixed to form a MOIW microemulsion containing the cannabis extract.

[0064] Example 3: Comparative Blood Uptake Rates for Buccal Delivery of Cannabis Extract CBD Three oral cannabis extract carrier systems were compared in terms of CBD blood uptake rate. In this example, CBD was used as the oil-soluble species because it is readily available, but blood uptake rate data is expected to be similar for other oil-soluble species such as THC, other cannabinoids, and terpenes. The first carrier system was a MOIW microemulsion consistent with Examples 1 and 2. The second carrier system was a conventional oil blend. The third carrier system was a conventional OIW emulsion.

[0065] A second oil blend carrier system was prepared by combining about 1.5% by weight of cannabis extract containing about 80% by weight of CBD with about 98.5% by weight of hemp seed oil to provide a conventional oil-only product. While hemp seed oil was used in this example, other oils, including sunflower, olive, and MCT, are expected to provide similar blood uptake rates.

[0066] A third carrier system for a conventional OIW emulsion contained a cannabis extract labeled as containing approximately 17 mg / mL of CBD, with the emulsion components being water, glycerin, MCT oil, natural lipids, polysaccharides xanthan and acacia gum, stevia, and potassium sorbate. The proportions of the OIW emulsion components were unknown when the OIW emulsion was commercially obtained, but the OIW emulsion was known to be a conventional, non-visually clear OIW emulsion. Independent testing revealed that the commercially obtained OIW emulsion actually contained 4.8 mg / mL of CBD, as opposed to the labeled approximately 17 mg / mL.

[0067] On an empty stomach, human subjects placed 1.2 mL of MOIW microemulsion, 1 mL of a conventional oil blend, or 2.14 mL of an OIW emulsion containing cannabis extract under their tongues. Slightly different volumes were used; all doses contained approximately 10 mg of CBD. For the commercially available OIW emulsion, 2.14 mL was used to provide the desired 10 mg CBD dose, given the emulsion's actual concentration of 4.8 mg / mL. Subjects held the liquid under their tongues for approximately 30 seconds to 2 minutes before swallowing.

[0068] Blood samples were collected from the subjects prior to administration of the carrier-based liquid and at various time intervals ranging from approximately 20 to 180 minutes after oral administration of the carrier-based liquid. The collected blood samples were analyzed for CBD concentrations using LCMS.

[0069] Figure 4 provides the results of the CBD blood uptake rate and concentration analysis in graphical form. The time after administration of the carrier-based liquid to the subject when the blood sample was collected is represented on the X-axis, while the average nanograms (ng) of CBD per milliliter (mL) determined for the blood sample is represented on the Y-axis.

[0070] The MOIW microemulsion line represents the blood uptake levels obtained with the MOIW microemulsion according to Examples 1 and 2. The oil blend line represents the blood levels obtained with the oil blend. The OIW emulsion line represents the blood levels obtained with a conventional OIW emulsion.

[0071] Figure 5 provides the cumulative area under the curve (AUC) values ​​in ug* (min / mL) determined from the bloodstream concentration analysis in graphical form. The AUC values ​​provide a measure of the cumulative amount of CBD in the bloodstream and, therefore, total exposure over a period of time.

[0072] The advantage of MOIW microemulsions over oil blends in rapidly delivering CBD to the bloodstream is readily apparent in terms of blood uptake. Total CBD exposure over time was determined at different times after oral administration by multiplying the AUC by the amount of CBD in the selected cannabis extract carrier system and dividing by the similarly calculated control value (hence, (AUC1 * carrier system 1) / (AUC control * carrier system control) at the selected time point), thus calculating the AUC as the cumulative amount of CBD in the bloodstream. This calculation involves dividing the total amount of CBD delivered by the carrier system liquid (numerator) by the total amount of CBD delivered by the carrier system liquid (denominator), so the resulting value relates to how many times more CBD was delivered by the carrier system liquid (numerator) compared to the carrier system liquid (denominator).

[0073] The results from the AUC calculations for the MOIW microemulsion as the numerator and the oil blend as the denominator, with extrapolation due to slight variations in blood sample collection times, are provided in Table 1 below. [Table 1]

[0074] At 20 minutes after oral administration, the CBD measured in blood from the oil blend administration was below the sensitivity of the LCMS instrument, making it impossible to determine a true delivery comparison value. The MOIW microemulsion's ability to provide a significantly enhanced blood uptake rate compared to the oil blend was demonstrated at 20 minutes, as the MOIW microemulsion achieved a blood concentration of approximately 1.2 ng / mL after administration, while the oil blend achieved a blood concentration of essentially 0. Thus, using oral administration of a 1 mL dose of MOIW microemulsion, the MOIW microemulsion can provide a blood CBD concentration of 0.3-1.5 ng / mL, preferably 0.6-1.5 ng / mL, and more preferably 0.8-1.5 ng / mL in human subjects within 20 minutes.

[0075] The significance of the 20-minute rapid delivery of the MOIW microemulsion is seen at 60 minutes, when the MOIW microemulsion cumulatively delivered approximately 22 times more CBD to the bloodstream than the oil blend (peak concentration of 2.9 ng / mL for the MOIW microemulsion vs. approximately 0.16 ng / mL for the oil blend). In fact, it was not until the 90-minute time point that a slower rate of increase in cumulative delivery was observed compared to the oil blend. By cumulatively delivered, we mean the total bloodstream-available CBD in a human subject from the introduction of the liquid carrier system through the selected time. It was not until approximately 180 minutes that the oil blend delivered CBD to the bloodstream at a rate comparable to that of the MOIW microemulsion.

[0076] For oil blends, the advantage of MOIW microemulsions in rapidly delivering CBD to the bloodstream compared to traditional OIW emulsions is also evident in terms of blood uptake. Results from AUC calculations for MOIW microemulsions as the numerator and OIW emulsions as the denominator, with extrapolation due to slight variations in blood sample collection times, are provided in Table 2 below. [Table 2]

[0077] At 20 minutes after oral administration, the CBD measured in blood from the OIW emulsion administration was below the sensitivity of the LCMS instrument, making it impossible to determine a true delivery comparison value. The ability of the MOIW microemulsion to provide a significantly enhanced blood uptake rate compared to the OIW emulsion was demonstrated at 20 minutes, as the MOIW microemulsion achieved a blood uptake concentration of approximately 1.2 ng / mL after administration, while the OIW emulsion achieved a blood concentration of essentially 0.

[0078] The significance of the MOIW microemulsion's rapid 20-minute delivery is readily seen at 60 minutes, when the MOIW microemulsion cumulatively delivered nearly 7 times more CBD to the bloodstream than the OIW emulsion (peak concentration of 2.9 ng / mL for the MOIW microemulsion vs. approximately 0.43 ng / mL for the oil blend). As with the oil blend, it was not until approximately 180 minutes that the OIW emulsion delivered CBD to the bloodstream at a rate comparable to the MOIW microemulsion.

[0079] Interestingly, between the 60-minute and 90-minute time points, the rate of increase in cumulative delivery for the MOIW microemulsion decreased, while for the OIW emulsion it continued to increase nearly linearly. This may indicate the enhanced ability of the MOIW microemulsion to deliver to the bloodstream intraorally, a distinction that differs from the preferred gastrointestinal bloodstream delivery route of the OIW emulsion. The substantially more rapid blood uptake (20 minutes) provided by the MOIW microemulsion compared to the OIW emulsion indicates the MOIW microemulsion's ability to substantially "bypass" the digestive tract. Both the oil blend and the OIW emulsion appear to deliver oil-soluble species substantially via the digestive tract, while the MOIW microemulsion appears to deliver oil-soluble species substantially via the mouth and esophagus.

[0080] Example 4: Total Exposure for Buccal Delivery of Cannabis Extract CBD The three oral cannabis extract carrier systems from Example 3 were also compared in terms of total CBD exposure. Approximately 10 mg of CBD was introduced to the subject using each extract carrier system. Therefore, by comparing the AUC values ​​for each of the three extract carrier systems within a selected time frame, the total amount of cannabis extract to which the subject was exposed can be compared.

[0081] At 60 minutes, the AUC was 94 ng*min / mL for the MOIW microemulsion, 14 for the conventional OIW emulsion, and 4.2 for the oil blend. Thus, at 60 minutes, of approximately 10 mg of CBD consumed by a subject, the MOIW microemulsion exposed the subject to approximately 7 times more CBD than the conventional OIW emulsion and approximately 22 times more CBD than the oil blend. The MOIW microemulsion was able to deliver 5 to 9 times, preferably 6 to 8 times, more CBD to the bloodstream of a human subject after 60 minutes than the OIW emulsion. The MOIW microemulsion was able to deliver 18 to 24 times, preferably 20 to 22 times, more CBD to the bloodstream of a human subject after 60 minutes than the oil blend.

[0082] At 180 minutes, the AUC was 273 ng*min / mL for the MOIW microemulsion, 122 for the conventional OIW emulsion, and 58 for the oil blend. At 180 minutes, the MOIW microemulsion and OIW emulsion carrier systems delivered CBD to the bloodstream at similar rates, but in terms of cumulative, and therefore total, delivery, the MOIW microemulsion delivered over two times more CBD to the bloodstream than the OIW emulsion. At 180 minutes, the oil blend carrier system delivered CBD to the bloodstream at a somewhat faster rate than the MOIW microemulsion, but in terms of cumulative, and therefore total, delivery, the MOIW microemulsion delivered approximately five times more CBD to the bloodstream than the oil blend.

[0083] Over a 180-minute period, of the approximately 10 mg of CBD consumed by the subject, the MOIW microemulsion exposed the subject to more than twice as much CBD as the conventional OIW emulsion and nearly five times as much CBD as the oil blend. Thus, over the 180-minute time frame, the MOIW microemulsion delivered at least 80%, preferably at least 100%, more CBD to the bloodstream than the OIW emulsion, and at least four, preferably at least five times as much CBD to the bloodstream as the oil blend.

[0084] The data show that to achieve a similar cannabis extract exposure over a 3-hour time frame as provided by approximately 1 mL of MOIW microemulsion, a subject would need to consume approximately 5 mL of conventional OIW emulsion or approximately 5 mL of oil blend. Even at these "large dose" conditions, conventional OIW emulsions and oil blends are unlikely to provide the same rapid 20-minute onset bloodstream concentrations provided by MOIW microemulsions. Thus, the ability of MOIW microemulsions to efficiently deliver cannabis extract to the bloodstream at substantially lower dosages is demonstrated.

[0085] Example 5: Blood uptake consistency for buccal delivery of cannabis extract CBD The MOIW microemulsion and oil-blended cannabis extract carrier systems from Example 3 were compared in terms of CBD bloodstream uptake consistency for 10 human subjects. Blood samples were collected from the subjects at various time intervals, approximately 20 to 180 minutes, after oral administration of the carrier system liquid. The collected blood samples were analyzed for CBD concentration using LCMS. The standard deviation between CBD blood concentrations was determined for each time point for the collected samples. The calculated standard deviation was then divided by the average CBD blood concentration determined for each time point to provide a percentage standard deviation of CBD blood concentrations. The determined values ​​are provided in Table 3 below. [Table 3]

[0086] When averaging the standard deviation percentages for the MOIW microemulsions, an average standard deviation percentage of 65% was determined. When averaging the standard deviation percentages for the oil blends, an average standard deviation percentage of 135% was determined. Thus, the MOIW microemulsions provided less than half the variability in blood uptake compared to that provided by the oil blends. This substantial increase in dosing reproducibility provided by the MOIW microemulsions compared to the oil blends is believed to be due to the ability of the MOIW microemulsions to provide a relatively consistent oral delivery compared to the oil blends, which provide inconsistent blood uptake that relies on GI absorption.

[0087] The low and inconsistent uptake provided by conventional delivery systems, coupled with the varying absorption capacities of different subjects, are factors in the inconsistent efficacy reports obtained from subjects using conventional oral cannabinoid delivery systems.

[0088] In order to provide a clearer and more consistent understanding of the specification and claims of this application, the following definitions are provided.

[0089] Oral delivery means that when the liquid containing the delivery substance is orally administered, a significant portion of the bloodstream delivery occurs through the mouth, throat and esophagus via transmucosal absorption before the liquid reaches the stomach.For droplets that are considered suitable for oral delivery, the average droplet diameter is at most 125 nm.It is believed that oral delivery increases with decreasing average droplet diameter, and an average droplet diameter of about 50 nm is preferred.

[0090] Oil-soluble species are species that are insoluble in water and soluble in medium-chain triglyceride (MCT) oil at 50 mg / mL or more, preferably 100 mg / mL or more. Oil-soluble species are generally soluble in MCT oil at room temperature and readily or highly soluble in MCT oil at temperatures above 70°C. Some highly purified oil-soluble species are barely soluble in MCT oil at room temperature, but readily or highly soluble in MCT oil above 70°C, and once solubilized in MCT oil at high temperatures, they remain solubilized at room temperature, hence the term "generally soluble in MCT oil at room temperature." Oil-soluble species are preferably pharmacologically active, more preferably drugs or supplements, both of which do not contain water. Therefore, although liquids and solids that are technically soluble in oil may exist, they are not "oil-soluble species" because they are also soluble in water or are not sufficiently soluble in MCT oil.

[0091] Phosphatidylcholine (PC) molecules are a subset of a larger group of phospholipids commonly used to form liposomes in water. When placed in water without other components, PC forms liposomes. In the presence of oil, sufficient shear forces can be applied to PC liposomes in water to produce unilamellar structures containing micelles. PC has a water-soluble head group and a tail group that is significantly less water-soluble than the head group. While PC is a neutral lipid, it carries an electric dipole moment of approximately 10 D between the head group and tail group, making the molecule polar.

[0092] Tocopheryl polyethylene glycol succinate 1000 (TPGS) is generally considered a surfactant with a non-polar, oil-soluble "vitamin E" tail and a polar, water-soluble polyethylene glycol head. TPGS is a member of a family of polyethylene glycol derivatives that also includes polysorbates 20, 40, 60, and 80.

[0093] Room temperature and pressure means 20-28 degrees Celsius at approximately 100 kPa.

[0094] Solid means a substance that is neither a liquid nor a gas at room temperature and pressure. A solid substance may have one of a variety of forms, including a simple solid, a powder, a gel, or a paste.

[0095] A liquid is a substance that is neither a solid nor a gas at room temperature and pressure. A liquid is an incompressible substance that flows and assumes the shape of its container.

[0096] In a solution, there is no discernible interface between the solubilizing molecules and the solvent: in a solution, the solubilizing molecules are in direct contact with the solvent.

[0097] Solubilization means that the oil-soluble species being delivered is in solution in the droplets. When solubilized, dissociation of the oil-soluble species (and therefore liquid separation or solid formation) does not result in an average droplet particle size greater than 200 nm, as determined by DLS, as discussed further below, or by the formation of macroscopic precipitated crystals of the oil-soluble species. Thus, if either an average particle size greater than 200 nm or macroscopic precipitated crystals form, the oil-soluble species is not solubilized in the droplet solution. If an oil-soluble species is not solubilized in solution, it is insoluble in solution. In many respects, solubility can be thought of as a concentration-dependent continuum. For example, the following descriptive terms can be used to express the solubility of a solute in a solvent at 25 degrees Celsius (grams of solids / mL of solvent): [Table 4]

[0098] Dissociation occurs when a previously solubilized solid or liquid leaves solution and is no longer in direct contact with the solution's solvent. Dissociation of a solid from a solvent occurs through recrystallization, precipitation, etc. Dissociation of a liquid from a solvent occurs through separation between the solvent and the dissociated liquid and the formation of a visible meniscus.

[0099] Storage-stable microemulsions can be determined in one of two ways. One way to demonstrate that a microemulsion is storage-stable when stored in a sealed container substantially excluding air and moisture is when no dissociation of solids occurs and the oil-in-water droplets do not change in average diameter by more than + / - 20% at about 25°C for a period of at least 3 months to 2 years, preferably at least 6 months to 2 years, and more preferably at least 1 year to 2 years. Another way to demonstrate that a microemulsion is storage-stable is when no dissociation of solids occurs and the oil-in-water droplets do not separate into visibly distinct phases with a visible meniscus when stored in a sealed container substantially excluding air and moisture at about 25°C for a period of at least 6 months to 2 years, and more preferably at least 1 year to 2 years. Either type of dissociation means that the microemulsion is not storage-stable.

[0100] A visually clear microemulsion has an average particle size of 200 nm or less and is free of precipitated solid crystals visible to the naked eye.

[0101] An emulsion is a mixture of two or more liquids that do not solubilize. Thus, one of the liquids carries droplets of the second liquid. The droplets of the second liquid may be said to be dispersed in a continuous phase of the first liquid. An interface, separation, or 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 primary differences between macroemulsions, microemulsions, and nanoemulsions are the average diameter of the droplets dispersed in the continuous phase and the stability of the emulsion over time. Pseudoemulsions are distinguished by the presence of solids in the emulsion.

[0102] The droplets or liquid particles are formed by the hydrophobic "oil" phase of the microemulsion and carried by the hydrophilic continuous phase. The exterior of the liquid droplets is defined by a boundary layer that surrounds the volume of each liquid droplet. The droplet boundary layer defines the outer surface of the droplet, which forms the dispersed oil phase of the microemulsion. The continuous phase of the microemulsion resides outside the droplet boundary layer and therefore carries the droplet.

[0103] Macroemulsions are thermodynamically unstable but kinetically stable dispersions of oil-in-water, where oil is defined as any water-immiscible liquid. Thermodynamically unstable means that once created, macroemulsions always return to the original immiscible state of the oil and water components (demulsification), but this decomposition is slow enough (hence, kinetically "stable") that the macroemulsion can be considered stable from the perspective of its intended practical use. Because their droplets are larger in diameter than the wavelength of visible light, macroemulsions effectively scatter light and therefore appear milky white. Macroemulsion droplets typically have an average droplet diameter of 10 to 50 micrometers. The IUPAC definition of a macroemulsion is "an emulsion in which the particles of the dispersed phase have diameters of approximately 1 to 100 micrometers." Macroemulsions are "unstable" in the sense that they contain large droplets and therefore either settle or float, depending on the densities of the dispersed phase and the dispersion medium.

[0104] Pseudoemulsions are oil-in-water dispersions, where oil is defined as any water-insoluble liquid containing tiny (microparticulated) solid granules that are not completely solubilized within the oil droplets. The term "pseudoemulsion" is used to indicate that these mixtures are not true emulsions because the solid granules are not completely solubilized within the droplets. Pseudoemulsion droplets have an average droplet diameter of 1 to 20 micrometers, and are therefore "solid granule-modified macroemulsions."

[0105] A microemulsion is a thermodynamically stable dispersion of oil-in-water, where oil is defined as any water-immiscible liquid. Microemulsions are created by simply mixing the components. Therefore, microemulsions form spontaneously and do not require high shear forces. Unlike macroemulsions, microemulsions do not substantially scatter light. The IUPAC definition of a microemulsion is "a dispersion made from water, oil, and surfactant, which is an isotropic and thermodynamically stable system with dispersion domain diameters varying from approximately 1 to 100 nm, usually 10 to 50 nm." Thus, microemulsion droplets are approximately three orders of magnitude smaller and more thermodynamically stable than macroemulsion droplets.

[0106] Nanoemulsions have an average droplet diameter of 10 to 125 nanometers, thus at least one order of magnitude smaller than macroemulsions and pseudoemulsions. Penetrating nanoemulsions have an average droplet diameter of 10 to 100 nanometers. Nanoemulsions are created by high mechanical shear forces. Although the average droplet diameters of nanoemulsions and microemulsions formally overlap, in practice, the average droplet diameter of nanoemulsions is larger or greater than that of microemulsions, because the lack of thermodynamic stability of microemulsions causes the average droplet diameter of microemulsions to permanently increase.

[0107] The continuous phase refers to the portion of the microemulsion that carries the droplets containing the substance to be delivered. For example, the modified oil-in-water microemulsions discussed herein (non-polar droplets in a polar continuous phase) have oil droplets containing the oil-soluble species to be delivered 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" (such as a polar oil), and "oil" can be any liquid that is less polar than "water." Thus, the terms "polar continuous phase" and "water continuous phase" are synonymous unless water is specifically discussed as one of the microemulsion components.

[0108] The average droplet diameter is determined by dynamic light scattering, sometimes referred to as photon correlation spectroscopy. Measurements are performed at 20-25°C. One example of an instrument suitable for determining average droplet diameter is the Nicomp 380 ZLS particle sizer, available from Particle Sizing Systems, Port Richey, FL. DLS can determine the diameter of droplets in a liquid by measuring the intensity of light scattered from the droplets to a detector over time. As droplets move due to Brownian motion, light scattered from two or more droplets interferes constructively or destructively at the detector. By calculating the autocorrelation function of the light intensity and assuming a droplet distribution, it is possible to determine droplet sizes from 1 nm to 5 μm. The instrument can also measure the zeta potential of the droplets.

[0109] Ingestible means capable of being ingested by a living mammal through the mouth, while edible means suitable for consumption as opposed to being unpalatable or toxic. Edible also means that the composition has less than acceptable levels of viable aerobic microorganisms and meets American Herbal Products Association (AHPA) guidelines for metals, impurities, toxins, residual solvents, and pesticides.

[0110] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value between the upper and lower limit of that range, to one-tenth of the unit of the lower limit, and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0111] While various aspects of the invention have been described, it will be apparent to those skilled in the art that other aspects and implementations are possible within the scope of this invention. Accordingly, the invention is not to be restricted except in light of the attached claims and their equivalents.

Claims

1. 1. A composition comprising: an oil-soluble species; a modified oil-in-water microemulsion comprising a modified oil phase and a modified polar continuous phase, the microemulsion being visually clear, shelf stable, ingestible and edible; the oil-soluble species are solubilized in the denatured oil phase, the denatured oil phase comprising a phospholipid, a polyethylene glycol derivative, an oil, and ethanol; the phospholipid comprises one or more of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide phosphorylethanolamine (Cer-PE), and ceramide phosphorylcholine (SPH); the polyethylene glycol derivative includes one or more of tocopheryl polyethylene glycol succinate 1000 (TPGS), polysorbate 40, polysorbate 60, and polysorbate 80; The oil comprises MCT oil, the denatured polar continuous phase comprises a sugar or sugar alcohol and water; the droplets of the modified oil phase have an average droplet diameter of 7 to 30 nanometers; the water is greater than 10% by weight and less than or equal to 25% by weight of the composition; the ratio of the phospholipid to the polyethylene glycol derivative is 1:1.6 to 1:4 by weight; the ratio of the oil to the ethanol is 1:1.5 to 1:3 by weight; The composition, wherein the sugar or sugar alcohol is selected from sucrose, cane sugar, pure maple syrup, glycerol, and combinations thereof.

2. 10. The composition of claim 1, wherein the modified oil-in-water microemulsion is configured to provide for uptake of the oil-soluble species into the bloodstream of a mammal at effective bloodstream concentrations across the oral and gastric mucosa of the mammal.

3. 10. The composition of claim 1, wherein the modified oil phase is configured to solubilize the oil-soluble species better than the oil alone.

4. 10. The composition of claim 1, wherein the oil-soluble species is selected from cannabis extracts, terpenes, and combinations thereof.

5. 5. The composition of claim 4, wherein the cannabis extract is selected from cannabidiol, tetrahydrocannabinol, other cannabinoids, and combinations thereof.

6. 5. The composition of claim 4, wherein the terpene is selected from limonene, pinene, linalool, beta-caryophyllene, retinol, phytol, myrcene, humulene, ocimene, terpinolene, geraniol, geranylgeraniol, and combinations thereof.

7. 10. The composition of claim 1, further comprising an alcohol-soluble delivery agent in the denatured oil phase, wherein the alcohol-soluble delivery agent is selected from a plant sterol, a polyphenol, an antimicrobial agent, and combinations thereof.

8. 8. The composition of claim 7, wherein the plant sterol is selected from Tribulus terrestris, Yohimbe, and combinations thereof.

9. 8. The composition of claim 7, wherein the polyphenol is selected from resveratrol, pterostilbene, curcumin, boswellia, quercetin, and combinations thereof.

10. 8. The composition of claim 7, wherein the antimicrobial agent is selected from artemisinin, monolaurin, panicle, and combinations thereof.

11. 2. The composition of claim 1, wherein the phospholipid is at least 80% by weight phosphatidylcholine.

12. 10. The composition of claim 1, wherein the MCT oil is selected from caprylic acid, capric acid, and combinations thereof.

13. The composition of claim 1, wherein the oil-soluble species comprises from 2% to 4% by weight of the composition.

14. The composition described in claim 1, wherein the ratio of the oil to the oil-soluble species is 1:0.05 to 0.3, including a deviation of up to 10%.

15. 10. The composition of claim 1, wherein the phospholipid comprises 2% to 10% by weight of the composition.

16. The composition of claim 1, wherein the polyethylene glycol derivative comprises 5% to 15% by weight of the composition.

17. The composition of claim 1, wherein the oil comprises from 5% to 15% by weight of the composition.

18. The composition of claim 1, wherein the ethanol comprises from 5% to 25% by weight of the composition.

19. 10. The composition of claim 1, wherein the sugar or sugar alcohol comprises 30% to 55% by weight of the composition.

20. 10. The composition of claim 1, wherein the sugar or sugar alcohol comprises 30% to 45% by weight of the composition.

21. The composition of claim 1, wherein the water comprises from 11% to 14% by weight of the composition.

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