Patent Description:
As a tumour grows, blood supply to the cancer cells can become inadequate due to poor vasculature supply, leading to low or irregular oxygen delivery and tumour hypoxia. Normally cells would die under hypoxic conditions. However, cancer cells can become adapted to the hypoxic environment by mutation. Such tissue hypoxia is a common feature of solid tumours and the cells in these hypoxic regions can be resistant to both radiotherapy and chemotherapy. There has been an increasing realization that effective anti-cancer therapy could exploit this tissue state to help combat the disease. In particular, one method of exploiting tumour hypoxia in anti-cancer therapy is to deliver oxygen locally to the hypoxic tumour together with chemotherapy, radiotherapy, photodynamic or sonodynamic therapy. Such therapies have been investigated by the intravenous injection of oxygen absorbing liquids (http://www. nuvoxpharma. However, such liquids use perfluorocarbons which pose a potential environmental and toxicity risk.

Low oxygen levels in muscle tissue is also recognized as a limiting factor in muscle function, such as muscle endurance and recovery. Therefore, the ability to manage the oxygen levels by delivery of oxygen to muscle tissue would provide an advantage to muscle function, for example in an athlete.

US patent application no. <CIT> describes a granular jelly beverage for medication used for taking crude drugs and/or herbal medicines.

An aim of the present invention is to provide an improved method of oxygen delivery to hypoxic tumours for treatment, or to tissue such as muscle for improved function.

According to a first aspect of the invention, there is provided a beverage composition in accordance with claim <NUM> herein.

Described here is a beverage composition comprising:.

The invention advantageously provides a drinkable formulation capable of increased stability of oxygen in suspension compared with existing microbubble formulations (intended for use as artificial respiration aids). This reduces the need for there being a very short period between preparing the drink and consuming it and improves the efficiency with which oxygen can be absorbed from the digestive tract into the blood stream and surrounding tissue. Enabling oral administration (as opposed to intravenous injection) reduces the risk of infection for hospital patients and greatly increases the range of uses of the product for consumer applications. The composition is also suitable for drinking, where the taste and texture are palatable, and it non-toxic, whilst also delivering sufficiently stable oxygen bubbles.

The term "drinkable" used herein is understood to mean that the composition is non-toxic and safe to drink for mammals, such as humans. For example, a drinkable composition may be consumed in reasonable quantities without negative health consequences.

The term "beverage" used herein is understood to mean a liquid composition intended to be consumed as a drink.

The surfactant may be provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v). The surfactant may be provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v). The surfactant may be provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v). In one embodiment the surfactant is provided in an amount of about <NUM> % (v/v).

In one description, the surfactant may comprise amphipathic surfactant molecules. The surfactant may comprise phospholipids. In one embodiment, the surfactant consists of, or comprises, lecithin. The lecithin may be purified lecithin, for example by a metal catalyst. The surfactant may comprise phospholipids purified from lecithin. Purified lecitihin may consist of Distearoyl-sn-glycero-<NUM>-phosphocholine (DSPC). In one embodiment, the surfactant comprises or consists of Distearoyl-sn-glycero-<NUM>-phosphocholine (DSPC). The surfactant may comprise phosphatidylcholine and/or phosphatidylethanolamine. The surfactant may consist of phosphatidylcholine and/or phosphatidylethanolamine. The surfactant may comprise a mixture of phosphatidyl choline, phosphatidyl inositol, phosphatidyl ethanolamine, and phosphatidic acid.

The lecithin may comprise soy-bean derived lecithin. In another embodiment, the lecithin may comprise egg derived lecithin. The lecithin may comprise sunflower oil-derived lecithin.

In one embodiment, soy-bean derived lecithin comprises:.

The viscosity modifying agent may comprise or consist of glycerol. In another description, the viscosity modifying agent may comprise or consist of glycyrrhizic acid. The viscosity modifying agent may comprise a viscosity modifying agent selected from glycerol, polypropylene glycol, polyethylene glycol, glycyrrhizic acid or a sugar-based syrup; or combinations thereof. In another embodiment, the viscosity modifying agent may comprise a viscosity modifying agent selected from glycerol, polypropylene glycol, polyethylene glycol, glycyrrhizic acid or a sugar-based syrup; or combinations thereof.

The viscosity modifying agent may be provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v). In another embodiment, the viscosity modifying agent may be provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v). In another embodiment, the viscosity modifying agent may be provided in an amount of about <NUM> % (v/v) or <NUM>% (v/v).

The percentage amount of viscosity modifying agent provided may be in addition to any viscosity modifying agent present in other components of the composition, e.g. any glycerol in lecithin provided as the surfactant.

In one embodiment citric acid is provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v). In another embodiment citric acid is provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v). In another embodiment citric acid is provided in an amount of about <NUM> % (v/v).

The oxygen bubbles may be encapsulated by the surfactant. In particular, surfactants are characterized by a having a hydrophobic group (their tails) and hydrophilic groups (their heads) which can self-arrange in a solution to encapsulate the oxygen. The oxygen bubbles may be nano-sized. The term "nano-sized" is understood to mean an average size range of between about <NUM> and about <NUM> in diameter. The nano-sized oxygen bubbles may average less than <NUM> in diameter. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter in as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles. The nano-sized oxygen bubbles may be between about <NUM> and about <NUM> in diameter as an average of the population of oxygen bubbles.

In one embodiment, the oxygen is pure oxygen. In another embodiment, the oxygen may be provided in a gas mixture, with another gas or gases. The gas mixture may comprise at least <NUM>% oxygen. Alternatively, the gas mixture may comprise at least <NUM>% oxygen. Alternatively, the gas mixture may comprise at least <NUM>% oxygen. The gas mixture may comprise at least <NUM>% oxygen. In one embodiment, the gas mixture comprises at least <NUM>% oxygen.

The oxygen partial pressure in the composition may be at least <NUM> relative KPa. In another embodiment, the oxygen partial pressure in the composition may be at least <NUM> relative KPa. In another embodiment, the oxygen partial pressure in the composition may be at least <NUM> relative KPa. In another embodiment, the oxygen partial pressure in the composition may be at least <NUM> relative KPa. In another embodiment, the oxygen partial pressure in the composition may be at least <NUM> relative KPa. The oxygen partial pressure may be measured under atmospheric pressure at room temperature, or at <NUM>.

The composition may not comprise perfluorocarbon. Additionally or alternatively, the composition may not comprise sulphur hexafluoride.

The composition may comprise one or more additional ingredients selected from flavour enhancers, colouring, preservative, fragrance, minerals, and nutrients; or combinations thereof.

The composition may additionally comprise an emulsifier, such as xanthan gum. The xanthan gum may be provided at a concentration of about <NUM>/ml.

In one description, the composition comprises or consists of lecithin as the surfactant; glycyrrhizic acid (GA) as the viscosity modifier; and water. The lecithin may be provided at about <NUM>/ml, and glycyrrhizic acid at about <NUM>/ml.

In one embodiment, the composition comprises or consists of lecithin as the surfactant; glycyrrhizic acid (GA) as the viscosity modifier; xanthan gum; and water. The lecithin may be provided at about <NUM>/ml, glycyrrhizic acid at about <NUM>/ml, and xanthan gum at about <NUM>/ml.

In one description, the beverage composition may comprise or consist of:.

Also described is a composition for forming a nanoencapsulated oxygen beverage, wherein the composition comprises.

In one embodiment, citric acid is provided in an amount of between about <NUM> % (v/v) and about <NUM> % (v/v).

In one embodiment, the composition for forming a nanoencapsulated oxygen beverage may comprise or consist of:.

Also described is a composition for mixing with water and forming a nanoencapsulated oxygen beverage, wherein the composition comprises.

The composition may be in the form of a paste (e.g. prior to adding water). The composition may be mixed or sparged with oxygen gas. The mixing may be by agitation of the composition in a container with oxygen.

Advantageously, the described combination of surfactants and viscosity agents is capable of producing a suspension of stable oxygen nanoparticles (i.e. in which oxygen is encapsulated) upon agitation or sparging of the composition with oxygen gas. The reduction in surface tension and diffusivity stabilise the oxygen in this form so that it is only released gradually over time.

Also described is a method of treating cancer in a subject comprising the oral consumption of a composition according to the description herein.

Also described is use of the composition according to the description herein for oral consumption to enhance oxygen delivery to muscle.

Also described is use of the composition according to the description herein for oral consumption to enhance athletic and/or muscle performance.

The enhanced athletic performance may comprise enhanced stamina, recovery, strength, reactivity or speed of a muscle performance.

Also described is a method of treating cancer in a subject comprising the oral consumption of a composition comprising:.

Also described is a composition for use in treating cancer in a subject, the composition comprising:.

The oral consumption of the composition by the subject may be in combination with an anti-cancer therapy. The anti-cancer therapy and the consumption of composition of the description may be concurrent or sequential.

The anti-cancer therapy may comprise one or more of chemotherapy, radiotherapy, photodynamic therapy or sonodynamic therapy.

The cancer may comprise a solid tumour cancer. The solid tumour may be characterized by, or susceptible to, tissue hypoxia. The solid tumour may be hypoxic. The skilled person will understand that the level of hypoxia may vary between patients and tissue types. However, is understood to include regions of tissue in which the partial pressure of oxygen is substantially below that typically found in a healthy equivalent tissue. Oxygen content in tissue (e.g. to determine hypoxia) can be measured in a number of ways known to the skilled person. For example a directly implanted probe can measure a change in fluorescence produced by oxygen absorption. Other techniques utilise the change in the colour of blood and hence optical absorption spectrum. For cancer diagnosis in human patients magnetic resonance spectroscopy is typically used. Histological techniques can also be used on biopsy samples to determine hypoxia.

The compositions, methods and use described here may provide a sustained increase in oxygen content in a hypoxic tumour following oral administration. The sustained oxygen increase may be over a period of at least <NUM> minutes. Alternatively, the sustained oxygen increase may be over a period of at least <NUM> minutes. Alternatively, the sustained oxygen increase may be over a period of at least <NUM> minutes.

Also described is a method of forming a beverage composition for oral administration of oxygen bubbles comprising:.

In one embodiment, the citric acid is provided in the mixture.

The composition and the oxygen gas may be, or arranged to be, separated in the container until required for use.

The surfactant, citric acid and viscosity modifying agent may be pre-mixed into a paste prior to adding it to the volume of water. In another embodiment, the surfactant, citric acid and viscosity modifying agent may be added separately from each other or in combinations.

In one embodiment, the citric acid is provided in the paste mixture.

The paste and volume of liquid may be, or arranged to be, separated in the container until required for use.

The volume of liquid may comprise or consist of water. The water may be distilled water. In one embodiment, the water may be filtered deionized water.

The volume of liquid may be oxygenated by sparging with oxygen, for example prior to packaging.

The method may further comprise the step of agitating the packaged composition to form oxygen bubbles in the composition. The agitation may comprise shaking, for example by hand. The agitation may be for a period of at least <NUM> seconds. Alternatively, the agitation may be for a period of at least <NUM> seconds. Alternatively, the agitation may be for a period of at least <NUM> seconds. Alternatively, the agitation may be for a period of at least <NUM> seconds. Alternatively, the agitation may be for a period of at least <NUM> seconds.

The agitation may be immediately prior to drinking. In one embodiment, the agitation is less than <NUM> minute prior to drinking. In another embodiment, the agitation is less than <NUM> minutes prior to drinking. In another embodiment, the agitation is less than <NUM> minutes prior to drinking.

The combined paste and volume of liquid may be stirred prior to packaging to form a homogenous composition. Alternatively, the combined paste and volume of liquid may be stirred to form a homogenous composition prior to agitation.

In one embodiment the composition is sterilised, or at least treated for sterilization or reducing the bio-burden of the composition.

The skilled person will understand that optional features of one embodiment or aspect of the invention may be applicable, where appropriate, to other embodiments or aspects of the invention.

Embodiments of the description will now be described in more detail, by way of example only, with reference to the accompanying drawings.

The aim of our formulation is to provide increased stability of oxygen in suspension compared with existing microbubble formulations (intended for use as artificial respiration aids e.g. http://www. gov/pmc/articles/PMC3563146/) and nanobubble waters (http://www. com/CQ/oxyscams. This reduces the need for there being a very short period between preparing the drink and consuming it and improves the efficiency with which oxygen can be absorbed from the digestive tract into the blood stream and surrounding tissue. Enabling oral administration (as opposed to intravenous injection) reduces the risk of infection for hospital patients and greatly increases the range of uses of the product for consumer applications.

It has been demonstrated in the present study that there is a sustained increase (><NUM> mins) in the oxygen content of a hypoxic tumour following oral delivery, which has not been shown before in other treatment methods. This differs from microbubble formulations that require intravenous injection and have been shown to affect blood oxygen and cardiac tissue oxygen levels.

Volume ratio can be scaled to required quantity.

Lecithin, citric acid and glycerol are combined by stirring to form a liquid paste. Immediately prior to use the paste is added to the purified water in a vessel at least twice the volume of the liquid contained therein. Gentle stirring to dissolve the paste is followed by filling the headspace of the vessel with oxygen and sealing. The vessel is then shaken vigorously for <NUM> seconds.

With reference to <FIG>, a Terumo oxygen meter was used to measure the oxygen content of water before and after addition of <NUM> samples of the above formulation. As a control the measurements were repeated with <NUM> of water that had been sparged with oxygen and shaken but without the addition of any other components. The formulation of the description demonstrated superior oxygen storage for a period of greater than <NUM> minutes relative to the control. Repeating the measurements at <NUM> showed a small (~<NUM>%) decrease in maximum oxygen partial pressure.

With reference to <FIG> and <FIG>, mice bearing hind limb pancreatic tumours were anaesthetized and the formulation (or control) was administered via gavage. An oxygen probe was implanted in the tumour and the change in oxygen level recorded over time.

Each line represents a different mouse. <FIG> shows the initial change in oxygen levels in the tumour following administration of the drink of the description. Mouse <NUM> was given the fully agitated mixture. Mouse <NUM> was given the mixture with gentle mixing only. The control mouse was given water treated in the same way but without the addition of the formulation ingredients. <FIG> shows the reading taken at a separate probe position approximately <NUM> minutes later indicating the sustainment of the rise in oxygen levels.

A number of different ingredient combinations were tested, with the reported result the consensus of a panel of <NUM>. Examples are:.

This mixture was provided to exploit properties of GA as an excellent foam stabilizer and sweetener but at lower concentration.

Despite the unpleasant taste, these compositions may be considered as useful compositions according to the description. For example in some applications, such as medicine, the taste may not be an issue.

Claim 1:
A beverage composition comprising:
water;
oxygen bubbles;
a surfactant comprising lecithin or purified surfactant components thereof in an amount of between <NUM> % (v/v) and <NUM> % (v/v);
one or more viscosity modifying agent(s) in an amount of between <NUM> % (v/v) and <NUM> % (v/v); and optionally
citric acid in an amount of between <NUM> % (v/v) and <NUM> % (v/v),
wherein the oxygen partial pressure in the composition is at least <NUM> relative kPa when measured at <NUM> degrees Celsius.