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AU2016324349A1 - Ubiquinone and ubiquinol compositions, and methods relating thereto - Google Patents

Ubiquinone and ubiquinol compositions, and methods relating thereto Download PDF

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AU2016324349A1
AU2016324349A1 AU2016324349A AU2016324349A AU2016324349A1 AU 2016324349 A1 AU2016324349 A1 AU 2016324349A1 AU 2016324349 A AU2016324349 A AU 2016324349A AU 2016324349 A AU2016324349 A AU 2016324349A AU 2016324349 A1 AU2016324349 A1 AU 2016324349A1
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oil
water
ubiquinone
soluble composition
ubiquinol
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George KOKKINIS
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Pharmako Biotechnologies Pty Ltd
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Pharmako Biotechnologies Pty Ltd
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Priority claimed from AU2015903795A external-priority patent/AU2015903795A0/en
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Priority to AU2018100110A priority Critical patent/AU2018100110A4/en
Publication of AU2016324349A1 publication Critical patent/AU2016324349A1/en
Priority to AU2022202308A priority patent/AU2022202308A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

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  • Life Sciences & Earth Sciences (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention provides an advantageous formulation of ubiquinone (CoQ10) and/or ubiquinol with greater bioavailability, thereby allowing for high concentrations of CoQ

Description

The present invention provides an advantageous formulation of ubiquinone (CoQlO) and/or ubiquinol with greater bioavailability, thereby allowing for high concentrations of CoQio and/or ubiquinol to be absorbed with lesser volumes of the desired lipophilic substance in the composition. The present invention provides this through a water- soluble composition comprising at least one bioactive lipophilic substance selected from one or more of ubiquinone, ubiquinol and semi-ubiquinone and micelle-promoting agents comprising one or more of carrier oils, solvents, emulsifiers, antioxidants and excipients.
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UBIQUINONE AND UBIOUINOL COMPOSITIONS, AND METHODS
RELATING THERETO
This document claims priority from AU 2015903795 and AU 2016901373, the entire contents of which are hereby incorporated by reference in their entirety.
TECHNICAL FIELD
The present invention generally relates to water-soluble compositions of bioactive lipophilic compounds, particularly relating to water soluble compositions of ubiquinone or ubiquinol, to compounds useful for the preparation of such compositions, to methods of preparing such compounds and compositions, to the use of such compositions as therapeutics, complementary medicines, cosmetics, dietary supplements, sports supplements and functional foods, and for the purpose of increasing the bioavailability of such bioactive lipophilic compounds.
BACKGROUND
Many bioactive compounds are highly lipophilic (hydrophobic), meaning that they are soluble in lipids (oils) and some organic solvents, while being substantially insoluble or only partially soluble in water.
The lack of solubility of a bioactive compound in aqueous media is an important factor limiting its therapeutic or clinical applications, and particularly making efficient administration of the compound to a patient difficult. When administered in the form of an oil solution or some kind of water and/or oil suspension or emulsion, lipophilic compounds typically show a poor bioavailability, meaning a low concentration and a long build-up time of the compound in the systemic circulation.
Bioactive lipophilic compounds in need of solubilization belong to various therapeutic categories, such as vitamins, antibiotics, free radical scavengers, immunosuppressants etc. One particularly important bioactive lipophilic compound is coenzyme Qio (CoQio), which is a natural compound whose therapeutic potential has been recently recognized and it is also of great interest to cosmetic industry, since it can be included into
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PCT/AU2016/050870 cosmetic preparations as an agent slowing down natural skin ageing processes, amongst other benefits.
C0Q10 has as its basic core unit a benzoquinone ring. This central ring structure exists in chemical equilibrium with its alternate redox forms; the partially-reduced form oxybenzoquinol, and the fully-reduced form of benzoquinol. The overall ubiquinone structure therefore exists in chemical equilibrium with its reduced forms; semiubiquinone (also known as semiquinone) and ubiquinol, respectively.
Semiquinone (the partially-reduced form of C0Q10) is a free radical, chemically unstable and thus unsuitable for clinical or cosmetic applications due to its low chemical stability. However, the fully-reduced form of C0Q10 (ubiquinol) is stable enough to see clinical or cosmetic application as an alternative to C0Q10, allowing the compound to be converted into C0Q10 by the body as needed. However, ubiquinol faces the same drawbacks as C0Q10 in that it also possesses a low level of absorption because, like C0Q10, it is lipophilic.
The biological activity of C0Q10 is believed to be linked to its ability to act as an antioxidant and free radical scavenger protecting integrity of cell membranes and to offset the inability of diseased cells to manufacture sufficient energy for cellular repair, by stimulating mitochondrial respiration and production of ATP. For effectiveness in both clinical and cosmetic applications, preparations of Coenzyme Qio with high bioavailability and solubility in aqueous media are usually required.
It is well known that the absorptivity of C0Q10 by oral administration is low due to its low solubility in water. C0Q10 is absorbed like fat-soluble vitamins into the living body mainly through lymph vessels and particularly through the small intestine. Since the amount which can be absorbed is very limited, the bioavailability of C0Q10 (ubiquinone) or ubiquinol is low.
The physiological process conducted by the body in an attempt to absorb C0Q10, ubiquinol and other lipophilic compounds of value to human physiology is known as
WO 2017/045034
PCT/AU2016/050870 micelle formation. Through interaction with chemicals carried in bile, the lipophilic species can be 'enveloped' in a micelle. The chemicals act as surfactants and are molecules formed from a long lipophilic tail with a hydrophilic head. A typical micelle in aqueous solution forms an aggregate with the hydrophilic head regions in contact with surrounding solvent, sequestering the hydrophobic single-tail regions in the micelle centre. The micelle can then be dispersed in the bulk solvent by virtue of the hydrophilic head groups that form the outer layer of the micelle.
Many attempts have been made to improve the bioabsorptivity and the stability of fatsoluble compositions that are minimally soluble in water. These compounds are dissolved in pharmaceutically acceptable solvents such as vegetable oils, e.g. sesame oil, peanut oil, olive oil, soybean oil, cottonseed oil and corn oil, or in animal oils, e.g. fish liver oil, or dispersed and emulsified in an aqueous liquid with various additives such as an emulsifier, a dispersing agent or a surfactant.
Previous approaches have also been made to provide water soluble compositions of ubiquinone. For example, International PCT patent publication no. WO 1996017626 discloses water soluble ubiquinone compositions and prodrugs, methods of their delivery, and methods of their use in the amelioration of apoptosis. However, these water soluble ubiquinone prodrugs comprise substituted functional groups in at least one of positions Cl and C4 of the molecule with the substituent independently selected from a solubilizing moiety and a targeting moiety.
United States patent no. 7,094,804 discloses a water soluble, essentially water-free ubiquinone concentrate comprising ubiquinone, a light oil containing triglycerides, and an emulsifier with an HLB value between 9 and 16, in which the emulsifier is a polysorbate and is present in a content of at least about 73 weight % of the total weight of the concentrate.
United States patent no. 7,026,361 discloses a composition comprising ubiquinone having superior dispersion-stability in an aqueous solution and high bioavailability. The ubiquinone(s) is dispersed and emulsified in an aqueous solution of a water-soluble
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PCT/AU2016/050870 material in the presence of an organic acid(s) to form a protective colloid, the average particle size of the suspended particles being not more than 5pm. The liquid composition can be adsorbed in or carried on an excipient, or dried.
As shown by the prior art discussed above, the use of micelles to allow compounds that are normally insoluble (in the solvent being used) to dissolve is well known. This occurs because the insoluble species can be incorporated into the micelle core, which is itself solubilized in the bulk solvent by virtue of the micelle head groups' favourable interactions with the solvent species. A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid.
Indeed, the human body itself utilizes micelles in the small intestine so as to absorb fatty substances. The absorption of life-essential nutrients, such as vitamins, minerals, trace elements is performed by the mucous membrane cells in the small intestine. The cells of the small intestine, for example, are covered with a microscopically fine water film so that the cells can directly absorb only such substances that are soluble in this water film. The bio-availability of water soluble substances, such as sugar, salts, and certain vitamins (for instance vitamin C) is therefore at an optimum.
However, fat soluble substances - such as commonly available coenzyme Qio and ubiquinol - are unable to penetrate the water film, but instead must be pre-treated in the small intestine. This occurs by means of micelle formation with the aid of bile salts. This micelle formation step is the reason that the absorption of fatty substances cannot occur as easily as for water soluble substances. This disadvantage is evident from the following facts:
• The micelle formation in the small intestine occurs at a time delay, or after the release of bile secretion (bile juice) and enzymes of the pancreas.
• The micelle formation that is considered the prerequisite for fat digestion absorb only part of the fatty substances received with food.
• During the comparatively long lasting formation and eating of micelles in the small intestine, the rest of the digestive processes (transport, etc.) continue
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PCT/AU2016/050870 without interruption so that the micelles formed, which contain the fat particles, are discharged largely undigested.
The facts described explain the very low bio-availability of fat soluble substances, which is at approximately 25 percent where no further treatment is made to the fatsoluble substance. To the consumer this means that he/she discharges a large part of the fat soluble substances absorbed with food or nutritional supplements, such as fat soluble coenzyme Qio capsules or similarly fat-soluble ubiquinol capsules, unutilized. Furthermore, some people are unable to absorb fat soluble substances due to certain metabolic diseases—unless they are present in water soluble form. The formation of micelles is absolutely crucial, and an indispensable prerequisite for the digestion, or for the cellular lipid resorption. In nature, the formation of micelles occurs either with the aid of bile salts and enzymes in the small intestine.
As discussed above, there are certain people who, due to medical reasons, cannot form micelles, even further lowering their body's absorption of essential lipophilic species. Further, old age is also known to reduce the ability of a person's digestive tract to take up a range of important chemicals, including fatty acids or other lipophilic compounds enclosed in micelles.
Therefore it would be advantageous to provide optimised water-soluble compositions of bioactive lipophilic compounds, particularly relating to water soluble ubiquinone composition. This would overcome at least some of the disadvantages of previously known approaches in this field, or would provide a useful alternative.
DISCLOSURE OF INVENTION
These and other advantages are met with the present invention. An embodiment of the present invention provides a water-soluble composition comprising at least one bioactive lipophilic substance selected from one or more of ubiquinone, ubiquinol and semi-ubiquinone and micelle-promoting agents comprising one or more of carrier oils, solvents, emulsifiers, antioxidants and excipients.
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In an embodiment of the present invention, the carrier oil may comprise one or more of medium chain triglycerides, long-chain triglycerides, caprylic and/or capric triglycerides, coconut oil, corn oil, cottonseed oil, olive oil, macadamia nut oil, sesame oil, soybean oil, peanut oil, castor oil and oleic acid.
In an embodiment of the present invention, the solvent may comprise one or more of citrus oil, ethanol, ethyl oleate, glycerine, glyceryl mono-oleate, limonene, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 and propylene glycol.
In an embodiment of the present invention, the emulsifier may comprise one or more of hydrogenated castor oil, lecithin, macrogolglycerol hydroxystearate, oat oil polar lipids, phosphatidylcholine, poloxamers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 20, polysorbate 60, polysorbate 80 and polyglycerol esters of fatty acids.
In an embodiment of the present invention, the antioxidant may comprise from one or more of ascorbyl palmitate, d-alpha-tocopherol, dl-alpha-tocopherol, d-alphaTocopheryl acetate, dl-alpha-Tocopheryl acetate, d-alpha-Tocopheryl acid succinate, dl-alpha-Tocopheryl acid succinate, mixed tocopherols, Olive polyphenols and Algal polyphenols.
In an embodiment of the present invention, the excipient may comprise from Colloidal silica, Corn starch, Hydroxypropylmethylcellulose (HPMC), Maltodextrin, Magnesium stearate, Magnesium hydroxide, Microcrystalline cellulose, dextrin, sorbitol, mannitol and Trehalose.
In an embodiment of the present invention, the composition may comprise Ubiquinone or Ubiquinol, from about 10 wt. % to about 85.5 wt. %; a carrier Oil, from about 4.5 wt. % to about 70 wt. %; a solvent, from about 1.0 wt. % to about 20 wt. % Emulsifier, from about 7.5 wt. % to about 30 wt. %; and an antioxidant, from about 0.005 wt. % to about 0.01 wt. %.
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A water-soluble composition of claim 1, further comprising an excipient selected from Colloidal silica, Corn starch, Hydroxypropylmethylcellulose (HPMC), Maltodextrin, Magnesium stearate, Magnesium hydroxide, Microcrystalline cellulose, dextrin, sorbitol, mannitol and Trehalose.
In an embodiment of the present invention, the composition may comprise Ubiquinoneor Ubiquinol, from about 5 wt. % to about 66.5 wt. %; a carrier oil, from about 2.5 wt. % to about 45 wt. %; a solvent, from about 1.25 wt. % to about 10 wt. %; an emulsifier, from about 3.75 wt. % to about 15 wt. %; an antioxidant, from about 0.005 wt. % to about 0.01 wt. %; and an excipient, to 100 wt. %
A water-soluble composition of claim 1 wherein the absorption of ubiquinone and/or ubiquinol is improved by at least four times.
A water-soluble composition of claim 1 wherein upon dissolution at a concentration of 4g/L of the composition in an aqueous solvent, the components form a population of micelles wherein the population mean micelle diameter is less than 20 micrometres and substantially all of the population of micelles havea diameter of less than 100 micrometres.
In an embodiment of the present invention, the percentage composition of the micellepromoting mixture is developed so as to ensure that the mean diameter of the resulting micelles is under 30 microns. In an embodiment of the present invention, more than 20% of the total population of micelles may have a diameter of less than 10 microns and substantially all of the micelles may have a diameter of less than 100 microns.
In an embodiment, the bioavailability of the lipophilic bioactive compound may be improved by the use of the present invention by more than 400% relative to traditional means of delivering the bioactive lipophilic substance.
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In an embodiment, the composition may be chemically stable at ambient temperature and humidity for 12 months.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the stability of a composition of the present invention at ambient conditions over a period of twelve months.
Figure 2 is a graph showing comparison data between the concentration of CoQio in the blood plasma of a sample group over a period of twenty-four hours following administration of a typical CoQio capsule or a Micelle-prepared CoQio capsule, measured relative to the baseline concentration level of CoQio in blood plasma.
Figure 3 is a graph showing the population size analysis of micelles formed upon dissolution of 1 gram of the current invention in 250 mL of water.
Figure 4 is a graph showing the volume size analysis of micelles formed upon dissolution of 1 gram of the current invention in 250 mL of water.
BEST MODE FOR CARRYING OUT THE INVENTION
An aspect of the present invention provides an advantageous formulation of ubiquinone (CoQio) and/or ubiquinol with greater bioavailability, thereby allowing for high concentrations of CoQio and/or ubiquinol to be absorbed with lesser volumes of the desired lipophilic substance in the composition. As both ubiquinol and CoQio are non-water soluble compounds, in order for the composition of the present invention to be water soluble it is incorporated into micelle cores (also known as protective colloids), which are solubilized in the bulk aqueous solvent by virtue of the micelle head groups' favourable interactions with the aqueous environment.
The micelle-shaped units that are formed when the product is ingested and subsequently dissolved in the gastric fluids, which contain the lipids (such as CoQio or ubiquinol), are stable with respect to temperature and acid effects in the stomach. They reach the small intestine unharmed, attach themselves to the mucous membrane
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PCT/AU2016/050870 cells across their entire surfaces, and can be easily absorbed, leading to a therefore minimum four times improved bioavailability, into the blood plasma, than is the case for a normal fat digestion.
In a first embodiment of the present invention there is provided a composition formed as an admixture of one or more of ubiquinone and ubiquinol and one or more micellepromoting agents. The ubiquinone/ubiquinol may further comprise trace quantities of semi-ubiquinone.
When the composition of the present invention is added to water - or a solution largely comprising water, such as milk or fruit juice - the ubiquinone/ubiquinol and the micelle-promoting agents will interact to form a population of micelles. This process can also occur on contact between the composition of the present invention and the aqueous environment of the stomach, if the composition is taken without being added to water or similar (for example, in a pill or gel form). These micelles are stable with respect to temperature and acid effects in the stomach and reach the small intestine undamaged, attach themselves to the mucous membrane cells located across the inner surface of the small intestine, and can be easily absorbed, thereby leading to higher bio-availability than is the case for a normal uptake of ubiquinone and/or ubiquinol by the body without the additional micelle-promoting agents.
The micelle-promoting agents comprise a mixture of one or more of a carrier oil, a solvent, an emulsifier and an antioxidant. In one embodiment of the present invention, the percentage composition of the micelle-promoting agents is developed so as to ensure that the mean diameter of the resulting micelles is under 30 microns. In an embodiment, more than 20% of the total population of micelles has a diameter of less than 10 microns. In a further embodiment, substantially all of the micelles have a diameter of less than 100 microns.
The carrier oil is selected from one or more of medium chain triglycerides, long-chain triglycerides, caprylic and/or capric triglycerides, coconut oil, corn oil, cottonseed oil, olive oil, macadamia nut oil, sesame oil, soybean oil, peanut oil, castor oil, fish oil and oleic acid.
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The solvent is selected from one or more of citrus oil, ethanol, ethyl oleate, glycerine, glyceryl mono-oleate, limonene, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 and propylene glycol.
The emulsifier is selected from one or more of hydrogenated castor oil, lecithin, macrogolglycerol hydroxystearate, oat oil polar lipids, phosphatidylcholine, poloxamers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 20, polysorbate 60, polysorbate 80 and polyglycerol esters of fatty acids.
The antioxidant is selected from one or more of ascorbyl palmitate, d-alphatocopherol, dl-alpha-tocopherol, d-alpha-Tocopheryl acetate, dl-alpha-Tocopheryl acetate, d-alpha-Tocopheryl acid succinate, dl-alpha-Tocopheryl acid succinate, mixed tocopherols, Olive polyphenols and Algal polyphenols.
Process
For the preparation of the composition of this invention, ubiquinone and/or ubiquinol is first dissolved into the carrier oil(s) and solvent(s). The emulsifier(s) and antioxidant(s) system are then added. These steps are carried out at a temperature of about 30-45°C. It is also possible to directly add ubiquinone powders into the preheated solution, in which the ubiquinone is melted and dispersed. This method is advantageous because it increases the process efficiency and can decrease the loss of raw material.
According to an embodiment of the invention, a solid composition can be produced by allowing the ubiquinone-containing composition to be adsorbed in or carried on an excipient. Any type of excipients capable of adsorbing or carrying the liquid composition and acceptable for the oral administration can be used for this purpose.
Moreover, the functionality and characteristics of the solid composition can be changed according to the selection of the excipient. For example, if sorbitol, dextrin and/or mannitol are used as an excipient, the solid composition becomes soluble in water. If
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PCT/AU2016/050870 lactose, cornstarch, sorbitol, and/or crystalline cellulose are used, the solid composition acquires plasticity and can be directly compacted into tablet. Moreover, chewable tablets, differentially soluble tablets, foaming tablets and the like can be prepared accordingly. In other embodiments of the invention, the composition can be used in the preparation of liquids, pastes and emulsions.
An alternative embodiment of the invention is as above, wherein the desired compound for delivery is a mixture of both ubiquinol and ubiquinone. There may additionally be trace levels of semi-ubiquinone.
Example 1 - Liquid/Paste Delivery
The preferable compositional range of the present invention is shown in the table below for all embodiments of the composition of the present invention intended for delivery and consumption in a liquid, gel, liquid/gel capsule form or similar:
Component Composition
Ubiquinone/Ubiquinol 10 - 85.5 wt. %
Carrier Oil 4.5-70 wt. %
Solvent 1.0-20 wt. %
Emulsifier 7.5 - 30 wt. %
Antioxidant 0.005 - 0.01 wt. %
Table 1: Compositions of Ubiquinone and/or Ubiquinol for Liquid/Paste type delivery
The compositions produced as mentioned above, either by directly drying it or by adsorbing it in an excipient or by carrying it on an excipient, have been dispersed and emulsified at the time of forming the protective colloid with an average particle size not more than 5 pm, preferably not more than 1 pm. And therefore they are promptly re-dispersed to fine particles when administered.
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Example 2 - Solid Delivery
According to a further embodiment of the invention, a solid composition can be produced by allowing the active-ingredient-containing composition to be adsorbed in or carried on an excipient. Any type of excipient capable of adsorbing or carrying the liquid composition and acceptable for the oral administration can be used for this purpose. The excipient is selected from one or more of colloidal silica, corn starch, hydroxypropylmethylcellulose (HPMC), maltodextrin, magnesium stearate, magnesium hydroxide, microcrystalline cellulose, dextrin, sorbitol, mannitol and trehalose.
The preferable compositional range of the present invention is shown in the table below for all embodiments of the composition of the present invention intended for delivery in a solid form, such as powders for dissolution or other purposes, hard tablets or similar:
Component Composition
Ubiquinone/Ubiquinol 5 - 66.5 wt. %
Carrier Oil 2.5 - 45 wt. %
Solvent 1.25 - 10 wt. %
Emulsifier 3.75 - 15 wt. %
Antioxidant 0.005 - 0.01 wt. %
Powder 30 - 90 wt. %
Table 2: Compositions of Ubiquinone and/or Ubiquinol for Solid-type delivery
Stability
Compositions produced by the above processes are stable under ambient storage conditions. The table below depicts the actual results of stability testing conducted on a formulation manufactured by the process of the present invention.
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Test date 11/6/15 13/8/15 20/1/16 8/6/16
Time (months) 0 3 6 12
CoQio Assay (wt.%) 20.04 22.71 20.34 23.9
Table 3: Stability test results for C0Q10 lipid based drug delivery system using methods and ingredients described in this invention.
As shown by the drawings, the stability of the composition of the present invention is further shown in Figure 1, which is a graphical representation of the information in Table 3. As Table 3 and Figure 1 show, the formulation of the present invention is stable in conditions as would be typically encountered by supplements and medications kept in ambient-temperature locations. Therefore, the composition of the present invention does not require specialised storage facilities for long-term storage. This provides industry-level and consumer-level benefit in that a medicament or supplement comprising the composition of the present invention will not rapidly degrade.
Pharmacokinetics
A comparative, controlled (parallel design) single-dose pharmacokinetic study was conducted with random assignment of subjects of both sexes. The protocol was approved by the Human Research Ethics Committee at the National Institute of Integrative Medicine in Hawthorn, Victoria, and informed consent was obtained from all of the subjects.
Two groups (nl=9, n2=10) of clinically healthy males and females (9 males, 10 females), between the ages of 18 to 50 years, participated in the study. Subjects were selected in accordance with the inclusion/exclusion criteria listed below. At the beginning of the study, the subjects were informed of the study, its aims and its execution. The data was acquired and stored in anonymous form.
Micelle CoQio: formulation comprising the composition of the present invention and containing the specified ingredients with 150 mg CoQio per dose.
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Standard CoQio: Control with 150 mg CoQio per dose. Product B is a commercially available formula and is the bestselling CoQio formulation, in its category, in Australia.
The subjects were randomized to receive 150 mg of CoQio by either taking one Product A dose or one Product B dose (Standard Qio preparation). The study preparations were given in the morning before breakfast on an empty stomach. The taking of blood samples and mealtimes occurred at predetermined regular time intervals. The same food was eaten by all participants and at the same time.
Samples were taken at 2 sites approximately 1 month apart. 4 participants in Brisbane and 15 participants in Sydney. All followed the same dosing and testing protocol, however only the Brisbane participants completed the 7.5 and 24 hour sample. Samples were collected at Medlab, Sydney and QML in Brisbane in a Lithium Heparin tube, centrifuged, wrapped in foil and frozen for transport Health Scope for analysis. Plasma concentrations of CoQio were determined by CHarom system - HPLC using a commercial Qio standard. All data was analysed using GraphPad Prism 6 software. The CoQio baseline levels, at time zero, were evaluated for statistical difference with a standard t-test for variability of means.
Pharmacokinetic parameters were assessed using the area under the observed concentration-time curve above baseline (AUC0-24h), the graph of which is shown in Figure 2. The observed maximum plasma concentration above baseline (Delta Cmax) was calculated for each individual subject and then average change was calculated. The AUC was calculated by Prism using the trapezoid rule. Statistical significance was indicated by a probability level of P<0.05. The CoQio baseline levels between the two groups were similar (no statistical significant difference observed, P=0.31).
After supplementation with CoQio both groups experienced significant increase in plasma levels. Maximum concentration was observed at between 3.5 and 6 hours. The highest DeltaCmax and Cmax were seen in the Micelle CoQio group. The plasma concentration of CoQio in that of the Micelle group remained well above that of the
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PCT/AU2016/050870 group that had consumed the standard CoQio over the duration of the study. The DeltaCmax for Product A CoQio and Product B were statistically different (p=0.009). The difference in AUC(o-24h), the bioavailability of Product A CoQio to Product B was 460%.
Micelle CoQio Standard CoQio
Baseline (pmol/ml) 1120 1170
Cmax (pmol/ml) 1991 1449
Delta Cmax (pmol/ml) 871 345
Tmax 3.5 hours 6 hours
AUC(0-24h) (pmol/hr) 8227 1784
Table 4: Pharmacokinetic parameters
As Table 4 above and the graph in Figure 2 shows, the composition of the present invention allows for a much higher bioavailability as represented by the respective AUC(o-24h) values. This shows that the composition of the present invention is advantageous in provision of bioactive lipids such as ubiquinol and ubiquinone.
Micelle Size
Pop. Stats Vol. Stats
Mean 17.32pm 42.9pm
S.Deviation 12.81pm 22.08pm
Median 16.17pm 39.18pm
Mode 0.5pm 33.86pm
DIO 2.96pm 22.04pm
D50 15.9pm 39.27pm
D90 35.37pm 69.1pm
% < lOpm 28.05% 0.4%
Table 5: Micelle Size Statistics
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With reference to Figure 3 and table 5, the micelles formed using one gram of the formulation detailed in Table 1 above in 250 ml water had a mean diameter of 17 microns and 27% of the total population was under 10 microns in size. As Figure 3 shows, there was an initial spike of very-low-size micelles, a lowered number of micelles of slightly larger diameter and then a spike in micelle population at increased sizes, peaking close to the mean micelle diameter of 17 microns. Substantially all of the micelle population was within the micron range and under 100 microns, with only trace numbers of the micelle population in the over-100 micron range.
Figure 4 shows the volume statistics of the same mixture, which are also contained in Table 5, above. The volume mean is calculated as 42.9 micrometres, with 90% of the micelle volume with a diameter of less than 70 micrometres.
It is known that micelle size has an inverse effect on the bio-absorption of the micelle and contained bioactive lipids. In general, as a micelle population's average diameter decreases, the ability of said micelles to pass into the bloodstream of a human increases. Therefore, the present invention is advantageous in that it offers the ability to produce a population of micelles with an average diameter well below 100 micrometres. This improves uptake of the bioactive compound such as CoQio or ubiquinol, increasing the overall bioavailability.
Dietary Requirements and the Food Effect
In the case of some drugs or bioactive compounds, the method of consumption frequently requires that the drug/bioactive compound be administered following a meal, so as to ensure that the necessary biological functions (such as provision of bilial secretions) are activated in order to induce uptake of the compound by the body. This is due to the hydrophobic nature of many of these compounds, requiring fats and other micelle-forming compounds in order to properly solubilise in the gastrointestinal tract and be absorbed. The timing, volume, temperature, calorific content and nutrient composition of a particular food, along with accompanying fluid ingestion, may impact the pharmacokinetics of a bioactive compound and is often known as the food effect.
WO 2017/045034
PCT/AU2016/050870
An advantage of the present invention is in the elimination or limitation of the food effect during the consumption of compositions of the present invention. This promotes flexibility, enabling it to be applicable across a greater range of people who may have different dietary needs, restrictions or habits and thus different compatibilities with various drugs or bioactive compounds.
While the invention has been described with reference to preferred embodiments above, it will be appreciated by those skilled in the art that it is not limited to those embodiments, but may be embodied in many other forms.
In this specification, unless the context clearly indicates otherwise, the word comprising is not intended to have the exclusive meaning of the word such as consisting only of, but rather has the non-exclusive meaning, in the sense of including at least. The same applies, with corresponding grammatical changes, to other forms of the word such as comprise, etc.
INDUSTRIAL APPLICABILITY
The present invention can be utilised in relation to compounds and compositions for use as therapeutics, complementary medicines, cosmetics, dietary supplements, sports supplements and functional foods, and for the purpose of increasing the bioavailability of such bioactive lipophilic compounds.
In particular, the water-soluble formulations of Coenzyme Qio and its fully-reduced form of ubiquinol having high bioavailability and solubility of the present invention are effective in clinical, therapeutic, cosmetic, dietary supplements, sports supplements and functional foods applications.
WO 2017/045034
PCT/AU2016/050870

Claims (11)

  1. CLAIMS:
    1. A water-soluble composition comprising at least one bioactive lipophilic substance selected from one or more of ubiquinone and ubiquinol and micelle-promoting agents comprising one or more of carrier oils, solvents, emulsifiers and antioxidants.
  2. 2. A water-soluble composition according to claim 1 wherein the carrier oil is selected from one or more of medium chain triglycerides, long-chain triglycerides, caprylic and/or capric triglycerides, coconut oil, corn oil, cottonseed oil, olive oil, sesame oil, soybean oil, peanut oil, castor oil and oleic acid.
  3. 3. A water-soluble composition according to claim 1 wherein the solvent is selected from one or more of citrus oil, ethanol, ethyl oleate, glycerine, glyceryl monooleate, limonene, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 and propylene glycol.
  4. 4. A water-soluble composition according to claim 1 wherein the emulsifier is selected from one or more of hydrogenated castor oil, lecithin, macrogolglycerol hydroxystearate, oat oil polar lipids, phosphatidulcholine, poloxamers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 20, polysorbate 60, polysorbate 80 and polyglycerol esters of fatty acids.
  5. 5. A water-soluble composition according to claim 1 wherein the antioxidant is selected from one or more of ascorbyl palmitate, d-alpha-tocopherol, dl-alphatocopherol, d-alpha-Tocopheryl acetate, dl-alpha-Tocopheryl acetate, d-alphaTocopheryl acid succinate, dl-alpha-Tocopheryl acid succinate, Olive polyphenols and Algal polyphenols.
  6. 6. A water soluble composition according to claim 1, comprising:
    Ubiquinone/Ubiquinol, from about 10 wt. % to about 85.5 wt. %
    Carrier Oil, from about 4.5 wt. % to about 70 wt. %
    WO 2017/045034
    PCT/AU2016/050870
    Solvent, from about 1.0 wt. % to about 20 wt. %
    Emulsifier, from about 7.5 wt. % to about 30 wt. %
    Antioxidant, from about 0.005 wt. % to about 0.01 wt. %
  7. 7. A water-soluble composition of claim 1, further comprising an excipient selected from Colloidal silica, Corn starch, Hydroxypropylmethylcellulose (HPMC), Maltodextrin, Magnesium stearate, Magnesium hydroxide, Microcrystalline cellulose, dextrin, sorbitol, mannitol and Trehalose.
  8. 8. A water soluble composition according to claim 7, comprising:
    Ubiquinone/Ubiquinol, from about 5 wt. % to about 66.5 wt. %
    Carrier Oil, from about 2.5 wt. % to about 45 wt. %
    Solvent, from about 1.25 wt. % to about 10 wt. %
    Emulsifier, from about 3.75 wt. % to about 15 wt. %
    Antioxidant, from about 0.005 wt. % to about 0.01 wt. %
    Excipient, to 100 wt. %
  9. 9. A water-soluble composition of claim 1 wherein the absorption of ubiquinone and/or ubiquinol is improved by at least four times.
  10. 10. A water-soluble composition of claim 1 wherein upon dissolution at a concentration of 4g/L of the composition in an aqueous solvent, the components form a population of micelles wherein the population mean micelle diameter is less than 20 micrometres and substantially all of the population of micelles havea diameter of less than 100 micrometres.
  11. 11. A water-soluble composition of claim 1 which is chemically stable at ambient temperature and humidity for 12 months.
    WO 2017/045034
    PCT/AU2016/050870
    1/2
    CoQlO Stability
    Figure 1
    Figure 2
    WO 2017/045034
    PCT/AU2016/050870
    25002/2
    Vofume {%} Population
    2000 5
    1500 5
    1000 5
    500
    8£ Oi PojaK&sSioo % 1
    100
    150 200
    Figure 3
    250
    300
    350
    30000
    2S000
    20000
    15000
    10000
    5003
    Cumufative Popuiatton
    100
    HO
    Figure 4
    2M
    300 iso'
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