US20150132371A1 - Use of tomato extract as antihypertensive agent and process for making water soluble sugar free tomato extract - Google Patents

Use of tomato extract as antihypertensive agent and process for making water soluble sugar free tomato extract Download PDF

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US20150132371A1
US20150132371A1 US14/395,884 US201314395884A US2015132371A1 US 20150132371 A1 US20150132371 A1 US 20150132371A1 US 201314395884 A US201314395884 A US 201314395884A US 2015132371 A1 US2015132371 A1 US 2015132371A1
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extract
tomato
composition
tomato extract
active fraction
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Asim K. Duttaroy
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Universitetet i Oslo
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A23L1/3002—
    • 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
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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    • A61K2236/30—Extraction of the material
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    • A61K2236/55—Liquid-liquid separation; Phase separation

Definitions

  • Cardiovascular disease is a leading cause of morbidity and mortality, and, thus, primary prevention and secondary prevention of cardiovascular disease are public health priorities.
  • High blood pressure, hyperlipidemia, and hyperactivity of platelets are the recognized risk factors for cardiovascular disease.
  • hypertension is recognized as a major chronic disease. It is defined as a systolic blood pressure above 140 mmHg and/or a diastolic blood pressure above 90 mmHg Hypertension affects up to 30% of the adult population in most countries. However, more than 50% of hypertensive individuals are unaware of their condition.
  • Essential hypertension is not caused by a single identifiable cause but by a cluster of factors, including heredity, age, body weight, environment, and diet. Treatment of moderate to severe hypertension is a life-long commitment and requires drug therapy in combination with changes in lifestyle, including weight reduction if overweight, limitation of alcohol, and reducing salt and fat intake. Essential hypertension can be treated with one of several types of medications, including diuretics, ⁇ -adrenoreceptor blockers, inhibitors of angiotensin converting enzyme (ACE), calcium channel blockers, ⁇ -adrenoreceptor blockers, vasodilators, and centrally acting agents.
  • diuretics ⁇ -adrenoreceptor blockers
  • ACE angiotensin converting enzyme
  • calcium channel blockers ⁇ -adrenoreceptor blockers
  • vasodilators vasodilators
  • the renin-angiotensin system is a powerful mechanism for controlling blood pressure.
  • the kidneys undergo several intrinsic reactions converting prorenin to renin.
  • renin enters the bloodstream, it hydrolyzes plasma angiotensinogen to release a peptide called angiotensin I.
  • angiotensin II When aginotensin I circulates to the small vessels of the lungs, it is immediately hydrolyzed to release an 8-amino acid peptide, angiotensin II, by ACE.
  • Angiotensin II circulates in the blood before it is inactivated by angiotensinase.
  • Angiotensin II is a very potent vasoconstrictor and raises blood pressure by severely constricting the arteries, causing an increase in peripheral resistance. It is also able to act on the kidneys to retain both salts and water, leading to an increase in the extracellular fluid volume and thus produces an increase in blood pressure. Finally, angiotensin II causes the adrenal glands to release aldosterone, which in turns increases reabsorption of water and salt in the kidneys.
  • ACE inhibitors block the formation of angiotensin II, which normally causes blood vessels to narrow and blood pressure to increase.
  • ACE is not specific for converting angiotensin I to angiotensin II.
  • ACE also cleaves a number of other peptides including bradykinin, a nonapeptide.
  • Bradykinin is a potent endothelium-dependent vasodilator, which causes natriuresis and a consequent drop in blood pressure.
  • ACE inhibitors not only decrease the formation of angiotensin II, but also increase the amount of bradykinin, thus further lowering blood pressure.
  • ACE angiotensin converting enzyme
  • compositions comprising the tomato extract described are useful in cardiovascular disease prophylaxis, e.g., as an oral tomato extract therapeutic that can be safely and effectively consumed to protect a person's cardiovascular system.
  • compositions of the sugar-free tomato extracts provided herein are effective as cardio-protective agents especially for people with obesity, insulin resistance, and sedentary life styles.
  • the technology provided herein is related to a composition
  • a composition comprising a tomato extract (e.g., a water-soluble, sugar-free tomato extract) or an active fraction thereof.
  • the tomato extract comprises or consists of components that have a molecular mass less than 1000 Da.
  • the composition is essentially free of lycopene and in some embodiments the composition is essentially free of nucleosides.
  • the composition is in the form of a dried powder.
  • the composition is in the form of a solution that will pass through a 0.2 ⁇ m filter without loss of solids.
  • the composition is formulated as an oral formulation, e.g., for oral administration.
  • the composition is formulated in a form selected from the group consisting of a solution, a suspension, a syrup, a tablet, a capsule, a lozenge, a snack bar, a health drink, an insert, and a patch.
  • a tomato extract comprising the steps of homogenizing a tomato to produce a tomato homogenate; filtering the tomato homogenate through a filter having a molecular weight cutoff of 1000 Da to produce a filtrate; and collecting the filtrate to provide an extract.
  • the methods also comprise the steps of freeze-drying the homogenate to produce a freeze-dried homogenate and dissolving the freeze-dried homogenate in water and/or freeze-drying the filtrate to produce a freeze-dried filtrate and dissolving the freeze-dried filtrate in water.
  • the methods comprise a step of removing a water-soluble sugar from the extract.
  • compositions comprising a tomato extract, obtainable by a method comprising the steps of homogenizing a tomato to produce a tomato homogenate; filtering the tomato homogenate through a filter having a molecular weight cutoff of 1000 Da to produce a filtrate; collecting the filtrate to provide an extract; and removing a water-soluble sugar from the extract.
  • Embodiments of the technology provided are related to compositions comprising a tomato extract for use as a medicament to treat hypertension and/or for use as a medicament to inhibit angiotensin converting enzyme (ACE) and/or conditions associated with increased ACE activity or levels.
  • the composition comprising a tomato extract or active fraction thereof is selected from the group consisting of juices, pastes, sauces, and soups.
  • the compositions are a water-soluble, sugar-free tomato extract.
  • some embodiments provide a tomato extract for use as a medicament to treat hypertension and/or for use as a medicament to inhibit angiotensin converting enzyme, wherein the composition is produced by a process comprising the steps of diluting in water a cold-break tomato paste of 28-30° Brix and a browning index less than 0.350 AU; removing particulate matter greater than 0.2 ⁇ m to produce a solution; and concentrating the solution to form a syrup of 62-65° Brix (see, e.g., International Patent Publications WO/1999/0055350, WO/2007/0141495, and WO/2006/085115, incorporated herein by reference in their entireties for all purposes).
  • Some embodiments provide a tomato extract for use as a medicament to treat hypertension and/or for use as a medicament to inhibit angiotensin converting enzyme, wherein the composition is produced by a process comprising the steps of homogenizing tomatoes; removing particulates by centrifugation and/or ultrafiltration; removing soluble sugars; and eluting non-sugar components in methanol (see, e.g., International Patent Publications WO/1999/0055350, WO/2007/0141495, and WO/2006/085115, incorporated herein by reference in their entireties for all purposes).
  • the composition is prepared by a method further comprising fractionating components from the non-sugar components using high-pressure liquid chromatography.
  • the present invention provides methods of treating a subject comprising: a) identifying a subject having or at risk of having a condition associated with hypertension or ACE activity; and b) administering a composition comprising a tomato extract or active fraction thereof to said subject.
  • the tomato extract inhibits ACE.
  • the tomato extract is an aqueous extract.
  • the tomato is peeled prior to the step of homogenizing.
  • the tomato extract is in the form of a concentrate or a dehydrate.
  • the tomato extract is in the form of a concentrate which is at least 2-fold concentrated.
  • the tomato extract has been dehydrated to give a dry extract.
  • the dry extract is in the form of a solid or semisolid dosage form. In some embodiments, the extract is contained within a capsule shell. In some embodiments, the extract contains a substantially heat stable water soluble compound or compounds having a molecular weight of less than 1000.
  • the condition or disorder is selected from the group consisting of stroke, aneurysm, coronary heart disease (CHD), heart attack, atherosclerosis, ischemic heart disease, left ventricular hypertrophy, encephalopathy, congestive heart failure, hypertensive retinopathy, gout, tachycardia, kidney dysfunction, diabetes, and disease states associated with ACE activity and/or hypertension.
  • the extract is in the form of an active fraction of the fruit capable of passing through an ultrafiltration filter having a molecular weight cut-off of 1000 and containing a substantially heat stable, colorless or straw-colored, water soluble compound or compounds having a molecular weight of less than 1000.
  • the composition comprising a tomato extract or active fraction thereof is selected from the group consisting of juices, pastes, sauces, and soups.
  • the present invention provides methods for the treatment a condition associated with hypertension, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a fruit extract having anti-hypertension activity, and wherein the fruit extract is obtained from a fruit of the plant family Solanaceae by a process comprising the steps of homogenizing the flesh of the fruit to form a homogenate and removing solids therefrom.
  • embodiments of the technology provide a pharmaceutical formulation comprising a tomato extract and an excipient suitable for treating hypertension or for inhibiting ACE.
  • embodiments provide an anti-hypertension agent and/or an ACE inhibitor comprising a tomato extract.
  • embodiments of the technology are also provided relating to a method of treating a subject comprising identifying a subject having or at risk of having hypertension; and administering a composition comprising a tomato extract or active fraction thereof to said subject. Additional embodiments will be apparent to persons skilled in the relevant art based on the teachings contained herein.
  • FIG. 1 provides a graph depicting the effect of sugar free tomato extract on inhibition of activity of pure ACE protein.
  • compositions and uses related to anti-hypertensive agents in tomatoes are provided herein.
  • sugar free tomato extracts prepared as described herein exhibit an ability to reduce ACE activity.
  • the term “or” is an inclusive “or” operator and is equivalent to the term “and/or” unless the context clearly dictates otherwise.
  • the term “based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise.
  • the meaning of “a”, “an”, and “the” include plural references.
  • the meaning of “in” includes “in” and “on.”
  • water soluble as applied to a tomato extract refers to the tomato extract being soluble at room temperature, e.g., at approximately 25° C.
  • this definition is not limiting as some compositions comprising extracts according to the technology are soluble at lower temperatures, e.g., at temperatures as low as approximately 4° C.
  • active refers to having the ability to modulate (e.g., lower) blood pressure and/or modulate (e.g., inhibit) ACE activity.
  • a “subject” is an animal, such as a vertebrate, and preferably a mammal, such as a human. Mammals are understood to include, but are not limited to, murines, simians, humans, bovines, cervids, equines, porcines, canines, felines, etc.
  • an “effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations.
  • an effective amount refers to the amount of a composition sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.
  • co-administration refers to the administration of at least two agents or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy.
  • a first agent/therapy is administered prior to a second agent/therapy.
  • the appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use.
  • compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.
  • Pharmaceutically acceptable compositions are known in the art such as those described in, for example, Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985), explicitly incorporated herein by reference for all purposes.
  • the term “treating” includes reducing or alleviating at least one adverse effect or symptom of a disease or disorder through introducing in any way a therapeutic composition of the present technology into or onto the body of a subject.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • terapéuticaally effective dose refers to an amount of a therapeutic agent sufficient to bring about a beneficial or desired clinical effect. Said dose can be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration, the type or extent of supplemental therapy used, ongoing disease process, and type of treatment desired (e.g., aggressive versus conventional treatment).
  • tomato extracts having activities that are beneficial for cardiovascular health.
  • data collected during the development of particular embodiments of the technology described show that the extract decreased ACE activity in normal serum in a dose dependent manner.
  • data collected also demonstrate that the active compounds in the tomato extract are water-soluble and have a very different structure that the lipid-soluble compounds.
  • the extract can be fractionated to isolate one or more active fractions therein by, for example, molecular weight filtration or chromatography on a suitable support.
  • the fractionation e.g., using a Lipidex-1000 column, results in the removal of lipids.
  • the extract is fractionated by solid phase extraction.
  • the active components of the extract pass through an ultrafiltration membrane having molecular weight cut-off 1000 Da.
  • the active extract is colourless, water soluble, and does not lose activity when boiled.
  • the active compound in the extract is not lycopene.
  • the technology encompasses extracts from tomato as well as other members of the family Solanaceae.
  • Solanaceae is a family of flowering plants including, e.g., Datura, Mandragora (mandrake), Atropa belladonna (deadly nightshade), Lycium barbarum (wolfberry), Physalis philadelphica (tomatillo), Physalis peruviana (Cape gooseberry flower), Capsicum (chili pepper, bell pepper), Solanum (potato, tomato, eggplant), Nicotiana (tobacco), and Petunia.
  • the technology comprises extracts from the genus Solanum, for example, tomato (e.g., S.
  • lycopersicum a potato (e.g., S. tuberosum ); eggplant (e.g., S. melongena ); Giant Devil's fig (e.g., S. chrysotrichum ); Ethiopian eggplant and gilo (e.g., S. aethiopicum ); naranjilla or lulo (e.g., S. quitoense ); Turkey berry (e.g., S. torvum ); pepino (e.g., S. muricatum ); “bush tomatoes” of Australia; and other members of the formerly independent genera Lycopersicon (the tomatoes) and Cyphomandra.
  • potato e.g., S. tuberosum
  • eggplant e.g., S. melongena
  • Giant Devil's fig e.g., S. chrysotrichum
  • Ethiopian eggplant and gilo e.g., S. aethiopicum
  • compositions comprising embodiments of the extracts produced as described in the Examples and as described, e.g., in International Patent Publications WO/1999/0055350, WO/2007/0141495; and WO/2006/085115 incorporated herein by reference in their entireties for all purposes.
  • the technology encompasses compositions, methods of producing compositions, pharmaceutical formulations, and other technology disclosed, e.g., in U.S. Pat. No. 6,958,164; EP 1334728; AU 772923; and DK 1083912, incorporated herein by reference in their entireties for all purposes.
  • the technology encompasses modifications of the compositions, methods, and technologies provided in these publications that are obvious to one of skill in the art.
  • some embodiments of the technology comprises the use of whole, chopped, pureed, sliced, or other non-fractionated forms of tomatoes (juices, pastes, sauces, soups, garnishes, etc.) to reduce blood pressure or inhibit ACE.
  • these various forms comprise an active fraction that reduces blood pressure and/or inhibits ACE activity in a target population (i.e., persons in need of blood pressure reduction or in need of treatment of diseases associated with increased ACE activity).
  • a tomato extract for reducing blood pressure and/or inhibiting ACE activity is an aqueous extract of tomato.
  • Such extracts may be prepared by homogenizing the flesh of a tomato, with or without its skin, and then filtering the homogenate to remove solids.
  • substantially all water-insoluble solids are removed, for example, by centrifugation and/or filtration.
  • the tomato extracts encompassed by the technology are water soluble extracts that are substantially free of lycopene.
  • the aqueous filtrate may be subjected to further fractionation to provide an active fraction containing a compound or compounds responsible for the biological or therapeutic effects described herein.
  • the filtrate may be evaporated to give a dry water-soluble extract. Filtration of the tomato homogenate may be accomplished in a single stage, or in a series of filtration steps, starting with a relatively coarse filtration or centrifugation step to remove larger particles of tomato skin and/or other water-insoluble fragments of tomato flesh.
  • the tomatoes are peeled as a first step to remove a large portion of the tomato skin prior to homogenization. Further filtration steps may then be used to produce a substantially clear solution, e.g., a solution that will pass through a 0.2 ⁇ m filter without loss of solids.
  • the tomato extract is a water soluble extract substantially free of lycopene and capable of passing through a 0.2 ⁇ m filter without loss of solids.
  • native sugars are removed from the tomato extracts.
  • commercially available tomato pastes may be used as the starting material for the preparation of the extracts.
  • the tomato pastes are typically diluted with water and then water-insoluble solids are removed, e.g., by centrifugation and/or filtration to give a substantially clear solution.
  • the starting material for the preparation of the extracts is a tomato paste, it is preferably one that has been produced by means of a “cold-break” process rather than a “hot-break” process.
  • the terms “cold-break” and “hot-break” are well-known in the field of tomato processing and commercially available tomato pastes are typically sold as either hot-break or cold-break pastes.
  • Cold-break pastes can be prepared by a process involving homogenization of the tomato followed by a thermal processing step in which the tomatoes are heated to temperature of no more than about 60° C., in contrast to hot-break pastes where the homogenized tomatoes are subjected to thermal processing at temperatures of about 95° C. (see, for example, Anthon et al., J. Agric. Food Chem. 2002, 50: 6153-6159).
  • an aqueous extract of tomatoes or tomato paste is produced by enzyme digestion of pectins and starch in homogenised fruit or paste, followed by removal of suspended solids from the homogenate, and micro- or ultrafiltration to remove large molecular weight proteins and remaining polysaccharides.
  • the extract can be refined by removing simple sugars, for example, glucose, fructose, and sucrose, leaving a concentrated water-soluble extract that contains a wide variety of low molecular weight ( ⁇ 1000 Da) non-sugar tomato components. Removal of simple sugars can be carried out by crystallization, for example, using low-temperature ultrasound-assisted crystallization or ethanol precipitation of crystalline glucose and fructose.
  • simple sugars can be separated from other extract components by a chromatographic procedure, for example, selective adsorption of bioactive extract components from the aqueous solution onto a polystyrene-based resin material, thus allowing the selective removal of glucose, fructose, and sucrose in the waste stream.
  • the adsorbed non-sugar compounds are then recovered from the adsorbent resin material by elution with ethanol followed by removal of the ethanol by evaporation.
  • the non-sugar components can be dried into a water-soluble powder by spray drying or drum drying or optionally resuspended in water to give an aqueous syrup.
  • Aqueous extracts prepared are provided by embodiments of the technology.
  • the extracts are dried powders, a concentrate, a dehydrate, a semi-solid, etc.
  • Concentrates are, in some embodiments, at least 2-fold concentrated, at least 4-fold concentrated, at least 8-fold, at least 40-fold, at least 100-fold, at least 200-fold, or at least 1000-fold concentrated.
  • Sugar-free tomato extracts typically contain a variety of compounds of molecular weight ⁇ 1000 Da and are provided herein as embodiments for use according to the technology described. Additionally, the tomato extracts are effective if they have no or low nucleoside content. Accordingly, in some embodiments, the tomato extract that find use in accordance with the technology have no or less that 10 nM nucleosides contained therein.
  • the tomato extracts encompassed by the technology comprise a number of bioactive components, e.g., phenolic compounds, amino acids, amino acid conjugates, and tomato flavor compounds.
  • the extracts comprise phenolic compounds selected from flavonoids and flavonoid derivatives, for example, derivatives of quercetin, kaempferol, and naringenin; hydroxycinnamic acids and derivatives, for example, ferulic acid, coumaric acid, and their conjugates; benzoic acids and derivatives such as benzoic acid, hydroxybenzoic acid, gallic acid, salicylic acid, and conjugates.
  • the extract comprises amino acids selected from tyrosine and hydroxytyrosine, phenylalanine, glutamine, and their conjugates.
  • the extracts comprise a flavor compound such as a hexanal derivative, dimethylsulfide, beta-damascenone, 3-methylbutyric acid, eugenol, and/or methional.
  • the tomato extracts is sub-fractionated by HPLC to produce three subfractions on the basis of polarity.
  • the extracts or active fractions thereof may be formulated for oral administration.
  • they can be formulated as, e.g., solutions, suspensions, syrups, tablets, capsules, lozenges, snack bars, inserts, and patches.
  • Such formulations are prepared in accordance with methods well known in the art.
  • the extracts or active fractions are formed into syrups or other solutions for administration orally.
  • the technology contemplates, e.g., health drinks, optionally comprisising one or more excipients selected from sugars, vitamins, flavouring agents, colouring agents, preservatives, and thickeners.
  • tonicity adjusting agents such as sodium chloride or a sugar are added to provide a solution of a particular osmotic strength, for example an isotonic solution.
  • pH-adjusting agents such as buffering agents, are also used in some embodiments to adjust the pH to a particular value and, e.g., maintain it at that value.
  • buffering agents include sodium citrate/citric acid buffers and phosphate buffers.
  • the extracts or active fractions thereof are dried, e.g., by spray drying or freeze drying, and the dried product formulated in a solid or semi solid dosage form, for example, as a tablet, lozenge, capsule, powder, granulate, or gel.
  • simple dried extracts are prepared according to particular embodiments of the technology without any additional components.
  • some embodiments provide dried extracts that are prepared by adsorption onto a solid support, for example, a sugar such as sucrose, lactose, glucose, fructose, mannose; a sugar alcohol such as xylitol, sorbitol, or mannitol; or a cellulose derivative.
  • a sugar such as sucrose, lactose, glucose, fructose, mannose
  • a sugar alcohol such as xylitol, sorbitol, or mannitol
  • Other particularly useful adsorbents include starch-based adsorbents such as cereal flours, for example, wheat flour and corn flour.
  • the dried extract is typically mixed with a diluent such as a sugar, e.g., sucrose or lactose; sugar alcohols such as xylitol, sorbitol, and mannitol; or modified cellulose or cellulose derivative such as powdered cellulose, microcrystalline cellulose, or carboxymethyl cellulose.
  • Tablets will also typically contain one or more excipients selected from granulating agents, binders, lubricants, and disintegrating agents.
  • disintegrants include starch and starch derivatives, and other swellable polymers, for example, crosslinked polymeric disintegrants such as cross-linked carboxymethylcellulose, crosslinked polyvinylpyrrolidone, and starch glycolates.
  • lubricants include stearates such as magnesium stearate and stearic acid.
  • binders and granulating agents include polyvinylpyrrolidone.
  • a sweetener can be added, for example, ammonium glycyrrhizinate or an artificial sweetener such as aspartame or sodium saccharinate.
  • dried extracts are formulated as powders, granules, or semisolids for incorporation into capsules.
  • the extracts are formulated together with any one or more of the excipients defined above in relation to tablets, or can be presented in an undiluted form.
  • the dried extracts are dissolved or suspended in a viscous liquid or semisolid vehicle such as a polyethylene glycol, or a liquid carrier such as a glycol, e.g., propylene glycol, glycerol, or a vegetable or fish oil such as an oil selected from olive oil, sunflower oil, safflower oil, evening primrose oil, soya oil, cod liver oil, herring oil, etc.
  • a viscous liquid or semisolid vehicle such as a polyethylene glycol, or a liquid carrier such as a glycol, e.g., propylene glycol, glycerol, or a vegetable or fish oil such as an oil selected from olive oil, sunflower oil, safflower oil, evening primrose oil, soya oil, cod liver oil, herring oil, etc.
  • a viscous liquid or semisolid vehicle such as a polyethylene glycol, or a liquid carrier such as a glycol, e.g., propylene glycol, glycerol, or
  • dried extracts are provided in a powder form for incorporation into snack food bars such as fruit bars, nut bars, and cereal bars.
  • snack food bars such as fruit bars, nut bars, and cereal bars.
  • the dried extracts are admixed with any one or more ingredients selected from dried fruits such as sun-dried tomatoes, raisins and sultanas; or groundnuts or cereals such as oats and wheat.
  • dried extracts are provided in a powder form for reconstitution as a solution.
  • they can also contain soluble excipients such as sugars, buffering agents such as citrate and phosphate buffers, and effervescent agents formed from carbonates, e.g., bicarbonates such as sodium or ammonium bicarbonate, and a solid acid, for example, citric acid or an acid citrate salt.
  • dried extract is provided in powder form optionally together with a preferred solid (e.g. powdered) excipient for incorporation into capsules, for example, a hard gelatine capsule.
  • the dried extract is one from which substantially all native sugars have been removed.
  • a solid or semisolid dosage form related to the technology contains up to about 1000 mg of the dried extract, for example, up to about 800 mg.
  • the extracts are presented in some embodiments as food supplements or food additives, or can be incorporated into foods, for example functional foods or nutraceuticals.
  • the compositions are provided in the form of unit dosage forms containing a defined concentration of extract or active fraction thereof.
  • unit dosage forms can be selected so as to achieve a desired level of biological activity.
  • a unit dosage form can contain an amount of up to 1000 mg (dry weight) of an extract or active fraction, more typically up to 800 mg, for example 50 mg to 800 mg, e.g., 100 mg to 500 mg.
  • Particular amounts of extract or active fraction that may be included in a unit dosage form may be selected from 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, and 800 mg.
  • the compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the quantity of extract or active fraction administered to a patient per day will depend upon the strength of the extract and the particular condition or disease under treatment and its severity, and ultimately it will be at the discretion of the physician.
  • the amount administered however will typically be a non-toxic amount effective to bring about the desired result.
  • a typical daily dosage regime for a human patient potentially at risk of suffering from high blood pressure may be from 0.0001 to 0.1 gram, e.g., in the range of 0.001 to 0.05 gram per kilogram body weight.
  • the amount of solid material administered can be reduced by an amount consistent with the increased purity of the fraction.
  • at least 100 mg (dry weight or dry weight equivalent), at least 200 mg, and usually at least 500 mg of the extract will be administered per day to a human patient.
  • the compositions are administered in single or multiple dosage units per day, for example, from one to four times daily, or from one or two times daily.
  • embodiments provide that the extracts of the invention are administered in solid, liquid, or semi-solid form.
  • the extracts are administered according to some embodiments in the form of tomato juice or concentrates thereof alone or in admixture with other fruit juices such as orange juice.
  • kits for treatment comprising: administering a pharmaceutically effective amount of a tomato extract, a fraction or derivative thereof, or a pharmaceutical preparation thereof, alone or in combination with another agent, to a subject with a condition associated with hypertension.
  • the administration causes a reduction in blood pressure or an inhibition of ACE.
  • the administration causes elimination of one or more symptoms of high blood pressure or ACE activity, prevention of increased severity of one or more symptoms of the condition, and/or reduction, prevention, or elimination of further diseases or conditions.
  • a subject is tested to assess the presence, the absence, or the level of a disease (e.g., hypertension or condition related to hypertension and/or ACE activity), e.g., by assaying or measuring a biomarker, a metabolite, a physical symptom, an indication, etc., to determine the risk of or the presence of hypertension and/or a related disorder, and thereafter the subject is treated with a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof, alone or in combination with other agents based on the outcome of the test.
  • a patient is tested, treated, and then tested again to monitor the response to therapy.
  • cycles of testing and treatment may occur without limitation to the pattern of testing and treating (e.g., test/treat, test/treat/test, test/treat/test/treat, test/treat/test/treat/test, test/treat/treat/test/treat/treat, etc), the periodicity, or the duration of the interval between each testing and treatment phase.
  • pattern of testing and treating e.g., test/treat, test/treat/test, test/treat/test/treat, test/treat/test/treat/test, test/treat/treat/test/treat/treat, etc.
  • the methods provided comprise testing a subject for a disease or condition related to hypertension or ACE activity, followed by administering a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof, alone or in combination with other agents.
  • the methods comprise administering to a subject a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof, alone or in combination with other agents, followed by testing the subject for a disease or condition related to hypertension or ACE activity.
  • the methods provided comprise testing a subject for a disease or condition related to hypertension or ACE activity, followed by administering a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof, alone or in combination with other agents, followed by a second round of testing for a disease or condition related to hypertension or ACE activity (e.g., to monitor the effect of the treatment).
  • methods comprise testing a subject for a disease or condition related to hypertension or ACE activity, followed by administering a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof, alone or in combination with other agents, followed by a second round of testing for a disease or condition related to hypertension or ACE activity, and a second administration of a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof, alone or in combination with other agents, with this second administration being modified in dose, duration, frequency, or administration route in a manner dependent upon the results of the prior testing.
  • a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof, is co-administered with one or more additional therapeutic agents or medical interventions.
  • co-administration involves co-formulation of two or more agents together into the same medicament.
  • the agents are in separate formulations but are administered together, either simultaneously or in sequence (e.g., separated by one or more minutes, hours, days, etc.).
  • the co-administered agent may be provided at a lower dose than would normally be administered if that agent were being used in isolation to treat the disease or condition.
  • one or more of the following agents or interventions is co-administered or co-applied with a composition comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof: low-fat diet, low-salt diet, exercise, a relaxation technique (e.g., meditation, biofeedback), an ACE inhibitor, smoking cessation, high-fruit diet, weight loss, reduced alcohol consumption, reduced caffeine consumption, vitamin D, and/or other changes in diet such as changing the diet to a diet rich in nuts, whole grains, fish, poultry, fruits, and vegetables.
  • a relaxation technique e.g., meditation, biofeedback
  • an ACE inhibitor e.g., smoking cessation, high-fruit diet
  • weight loss e.g., reduced alcohol consumption, reduced caffeine consumption, vitamin D
  • other changes in diet such as changing the diet to a diet rich in nuts, whole grains, fish, poultry, fruits, and vegetables.
  • compositions comprising a tomato extract, an active fraction thereof, or a pharmaceutical formulation thereof is administered to a subject.
  • multiple doses are administered over two or more time points, separated by hours, days, weeks, etc.
  • compositions are administered over a long period of time (e.g., chronically), for example, for a period of months or years (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months or years).
  • compositions may be taken on a regular scheduled basis (e.g., daily, weekly, etc.) for the duration of the extended period.
  • a tomato extract for use according to the technology described is prepared, for example, using a commercially available cold-break tomato paste of 28-30° Brix (e.g., 28-30% solids (w/w)) and having a browning index of less than 0.350 AU (where the browning index is defined as the absorbance at 420 nm of a solution having 12.5 g soluble solids per liter) as the starting material.
  • the paste is diluted, e.g., approximately 1 to 5, with ultrapure water and large particulate matter is removed by centrifugal filtration followed by clarification using a Westfalia MSB-14 Separator (a centrifugal disc clarifier) at room temperature. Smaller particulate matter is then removed by microfiltration at a temperature not exceeding 45° C.
  • This solution is concentrated by evaporation to form a syrup of 62-65° Brix using carefully controlled conditions and a temperature not exceeding 80° C. to inhibit non-enzymic browning reactions.
  • a flash pasteurization step e.g., at 105° C. for 3 seconds
  • the final product is typically characterized by a browning index of less than 0.600 AU and a microbial total plate count of less than 1000.
  • the concentrated extract is added in some embodiments to an orange juice matrix for administration, e.g., to patients.
  • An alternative preparation of tomato extract and sub-fractions thereof is prepared from tomatoes to produce an aqueous extract.
  • an aqueous extract from ripe tomato fruit is prepared by homogenization of fresh tomatoes (Lycopersicon esculentum, sourced locally), centrifugation, and clarification of the resulting straw-colored liquid by ultrafiltration (ultrafiltration membrane, MW cut-off 1000 Da, Millipore (UK) Ltd., Watford, UK).
  • ultrafiltration membrane ultrafiltration membrane, MW cut-off 1000 Da, Millipore (UK) Ltd., Watford, UK.
  • a typical analysis demonstrates that the tomato aqueous extract consists largely of soluble sugars (85-90% of dry matter).
  • Non-sugar components are retained on the cartridges and eluted in methanol.
  • non-sugar material accounts for approximately 4% of the aqueous extract dry matter.
  • semi-preparative HPLC is used to subfractionate components from the non-sugar material into three broad groups.
  • HPLC using Synergy Polar-RP, 4 ⁇ m, 250 ⁇ 10 mm and Luna C18(2), 3 ⁇ m, 250 ⁇ 10 mm columns (Phenomenex, Macclesfield, UK) and acetonitrile/0.05% TFA gradients provides one method for this step.
  • HPLC fractions in some embodiments, are reconstituted to known concentrations in phosphate-buffered saline (PBS, Sigma-Aldrich, Poole, UK) and optionally adjusted to pH 7.4 before use, e.g., for in vitro experiments.
  • PBS phosphate-buffered saline
  • tomato extracts were prepared and tested.
  • the tomatoes were homogenised with a Brown Turbo Mixer for 20-30 seconds at highest speed.
  • the homogenate was then centrifuged at 9000 ⁇ g for 15 minutes at 4° C.
  • the supernatant was then boiled for 30 minutes and centrifuged again.
  • the supernatant was removed and freeze-dried overnight.
  • the dried material was dissolved in double distilled water and the pH was adjusted to 7.4.
  • the samples were subjected to ultrafiltration using a MicrosepTM Centrifugal Device (Pall Corporation, US) having a molecular weight cut-off of 1000 kDa.
  • the ultrafiltrate was collected, freeze dried, and reconstituted in water; the pH was adjusted to 7.4 for further studies.
  • a tomato extract contained more than 50% inactive water soluble sugars. Accordingly, these sugars were removed from the extract. Solid phase extraction column chromatography was used for removing sugars, e.g., using a Bond Elut ENV cartridge (Agilent). The Bond Elut ENV cartridges were conditioned with 2 ⁇ 4 ml 100% methanol and then equilibrated with 2 ⁇ 4 ml distilled water. A volume of 4 ml of the prepared sample (comprising approximately 1 g of the tomato extract) was loaded onto the cartridge. Cartridges were washed with 2 ⁇ 3 ml of double distilled water, and then the water-soluble component was eluted from the cartridge using water.
  • the cartridges were then dried completely before eluting the non-sugar components. After drying, the non-sugar components were eluted with 3 ⁇ 2 ml of 100% methanol using a slow (e.g., drop wise) flow rate and eluates were collected into tubes. The eluted samples were evaporated to dryness under N 2 at 45° C. and then dissolved in 500 ⁇ l of milliQ water. Both the water eluate and methanol eluate were then tested for their inhibitory activities against ACE. The freeze-dried material from each of these steps was used to test for the presence of anti-platelet activities.
  • Angiotensin I-converting enzyme (ACE, EC 3.4.15.1) is a circulating enzyme that participates in the body's renin-angiotensin system that regulates blood pressure.
  • ACE Angiotensin I-converting enzyme
  • Angiotensin I-converting enzyme (ACE, EC 3.4.15.1) is a circulating enzyme that participates in the body's renin-angiotensin system regulates blood pressure.
  • ACE Angiotensin I-converting enzyme
  • the effect of tomato juice and sugar-free tomato extract on the serum ACE activity was measured using the Angiotensin Converting Enzyme Assay REA Direct kit (radio enzymatic assay) (Buhlmann, Germany).
  • the serum 50 ⁇ L was incubated with different amounts of sugar free extract or volumes of kiwifruit juice for 15 min at 37 C. After the incubation the ACE activity of the serum was measured using the ACE kit.
  • Anti-platelet activity of the sugar-free tomato extract was measured in platelet rich plasma (PRP).
  • PRP platelet rich plasma
  • the pH of all samples was adjusted to 7.4 prior testing their effect on platelet aggregation.
  • Venous blood was collected from volunteers who had not taken any medications for at least 14 days before donation.
  • Blood (20-30 ml) was collected using a 19G butterfly needle and coagulation was prevented by mixing the blood samples with acid citrate, (135 mM) in the ratio of 9 parts by volume of blood up to 1 part by volume of acid citrate.
  • PRP was prepared from the samples by centrifuging the blood at 180 ⁇ g for 15 min. at room temperature.
  • the amounts of tomato extract as indicated in the table was incubated with 0.225 ml of PRP at 37° C. for 15 min.
  • FIG. 1 also provides a graph depicting the effect of sugar free tomato extract on inhibition of activity of pure ACE protein.
  • ACE activity was measured by a radioactivity assay as described.
  • ACE enzyme from rabbit lung (Sigma product no A6778) EC 3.4.15.1 CAS number 9015-821-1 was used.
  • Increasing amounts of ACE protein were incubated in the absence and presence of 30 uL of sugar free tomato extract (Fruitflow) for 30 min at 37 C and the residual ACE activity was then measured.
  • the tomato extract completely almost inhibited ACE activity compared with the untreated control ACE activity.

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