Self-Microemulsifying Multi-Deliverable Systems

Abstract

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

Claims

1. A composition for delivering a deliverable to the gastrointestinal tract, the composition comprising: an exterior capsule enclosing an oil-based solution, where the oil-based solution comprises an emulsion system and a deliverable, where the emulsion system comprises a surfactant system, an emulsion oil system, and a resin system, and where the deliverable is chosen from an oil-soluble species, an alcohol-soluble species, and combinations thereof.

2. The composition of claim 1 configured to form an oil-in-water microemulsion comprising monolayer surfactant bound particles in an aqueous gastrointestinal tract of a mammal.

3. The composition of claim 2, where the oil-in-water microemulsion is thermodynamically stable.

4. The composition of claim 2 further configured to form liposomes in the aqueous gastrointestinal tract of a mammal, where the liposomes are water-core liposomes comprising a water-soluble deliverable.

5. The composition of claim 2, where the monolayer surfactant bound particles are layered structures having an inner oil-based core, an intermediate resinous layer encapsulating the inner core, and an outer surfactant monolayer encapsulating the intermediate layer.

6. The composition of claim 2, where the monolayer surfactant bound particles have an average droplet diameter of 10 to 100 nanometers.

7. The composition of claim 2, where the monolayer surfactant bound particles have an average droplet diameter of 10 to 80 nanometers.

8. The composition of claim 2, where the monolayer surfactant bound particles have an average droplet diameter of 10 to 60 nanometers.

9. The composition of claim 1, where the surfactant system comprises a phospholipid and a polyethylene glycol derivative.

10. The composition of claim 9 where the phospholipid is a glycerophospholipid isolated from lecithin.

11. The composition of claim 10, where the phospholipid is chosen from phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide phosphoryl ethanolamine (Cer-PE), ceramide phosphoryl choline (SPH), and combinations thereof.

12. The composition of claim 10, where the phospholipid is chosen from phosphatidylcholine, phosphatidylethanolamine, and combinations thereof.

13. The composition of claim 10, where the phospholipid is at least 80% by weight phosphatidylcholine.

14. The composition of claim 9, where the polyethylene glycol derivative is chosen from tocopheryl polyethylene glycol succinate 1000, polysorbate 40, polysorbate 60, polysorbate 80, and combinations thereof.

15. The composition of claim 9, where the polyethylene glycol derivative is chosen from tocopheryl polyethylene glycol succinate 1000, polysorbate 40, and combinations thereof.

16. The composition of claim 1, where the surfactant system comprises from 27% to 35% by weight of the oil-based solution.

17. The composition of claim 9, where a ratio of the phospholipid to the polyethylene glycol derivative is from 1:5 to 1:30 in the oil-based solution.

18. The composition of claim 1 where the emulsion oil system comprises an associating oil chosen from a medium chain triglyceride oil, a citrus oil, and combinations thereof.

19. The composition of claim 18, where the medium chain triglyceride is chosen from caproic acid (hexanoic acid), caprylic acid (octanoic acid), capric acid (decanoic acid), lauric acid (dodecanoic acid), and combinations thereof.

20. The composition of claim 18, where the medium chain triglyceride chosen from caprylic acid, capric acid, and combinations thereof.

21. The composition of claim 18, where the citrus oil is chosen from orange oil, lemon oil, and combinations thereof.

22. The composition of claim 18, where the emulsion oil system further comprises a terpene oil.

23. The composition of claim 22, where the terpene oil is chosen from turmeric oil, cinnamon oil, peppermint oil, spearmint oil, and blends of these terpene oils.

24. The composition of claim 22, where the terpene oil is turmeric oil.

25. The composition of claim 1, where the emulsion oil system comprises from 38% to 55% by weight of the oil-based solution.

26. The composition of claim 1 where the emulsion oil system comprises a ratio of associating oil to terpene oil from 1:1.7 to 1:5.5 in the oil-based solution.

27. The composition of claim 1, where the resin system comprises a resin chosen from turmeric oleoresins, propolis, astaxanthin oleoresin, pine resin, ginger oleoresin, and combinations thereof.

28. The composition of claim 1, where the resin system consists essentially of turmeric oleoresin.

29. The composition of claim 1, where the resin system consists essentially of propolis.

30. The composition of claim 1, where the resin system consists essentially of turmeric oleoresin and propolis.

31. The composition of claim 1, where the resin system comprises from 3% to 18% by weight of the oil-based solution.

32. The composition of claim 30, where a ratio of the propolis to the turmeric oleoresin is from 1:1.7 to 1:5 in the oil-based solution.

33. The composition of claim 1, where a ratio of the resin system to the surfactant system to the emulsion oil system is 1:2-4:3.5-6±20% by weight in the oil-based solution.

34. The composition of claim 1, where the deliverable is chosen from curcumin, Boswellia serrata, quercetin, berberine HCl, milk thistle extract, artemisinin, andrographis, luteolin, resveratrol, diindolylmethane, hesperetin, beta caryophyllene, cannabis extracts, and combinations thereof.

35. The composition of claim 1, where the alcohol-soluble species deliverable is chosen from curcumin, Boswellia serrata, quercetin, berberine HCl, milk thistle extract, artemisinin, andrographis, luteolin, resveratrol, diindolylmethane, hesperetin, and combinations thereof.

36. The composition of claim 1, where the oil-soluble species deliverable is chosen from beta caryophyllene, cannabis extracts, and combinations thereof.

37. The composition of claim 34, where the deliverable further comprises a water-soluble deliverable that is soluble in the oil-based solution.

38. The composition of claim 37, where the water-soluble deliverable is a mineral salt.

39. The composition of claim 37, where the water-soluble deliverable is chosen from a zinc salt, a magnesium salt, a calcium salt, and combinations thereof.

40. The composition of claim 1, where the oil-based solution is configured to solubilize from 50 mg to 200 mg of the deliverable per gram of the oil-based solution.

41. The composition of claim 1, where the oil-based solution comprises 10% to 20% of the deliverable by weight.

42. The composition of claim 1, where the ratio of the deliverable to the emulsion is from 1:4-8±20% by weight.

43. The composition of claim 1, where the oil-based solution is configured to deliver the deliverable chosen from the alcohol-soluble species, the oil-soluble species, and the combinations thereof, through the gastrointestinal tract of a mammal and provide a measurable plasma concentration of the deliverable in a non-metabolized form within 20 minutes of the mammal orally-consuming the composition on an empty stomach.

44. An ingestible and edible composition for pain relief, the composition comprising: an encapsulated oil-based solution including from 2 to 3 percent by weight phospholipid, from 24 to 30 percent by weight polyethylene glycol derivative, from 8 to 13 percent by weight turmeric oleoresin, from 1 to 2.5 percent by weight propolis, from 12 to 18 percent by weight emulsion oil, from 23 to 31 percent by weight turmeric oil, from 5 to 9 percent by weight beta caryophyllene, from 1.5 to 4 percent by weight hemp oil, from 1 to 3 percent by weight piperine, from 4 to 4 percent by weight curcumin, and from 2 to 4 percent by weight Boswellia serrata.

45. An ingestible and edible composition for balancing microbial load in a mammal, the composition comprising: an encapsulated oil-based solution including from 3.2 to 5 percent by weight phospholipid, from 26.3 to 30 percent by weight polyethylene glycol derivative, from 3 to 7 percent by weight turmeric oleoresin, from 2.6 to 4 percent by weight propolis, from 18.2 to 23 percent by weight emulsion oil, from 11 to 20 percent by weight turmeric oil, from 1 to 5 percent by weight cinnamon oil, from 1 to 5 percent by weight peppermint oil, from 0.2 to 1.3 percent by weight hemp oil, from 0.3 to 2 percent by weight berberine HCl, from 2 to 5 percent by weight milk thistle extract, from 3 to 7 percent by weight artemisinin, from 0.3 to 2 percent by weight andrographis, from 2 to 6 percent by weight Boswellia serrata, and from 2 to 4 percent by weight quercetin.

46. An ingestible and edible composition for controlling inflammation, the composition comprising: an encapsulated oil-based solution including from 1 to 3 percent by weight phospholipid, from 25 to 34 percent by weight polyethylene glycol derivative, from 6 to 10 percent by weight turmeric oleoresin, from 8 to 13 percent by weight associating oil, from 27 to 35 percent by weight turmeric oil, from 2 to 6 percent by weight cinnamon oil, from 7 to 10 percent by weight spearmint oil, from 2 to 5 percent by weight berberine HCl, from 2 to 5 percent by weight milk thistle extract, from 2 to 5 percent by weight resveratrol, from 2 to 5 percent by weight hesperetin, and from 2 to 5 percent by weight quercetin.

47. An ingestible and edible composition for supplementing dietary zinc in a mammal, the composition comprising: an encapsulated oil-based solution including from 1 to 3 percent by weight phospholipid, from 25 to 34 percent by weight polyethylene glycol derivative, from 7 to 10 percent by weight propolis, from 22 to 30 percent by weight associating oil, from 10 to 15 percent by weight turmeric oil, from 10 to 15 percent by weight spearmint oil, from 3 to 5 percent by weight zinc acetate, from 2 to 5 percent by weight luteolin, from 2 to 5 percent by weight hesperetin, and from 2 to 5 percent by weight quercetin.

48. A method of forming an oil-based solution for delivering a deliverable to the gastrointestinal tract, the method comprising: heating an alcohol and water solution to a low temperature of 65° C. to 78° C., where the alcohol and water solution has an alcohol to water ratio from 80:20 to 97:3 on a volume basis to form a heated solvent solution; combining an alcohol-soluble species 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; increasing the heated deliverable mixture above 78° C. to form a reduced solution; and combining an emulsion oil system with the reduced solution to form an oil-based solution.

49.-83. (canceled)

Description

DESCRIPTION OF THE FIGURES

[0045] The invention can be better understood with reference to the following figures and description. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

[0046] FIG. 1A and FIG. 1B represent a liposome having a double wall (bilayer) of phospholipids formed from a hydrophilic exterior wall and a hydrophilic interior wall.

[0047] FIG. 2 represents a flattened side view of the double wall (bilayer) of phospholipids that forms the liposome.

[0048] FIG. 3 represents a micelle having a single wall of phospholipids (monolayer) forming a hydrophilic exterior and a hydrophobic interior lacking the hydrophilic capsule interior of a liposome.

[0049] FIG. 4 represents a monolayer surfactant bound particle where an associated oil component is associated with the hydrophobic tails of a surfactant.

[0050] FIG. 5 represents a method of making the composition including the encapsulated oil-based solution.

[0051] FIG. 6 provides the results from a LC/MS/MS plasma curcumin analysis at the 0, 10, 20, 40, 60, 90, 120, 180, and 480 (commercially available only) minute time intervals.

[0052] FIG. 7 provides the results from a LC/MS/MS plasma curcumin-glucuronide analysis at the 0, 10, 20, 40, 60, 90, 120, 180, and 480 (commercially available only) minute time intervals.

DETAILED DESCRIPTION

[0053] Compositions in the form of oil-based solutions that form oil-in-water (OIW) microemulsions in the aqueous environment of the GI tract when taken orally via a hard or soft capsule are described. The resulting microemulsions that form from the oil-based solution within the GI tract can rapidly deliver oil-soluble species and alcohol-soluble species (including PEG derivative assisted alcohol-soluble species) deliverables to the bloodstream through the tissues forming the GI tract. The in situ formed microemulsions resulting from consumption of the encapsulated oil-based solutions include oil-phase microemulsion droplets of monolayer surfactant bound particles suspended in the aqueous continuous phase of the GI tract. The oil-based solutions also may in situ form water-core liposomes suspended in the aqueous continuous phase of the GI tract.

[0054] The exterior capsule containing the oil-based solutions may be of the “hard shell” or “soft shell” variety. Useful hard-shell capsules are made from aqueous solutions of gelling agents, such as animal protein (mainly gelatin) or plant polysaccharides or their derivatives (such as carrageenan and modified forms of starch and cellulose). Other additional ingredients are a gelling agent such as glycerin or sorbitol to decreases the capsule's hardness, coloring agents, preservatives, disintegrates, lubricants and surface treatments. Examples of exterior hard-shell capsules include Nutra Pak capsules as available from NutraPak USA, East Rutherford, N.J. or QUALICAPS™ as available from Qualicaps, Inc., Whitsett, N.C. Useful soft-shell capsules are typically a combination of gelatin, water, opacifier and a plasticizer such as glycerin or sorbitol. The main source of gelatin is collagen, found in the skin and bones of animals, and is typically sourced from bovine or porcine. Vegetarian capsules are mainly made from Hydroxy Propyl Methyl Cellulose (HPMC) and alternatively polyethylene oxides (PEOs). Examples of exterior soft-shell capsules are available from NutraPak USA or from Soft Gel Technologies, Inc., Los Angeles, Calif. In either instance, the hard- or soft-shell capsule material is selected to not adversely affect the encapsulated oil-based solution that is released into the GI tract.

[0055] In the oil-based solutions that are encapsulated by the exterior capsule, solid deliverables are solubilized in the liquids of the oil-based solution. The resulting solutions are believed to form microemulsion droplets having an inner oil-based core, and intermediate resinous layer encapsulating the inner core, and an outer surfactant monolayer encapsulating the intermediate layer when placed in aqueous environments, such as the GI tract. While being solubilized in each other, the different solubilities throughout these layered structures are believed to allow for the inclusion of a wide diversity of deliverables, including those having alcohol- and/or oil-solubility. The compositions provide improved deliverable solubility and bloodstream uptake in relation to conventional SMEDS when introduced into the GI tract.

[0056] The emulsion system that forms the encapsulated oil-based solution of the SMEDS, includes a surfactant system, an emulsion oil system, and a resin system. The emulsion system may be designed to produce water-core liposomes in addition to microemulsion droplets in an aqueous continuous phase, such as the GI tract. Regardless of the specific constituents used in the emulsion system, one or more deliverables are included and solubilized in the encapsulated oil-based solution. Thus, the surfactant system, the emulsion oil system, the resin system, and the deliverable/s form the oil-based solution. This is believed to contrast with conventional SMEDS systems where the deliverable/s are not fully or poorly solvated in the emulsion forming components or where the conventional emulsion system is water- as opposed to oil-based.

[0057] When released into the aqueous environment of the GI tract, the oil-based solution forms microemulsion droplets, and optionally liposomes, that include the deliverables and have an average droplet diameter of 10 to 100 nanometers (nm) and a preferable average droplet diameter of 10 to 80 nm. More preferably, the formed microemulsion droplets and any included liposomes have an average particle diameter of 10 to 60 nm. Thus, these average droplet diameters are observed in an aqueous environment for the formed microemulsion droplets including any deliverables and for any formed liposomes including water-soluble deliverables.

[0058] The surfactant system of the emulsion system includes a phospholipid, such as phosphatidylcholine (PC), and a polyethylene glycol derivative, such as tocopheryl polyethylene glycol succinate (TPGS). Additional surfactants may be included in the surfactant system, if the additional surfactants are compatible with formation of the desired monolayer surfactant bound particles forming the microemulsion droplets and the optional water-core liposomes.

[0059] The phospholipid of the surfactant system is a glycerophospholipid preferably isolated from lecithin. As the phospholipid is preferably a lecithin isolate, the named isolates preferably include 80% (w/w) of the specified phospholipid with the remaining constituents being one or more additional phospholipids isolated from the lecithin or other lecithin isolates. Preferred phospholipid lecithin isolates include phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide phosphoryl ethanolamine (Cer-PE), ceramide phosphoryl choline (SPH), and combinations thereof, with PC, PE, and combinations thereof being more preferred.

[0060] The polyethylene glycol derivative of the surfactant system may 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 derivate 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 often thought of as interchangeable. However, polysorbate 20 is less preferred as it is less likely to form the desired microemulsions in combination with the phospholipid.

[0061] Preferably, the surfactant system constitutes from 27% to 35% by weight of the oil-based solution including one or more deliverables that forms the OIW microemulsion when released into the GI tract. The phospholipid preferably constitutes from 1% to 5% of the oil-based solution, while the polyethylene glycol derivative preferably constitutes from 26% to 30% of the oil-based solution. Thus, the preferred ratio of phospholipid to polyethylene glycol derivative in the oil-based solution is from 1:5 to 1:30.

[0062] The emulsion oil system of the emulsion system includes an associating oil including at least one of medium chain triglycerides (MCT), citrus oil, and combinations thereof. By “associating” it is meant that the oil can be held within the phospholipid/polyethylene glycol derivative monolayer. MCT oils are triglycerides whose fatty acids have an aliphatic tail of 6-12 carbon atoms. Preferable 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.

[0063] In addition to the associating oil, the emulsion oil system preferably includes a terpene oil, such as turmeric oil, cinnamon oil, peppermint oil, spearmint oil, or a blend of terpene oils.

[0064] Preferably, the emulsion oil system constitutes from 38% to 55% by weight of the oil-based solution including one or more deliverables that forms the OIW microemulsion when released into the GI tract. The associating oil preferably constitutes from 8% to 28% of the oil-based solution. When included, the terpene oil or terpene oil blend preferably constitutes from 18% to 46% of the oil-based solution. Thus, the preferred ratio of associating oil to terpene oil or terpene oil blend in the oil-based solution is from 1:1.7 to 1:5.5, when a terpene oil or terpene oil blend is included.

[0065] The resin system of the emulsion system includes at least one resin chosen from turmeric oleoresins, propolis, astaxanthin oleoresin, pine resin, ginger oleoresin, and combinations thereof. The resin of the resin system may be a solid or semisolid with some viscous oily fluid content and is insoluble in water. While the resin system may include some oil, there is enough solid component that it would not be considered a liquid, at most being considered to have a tightly bound liquid oil constituent. The resin or resins of the resin system are part of the emulsion system; however, they also may provide biological activity.

[0066] Turmeric oleoresins are oil-soluble species and are extracted from the Curcuma longa plant, but in relation to curcuminoids, which are “hard” solids, turmeric oleoresins are thick, waxy pastes that may include an oil component. Turmeric oleoresins include from 37-55% curcuminoids by weight and up to 25% volatile oil by weight. Turmeric oleoresin is isolated as one of the three recovered fractions from processing turmeric rhizomes. As turmeric oleoresin includes curcuminoids, the oleoresin may provide the biological activity of curcumin.

[0067] To obtain turmeric oleoresins, generally, turmeric rhizomes are dried and ground into a powder. Then the powder is extracted with solvents (some combination of acetone, dichloromethane, 1,2-dichloromethane, methanol, ethanol, isopropanol, and hexane) to provide a solid, waxy component that is the turmeric oleoresin, turmeric oil, and solvent solubilized solid curcumin. Thus, while the oleoresin includes some oil, it is the oil trapped in or with the solids, as the light or “essential turmeric oil” is removed during extraction processing. The “light” or “essential” recovered turmeric oil may form part of the emulsion oil system of the oil-based solution as previously discussed. The solvent is removed from the extraction solvent solubilized curcumin to produce curcumin powder, as also previously discussed.

[0068] Propolis is a resinous substance including polyphenols of the flavonoid class that is produced by honeybees from tree buds and is used by the bees to fill crevices and otherwise seal honeycombs. Propolis generally includes about 50% resin, 30% wax, 10% oil, 10% pollen, and organics. Due to the varied components, propolis may be considered a complex mixture having water-, alcohol-, and oil-soluble constituents when extracted. Preferably, a propolis ethanol extract may be used as the resin “propolis” to form the or a portion of the resin system for the oil-based solution; however, other propolis extracts may be used in the resin system. More preferably, the propolis extract used in the resin system includes at least 50%, most preferably at least 60%, extracted propolis by weight. Propolis is attributed with improving the immune system, reducing inflammation, and promoting better blood circulation, in addition to other benefits.

[0069] Astaxanthin oleoresin is a waxy-solid, alcohol-soluble species that is insoluble in water. Astaxanthin oleoresin may be extracted from algae, plants, and animals. Astaxanthin is a terpene known to have antioxidant properties that provides the red color to shrimp, lobster, and salmon, for example. Astaxanthin cannot be synthesized by mammals, and thus must be provided through the diet.

[0070] Preferably, the resin system constitutes from 3% to 18% by weight of the oil-based solution including one or more deliverables that forms the OIW microemulsion when released into the GI tract. When used, the turmeric oleoresin preferably constitutes from 3% to 14% of the oil-based solution, while when used, propolis preferably constitutes from 1% to 10% of the oil-based solution. When used in combination, ratios of propolis to turmeric oleoresin from 1:1.7 to 1:5 are preferred.

[0071] The ratio of the resin system to the surfactant system to the emulsion oil system is preferably 1:2-4:3.5-6 by weight, with deviations up to 20% by weight being included, and with deviations up to 10% being more preferred, thus 1:2-4:3.5-6±20% by weight or 1:2-4:3.5-6±10% more preferred by weight.

[0072] The oil-based solution may optionally include other ingredients or “adjuvants” that are chemically compatible with the oil-soluble species or alcohol-soluble species deliverables and the emulsion system 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.

[0073] The deliverable may be in liquid and/or solid form and be an alcohol-soluble species, an oil-soluble species, or water-soluble. Preferably at least one solid deliverable is included. More preferably, the oil-based solution includes at least two deliverables, with at least one alcohol-soluble and at least one oil-soluble being included. A benefit of the emulsion system in relation to conventional SMEDS is the emulsion system's ability to solubilize multiple, different alcohol- and oil-soluble species, thus allowing for substantially simultaneous delivery of both alcohol- and oil-soluble species deliverables to the GI tract. The emulsion system's believed ability to also form water-core liposomes in addition to the OIW microemulsion and thus deliver water-soluble deliverables via liposome simultaneously with the alcohol- and/or oil-soluble species deliverables is additionally beneficial.

[0074] Useful alcohol-soluble species deliverables include curcumin, Boswellia serrata, quercetin, berberine HCl, milk thistle extract, artemisinin, andrographis, luteolin, resveratrol, diindolylmethane, and hesperetin. Other alcohol-soluble species may be used with the emulsion system that do not interfere with microemulsion formation and that may be solubilized in the oil-based solution.

[0075] Useful oil-soluble species deliverables include beta caryophyllene and cannabis extracts. Other oil-soluble species may be used with the emulsion system that do not interfere with microemulsion formation and that may be solubilized in the oil-based solution.

[0076] Useful water-soluble deliverables include mineral salts, such as zinc, magnesium, and calcium salts. Other water-solubles may be used with the emulsion system that do not interfere with microemulsion formation and that may be solubilized in the oil-based solution due to the non-polar character of the counterion associated with the mineral.

[0077] One gram of the oil-based solution can solubilize from 50 mg to 200 mg of deliverable, preferably from 100 mg to 200 mg of deliverable, and more preferably from 120 mg to 180 mg of deliverable, based on the specific deliverables selected for inclusion in the oil-based solution that forms the OIW microemulsion when released into the GI tract. Thus, the encapsulated oil-based solution includes from 10% to 20% deliverable by weight, preferably from 12% to 18% delivered by weight. While higher deliverable loading may be used, solubility of the solid phase deliverables is less likely and insolubilized deliverables will have significantly decreased to no bioavailability. Thus, including insolubilized oil- or alcohol-soluble species deliverables in the oil-based solution will provide little to no increase in bioavailability of the insolubilized deliverable, waste deliverable, and potentially put an increased strain on the liver.

[0078] The ratio of the deliverable to the emulsion system is preferably from 1:4-8 by weight, with deviations up to 20% by weight being included, and with deviations up to 10% being more preferred, thus 1:4-8±20% by weight or 1:4-8±10% more preferred by weight. The relatively large amount of deliverable solubilized in the described emulsion systems in relation to conventional systems, where an approximately 2-3% solubilized deliverable is expected, is a significant and unexpected improvement that may be attributable to the believed layered structures of the formed microemulsion droplets.

[0079] Another believed benefit from the oil-based solution is the ability to form water-core liposomes in addition to the monolayer surfactant bound particles that form the microemulsion in the GI tract. Thus, the previously described zinc and other salts are believed delivered by in situ formed liposomes. The ability of the emulsion system to form water-core liposomes in addition to the surfactant bound particle microemulsion in the GI tract is believed to provide the ability to concurrently deliver alcohol-soluble species, oil-soluble species, and water-soluble deliverables to the tissue of the GI tract. The ability of the oil-based solution to provide such a diverse group of different deliverables with significantly enhanced bioavailability to the bloodstream of a mammal with a single capsule is another significant and unexpected benefit.

[0080] FIG. 5 represents a method 500 of making the composition including the encapsulated oil-based solution. The oil-based solution may optionally include water-soluble deliverables.

[0081] In 510, a solvent solution of alcohol and water is heated to form a heated solvent solution 512. The heated solvent solution 512 preferably includes ethanol and water. However, other alcohols may be used that are compatible with later OIW microemulsion formation in the GI tract and the desired deliverables. The ratio of alcohol to water in the heated solvent solution 512 is preferably from 80:20 to 97:3 on a volume basis, more preferably from 90:10 to 95:5 on a volume basis. The heated solvent solution 512 is preferably heated to a temperature from 65° C. to 78° C., more preferably from 68° C. to 75° C.

[0082] In 520, alcohol-soluble species deliverables and/or optional water-soluble deliverables are combined with the heated solvent solution 512 with stirring to form a heated deliverable mixture 522. Depending on the solubility of deliverable, some deliverables will fully dissolve during this addition, while others may not. For example, a deliverable with the solubility characteristics of berberine, is unlikely to fully dissolve at this stage.

[0083] In 530, the surfactant and resin systems of the emulsion system are combined with the heated deliverable mixture 522 with continued stirring to form a solution 532.

[0084] In 540, the temperature of the solution 532 is increased above 78° C., which is the boiling point of ethanol. Preferably the temperature of the solution 532 is then increased above 100° C., which is the boiling point of water. Preferably, the temperature of the solution 532 does not exceed 120° C. Heating and stirring are continued until the ethanol and water are substantially removed to form a reduced solution 542.

[0085] In 550, the emulsion oil system of the emulsion system including any oil-soluble species deliverables is combined with the reduced solution 542 to form an oil-based solution 552.

[0086] In 560, the oil-based solution 552 is permitted to cool with stirring to room temperature.

[0087] In 570, the oil-based solution 552 is encapsulated with an exterior capsule.

[0088] The following examples are provided to illustrate one or more preferred embodiments of the invention. Numerous variations can be made to the following examples that lie within the scope of the invention.

EXAMPLES

[0089] Example 1: Formation of an oil-based solution including oil-soluble species, alcohol-soluble species, and/or water-soluble deliverables that forms an OIW microemulsion when released into the GI tract.

[0090] The desired alcohol-species and/or water-soluble deliverables were added to a heated water/alcohol solution to at least partially solubilize the deliverables and form a heated deliverable mixture. The surfactant and resin systems of the emulsion system were then added to form a solution. The temperature of the solution was then increased above 100° C. The emulsion-oil system including any oil-soluble species deliverables was then added to the solution. The solution was then allowed to cool to room temperature. Stirring was used throughout until the solution cooled to room temperature. The resulting oil-based solution was then placed into an exterior capsule to form any orally consumable SMEDS.

[0091] Example 2: An oil-based solution including deliverables that forms an OIW microemulsion when released into the GI tract for pain relief.

[0092] The general method of Example 1 was used to combine the following: from 2 to 3 percent by weight phospholipid, from 24 to 30 percent by weight polyethylene glycol derivative, from 8 to 13 percent by weight turmeric oleoresin, from 1 to 2.5 percent by weight propolis, from 12 to 18 percent by weight associating oil, from 23 to 31 percent by weight turmeric oil, from 5 to 9 percent by weight beta caryophyllene, from 1.5 to 4 percent by weight cannabis extract (“hemp oil”), from 3 to 4 percent by weight curcumin extract, preferably constituting greater than 90% by weight curcumin, and from 2 to 4 percent by weight Boswellia serrata. The composition optionally may include from 1 to 3 percent by weight piperine.

[0093] Example 3: An oil-based solution including deliverables that forms an OIW microemulsion when released into the GI tract for balancing microbial load in a mammal.

[0094] The general method of Example 1 was used to combine the following: from 3.2 to 5 percent by weight phospholipid, from 26.3 to 30 percent by weight polyethylene glycol derivative, from 3 to 7 percent by weight turmeric oleoresin, from 2.6 to 4 percent by weight propolis, from 18.2 to 23 percent by weight associating oil, from 11 to 20 percent by weight turmeric oil, from 1 to 5 percent by weight cinnamon oil, from 1 to 5 percent by weight peppermint oil, from 0.2 to 1.3 percent by weight cannabis extracts (“hemp oil”), from 0.3 to 2 percent by weight berberine HCl, from 2 to 5 percent by weight milk thistle extract, from 3 to 7 percent by weight artemisinin, from 0.3 to 2 percent by weight Andrographis, from 2 to 6 percent by weight Boswellia serrata, and from 2 to 4 percent by weight quercetin.

[0095] Example 4: An oil-based solution including deliverables that forms an OIW microemulsion when released into the GI tract for controlling inflammation.

[0096] The general method of Example 1 was used to combine the following: from 1 to 3 percent by weight phospholipid, from 25 to 34 percent by weight polyethylene glycol derivative, from 6 to 10 percent by weight turmeric oleoresin, from 8 to 13 percent by weight associating oil, from 27 to 35 percent by weight turmeric oil, from 2 to 6 percent by weight cinnamon oil, from 7 to 10 percent by weight spearmint oil, from 2 to 5 percent by weight berberine HCl, from 2 to 5 percent by weight milk thistle extract, from 2 to 5 percent by weight resveratrol, from 2 to 5 percent by weight hesperetin, and from 2 to 5 percent by weight quercetin.

[0097] Example 5: An oil-based solution including deliverables that forms an OIW microemulsion when released into the GI tract for supplementing dietary zinc.

[0098] The general method of Example 1 was used to combine the following: from 1 to 3 percent by weight phospholipid, from 25 to 34 percent by weight polyethylene glycol derivative, from 7 to 10 percent by weight propolis, from 22 to 30 percent by weight associating oil, from 10 to 15 percent by weight turmeric oil, from 10 to 15 percent by weight spearmint oil, from 3 to 5 percent by weight zinc acetate, from 2 to 5 percent by weight luteolin, from 2 to 5 percent by weight hesperetin, and from 2 to 5 percent by weight quercetin.

Example 6: Comparative Blood Uptake Rates for Oral Curcumin Delivery Via Capsule

[0099] An oil-based solution delivery system generally in accord with Example 2 was compared to a commercially available purported capsulated emulsion delivery system for curcumin delivery and bioavailability. The commercially available product was stated on its label to be a cellulose soft gel capsule including sunflower lecithin and 400 mg of curcuminoid powder. The commercially available product is believed to also include TPGS and turmeric oil. The commercially available product may or may not include additional ingredients.

[0100] Analysis of the commercially available product determined that an individual capsule included approximately 1 mL of liquid containing 266 mg of curcumin, 76 mg of demethoxycurcumin, and 38 mg of bisdemethoxycurcumin. Performing the same analysis on the encapsulated oil-based solution capsules established 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.

[0101] To provide the same amount of curcumin for accurate uptake performance and bioavailability comparison the following steps were taken. The liquid contents of one and approximately one half of a second of the commercially available capsules was consumed to provide a dose of approximately 400 mg of curcumin, as each capsule was known to contain approximately 266 mg. Thus, one “dose” of the commercially available product included approximately 400 mg of curcumin and had a total encapsulated volume of approximately 1.5 mL. For the oil-based solution capsules, 8 of the capsules were consumed to provide the approximately 400 mg of curcumin, as each capsule was known to contain approximately 50 mg of curcumin. Thus, one “dose” of the oil-based solution included approximately 400 mg of curcumin and had a total encapsulated volume of approximately 6 mL.

[0102] On an empty stomach, a human subject took via mouth one dose of either the commercially available product or the oil-based solution. For each, venous blood samples were collected from the human subject before and after dosing (consumption of capsules) at varying time intervals out to approximately three hours for the oil-based blend and out to approximately eight hours for the commercially available product. Thus, a baseline blood sample was collected prior to consumption of either dose. The collected blood samples were subjected to plasma separation via 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.

[0103] FIG. 6 provides the results from the LC/MS/MS plasma curcumin analysis at the 0, 10, 20, 40, 60, 90, 120, 180, and 480 (commercially available only) minute time intervals. This analysis was directly performed for curcumin, without prior enzyme cleavage of glucuronide. The time after dose consumption by the subject 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 samples is represented on the Y-axis.

[0104] As can be seen in the figure, the commercially available product provided no measurable plasma free curcumin concentration out to 8 hours. In comparison, the oil-based solution provided a free curcumin plasma maximum concentration of 3.14 ng/mL 20 minutes post consumption and maintained a measurable free curcumin plasma concentration past 2 hours. We believe a therapeutically effective dose of free curcumin is approximately 1 ng/mL, which was maintained by the oil-based solution from approximately 10 minutes until approximately 2 hours after consumption.

[0105] It is impossible to compare uptake performance of the oil-based solution with the commercially available product regarding free curcumin bloodstream delivery and bioavailability, as the commercially available product was unable to produce a measurable free curcumin concentration in the plasma. Hence, the commercially available product was incapable of delivering unmetabolized curcumin to the bloodstream of a human subject, while the oil-based solution delivered significant unmetabolized, and thus “free”, curcumin to the bloodstream. A similar result would be expected in other mammals.

[0106] FIG. 7 provides the results from the LC/MS/MS plasma curcumin-glucuronide analysis at the 0, 10, 20, 40, 60, 90, 120, 180, and 480 (commercially available only) minute time intervals. This analysis was directly performed for curcumin-glucuronide. The time after dose consumption by the subject when the blood sample was collected is represented on the X-axis, while the nanograms (ng) of curcumin-glucuronide per milliliter (mL) determined for the plasma samples is represented on the Y-axis. Unlike the analysis of FIG. 4, which determined direct bloodstream delivery of free curcumin, the FIG. 5 analysis determined the concentration of the primary metabolite of curcumin generated in the bloodstream in response to dose consumption for the oil-based solution and for the commercially available product.

[0107] The oil-based solution provided a peak curcumin-glucuronide concentration of approximately 800 ng/mL approximately 1.5 hours after capsule consumption and maintained a plasma concentration above 300 mg/mL from 10 to 180 minutes after capsule consumption. The commercially available product provided a peak curcumin-glucuronide concentration of approximately 68 ng/mL approximately 1.5 hours after capsule consumption, did not produce a meaningful measured concentration until approximately 40 minutes after capsule consumption, and provided an approximately 60 ng/mL concentration between 3 and 8 hours.

[0108] A comparison of metabolized curcumin delivery peak performance shows that the delivery provided by the oil-based solution was approximately twelve times greater, thus more than an order of magnitude greater, than that provided by the commercially available product. From a post-consumption time perspective, the oil-based solution, and the commercially available product, both provided peak bloodstream concentrations of curcumin-glucuronide approximately 1.5 hours after dose consumption. A substantial timing difference between the oil-based solution and the commercially available product was the relatively rapid plasma concentration post-peak decrease of the curcumin-glucuronide provided by the oil-based solution in comparison to the substantially lower, but longer lasting bloodstream curcumin-glucuronide concentration provided by the commercially available product. The constant, low curcumin-glucuronide concentration provided by the commercially available product suggests that the 68 ng/mL plasma concentration for the metabolized curcumin-glucuronide is unlikely to be the byproduct of a therapeutic free curcumin dose.

[0109] An Area Under the Curve (AUC) calculation was performed to determine the total curcumin-glucuronide generated from the oil-based solution in relation to the commercially available product. The AUC values provide a measure of the cumulative amount of curcumin-glucuronide in the bloodstream, thus total exposure across a period of time. By cumulative amount it is meant the total bloodstream available curcumin-glucuronide as metabolized from curcumin until the selected time.

[0110] The plasma curcumin-glucuronide concentration values for the commercially available product where used as the control (denominator) while the plasma curcumin-glucuronide concentration values for the oil-based solution were used as the numerator to determine the AUC bioavailability values. This was possible as both capsules included approximately 400 mg of curcumin. Thus, the AUC values reflect how many more times of curcumin-glucuronide the oil-based solution generated in the bloodstream at a selected time in relation to the commercially available product.

[0111] Table I below provides the calculated results over 3-hours from capsule consumption with estimation due to the slight variability in the withdrawal times of the blood samples.

TABLE-US-00001 TABLE I Oil-Based Solution Time (minutes) Bioavailability Increase 0 0 10 50 20 78.3 40 60.7 60 36.3 90 22.3 120 17.1 180 12.7

[0112] The substantial and rapid generation of metabolized curcumin in the bloodstream by the oil-based solution in relation to the commercially available product is seen during the 10 to 60 minute post-dose time period, with the oil-based solution generating 78 times more metabolized curcumin in the bloodstream after 20-minutes. After 60 minutes, the delivery difference falls, with an average of about 17 times as much being delivered by the oil-based solution in relation to the commercially available product. In combination, these results suggest that the commercially available product fails to form a microemulsion in the GI tract, or at least fails to form a microemulsion that can deliver curcumin to the bloodstream much more effectively than consuming powdered curcumin.

[0113] To provide a clear and more consistent understanding of the specification and claims of this application, the following definitions are provided.

[0114] An oil-soluble species is a species that is insoluble in water and soluble in medium chain triglyceride (MCT) oils at 50 mg/mL and higher, preferably 100 mg/mL and higher. Oil-soluble species are generally soluble in MCT oils at room temperature and are freely or very soluble in MCT oils at temperatures of 70 degrees Celsius and greater. The term “generally soluble in MCT oils at room temperature” is used because some high purity oil-soluble species are sparingly soluble in MCT oils at room temperature, but are freely or very soluble in the MCT oils above 70 degrees Celsius, and once solubilized in the MCT oils at elevated temperature, will remain solubilized at room temperature. Oil-soluble species neither include nor are water. Thus, liquids and solids may exist that technically are soluble in oil, but because they also are soluble in water or not sufficiently soluble in MCT oils are not “oil-soluble species”.

[0115] An alcohol-soluble species is a species that is insoluble in water and has a greater solubility in ethanol than in medium chain triglyceride (MCT) oils. For example, the nonderivatized hormone DHEA is soluble in ethanol up to approximately 150 mg/mL, thus being freely soluble, while having a solubility in MCT oil of only up to approximately 10 mg/mL, thus being only sparingly soluble. Alcohol-soluble species neither include nor are water. Thus, liquids and solids may exist that technically are soluble in alcohol, but because they also are soluble in water or more or equivalently soluble in MCT oils than in ethanol are not “alcohol-soluble species”.

[0116] Phosphatidylcholine (PC) molecules are a subset of the larger set of phospholipids and are commonly used to form liposomes in water. When placed in water without other constituents, PC forms liposomes. In the presence of an oil, the application of sufficient shear forces to the PC liposomes in water can produce monolayer structures, including micelles. PC has a head that is water-soluble and a tail that is much less water-soluble in relation to the head. PC is a neutral lipid, but carries an electric dipole moment of about 10 D between the head and the tail, making the molecule itself polar.

[0117] Tocopheryl polyethylene glycol succinate 1000 (TPGS) is generally considered a surfactant having a non-polar, oil-soluble “Vitamin E” tail and a polar, water-soluble polyethylene glycol head. TPGS is a member of the polyethylene glycol derivatives that also include polysorbate 20, 40, 60, and 80.

[0118] Room temperature and pressure means from 20 to 28 degrees Celsius at approximately 100 kPa.

[0119] Solid means a substance that is not a liquid or a gas at room temperature and pressure. A solid substance may have one of a variety of forms, including a monolithic solid, a powder, a gel, a wax, or a paste.

[0120] Liquid means a substance that is not a solid or a gas at room temperature and pressure. A liquid is an incompressible substance that flows to take on the shape of its container.

[0121] Solutions lack an identifiable interface between the solubilized molecules and the solvent. In solutions, the solubilized molecules are in direct contact with the solvent.

[0122] Solubilized means that the deliverable is in the solution of the droplet. When solubilized, dissociation (thus, liquid separation or solid formation) of the deliverable does not result in droplet average particle diameters in excess of 200 nm as determined by DLS and discussed further below, or by the formation of precipitated crystals of the deliverable visible with the naked eye. Thus, if either average particle diameters more than 200 nm or precipitated crystals visible to the naked eye form, the deliverable is not solubilized in the solution of the droplet. If a deliverable is not solubilized in the solution, it is insoluble in the solution. In many respects, solubility may be thought of as a concentration dependent continuum. For example, the following descriptive terms may be used to express solubility of a solute in a solvent (grams solid/mL of solvent) at 25 degrees Celsius:

TABLE-US-00002 Descriptive Level Parts solvent per 1 part of solute Very Soluble Less than 1 Freely Soluble From 1 to 10 Soluble From 10 to 30 Sparingly Soluble From 30 to 100 Slightly Soluble From 100 to 1000 Very Slightly Soluble From 1000 to 10,000 Insoluble More than 10,000

[0123] Dissociation occurs when a previously solubilized solid or liquid leaves a solution and is no longer in direct contact with a solvent of the solution. Dissociation of solids from the solvent occurs through recrystallization, precipitation, and the like. Dissociation of liquids from the solvent occurs through separation and the formation of a visible meniscus between the solvent and the dissociated liquid.

[0124] Emulsions are mixtures 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 may be macroemulsions, pseudo-emulsions, 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. Pseudo-emulsions are differentiated as solids are present in the emulsion.

[0125] Droplets or liquid particles are formed by the hydrophobic “oil” phase of a 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 a droplet defines the exterior surface of the droplets forming the dispersed oil phase of the microemulsion. The continuous phase of the microemulsion resides exterior to the boundary layer of the droplets, and thus, carries the droplets.

[0126] Microemulsions are thermodynamically stable dispersions of oil in water, with oil being defined as any water-insoluble liquid. Microemulsion are made by simple mixing of the components. Thus, microemulsions spontaneously form 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 of water, oil, and surfactant(s) that is an isotropic and thermodynamically stable system with dispersed domain diameter varying approximately from 1 to 100 nm, usually 10 to 50 nm.” Thus, the droplets of a microemulsion are approximately three orders of magnitude smaller than the droplets of a macroemulsion and are thermodynamically stable.

[0127] A visually clear microemulsion has an average particle diameter of 200 nm and less and lacks precipitated solid crystals visible to the naked eye.

[0128] Continuous phase means the portion of a microemulsion that carries the droplets that include the deliverable. For example, the oil-in-water (OIW) microemulsions (non-polar droplets in polar continuous phase) addressed herein have oil droplets including the deliverable to be delivered carried in a polar, “water” continuous phase. While the words “water” and “oil” are used, the “water” can be any liquid that is more polar than the “oil” (such as a polar oil), and the “oil” can be any liquid that is less polar than the “water. Thus, the terms “polar continuous phase” and “water continuous phase” are synonymous, unless water is specifically being discussed as one of the microemulsion components.

[0129] Average droplet diameter is determined by dynamic light scattering, sometimes referred to as photon correlation spectroscopy. The determination is made between 20 and 25 degrees Celsius. One example of an instrument suitable for average droplet diameter determination is a Nicomp 380 ZLS particle sizer as available from Particle Sizing Systems, Port Richey, Fla. 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 the droplets move due to Brownian motion the light scattered from two or more droplets constructively or destructively interferes at the detector. By calculating the autocorrelation function of the light intensity and assuming a droplet distribution, it is possible to determine the sizes of droplets from 1 nm to 5 micrometers (um). The instrument is also capable of measuring the Zeta potential of droplets.

[0130] Ingestible means capable of being ingested through the mouth by a living mammal while edible means fit to be eaten, thus in contrast to being 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, adulterants, toxins, residual solvents, and pesticides.

[0131] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range, 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 limits, ranges excluding either or both included limits are also included in the invention.

[0132] While various aspects of the invention are 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. Accordingly, the invention is not to be restricted except by the attached claims and their equivalents.