HK1108563B - Leucine-enriched nutritional compositions - Google Patents

Description

Leucine-rich nutritional composition

Methods and nutritional compositions for promoting muscle protein synthesis or controlling tumor-induced weight loss, such as cancer cachexia, are disclosed.

Cachexia is a disease of severe malnutrition and negative nitrogen balance characterized by loss of appetite, i.e. loss or severe loss of appetite, weight loss and muscle atrophy. Physiological, metabolic and behavioral changes in cachexia are associated with patient complaints of weakness, fatigue, gastrointestinal discomfort, sleep/wake disturbances, pain, lassitude, shortness of breath, lethargy, depression, discomfort and fear of burden to the family and to the friends. Although cachexia has traditionally been associated with chronic infections and malignant disease, cachexia has also been identified in patients after extensive traumatic injury and sepsis and in elderly patients with developmental arrest syndrome.

The loss of lean body mass associated with cancer cachexia not only weakens the individual and makes daily activities difficult, but may also weaken the patient to the point that they are not as powerful for chemotherapy and/or radiation therapy.

Two major factors contribute to cancer cachexia, namely craving deficiency and metabolic response to stress, which results in preferential reduction of muscle at a rate greater than would be expected from lack of nutrient intake alone. Therefore, nutritional supplements that improve the rate of muscle mass reduction in cancer patients have important clinical effects.

The inventors have found that: dietary supplements must be more effective than normal food intake to provide beneficial effects when dietary intake is limited below optimal levels for physiological or pathophysiological reasons. This is because in this case, normal food intake is likely to be reduced by the caloric equivalent when dietary supplements are administered. Thus, supplements designed to limit cancer cachexia should stimulate muscle protein synthesis to a higher degree than normal food intake, and should not interfere with the response to dietary intake.

Conventional nutritional supplement testing in cancer cachectic patients does not show significant benefits in terms of weight gain or quality of life. Therefore, there is an urgent need for effective nutritional means that can treat or prevent or ameliorate the effects of tumor-induced weight loss such as cancer cachexia and/or anorexia.

The inventors have now found that: formulations containing free essential amino acids rather than intact proteins are preferred. In particular and surprisingly, the present inventors have found that: nutritional compositions comprising a mixture of essential amino acids, in free and/or salt form, comprising a particularly high amount of leucine, instead of intact proteins, are effective in stimulating muscle protein synthesis.

The compositions of the invention, e.g. in the form of dietary products, e.g. supplements or nutritional or pharmaceutical preparations, for use in the treatment or prevention of cachexia, e.g. cancer cachexia and/or anorexia, can be self-administered for a prolonged period of time without the risk of adverse side effects, but instead have the ability to reverse cachexia, e.g. cancer cachexia and/or to ameliorate the associated symptoms that affect quality of life. The compositions as described hereinafter have excellent taste and thus particularly good convenience and patient acceptance due to increased convenience of administration and ingestion.

In one aspect the present invention provides a composition comprising at least one of isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine or histidine, for example leucine, and at least one of isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine or histidine, in free form and/or in salt form, for example in the form of a pharmaceutically or nutritionally acceptable salt, wherein the leucine content is at least about 10 to about 95%, for example about 10 to about 60%, for example at least about 15, 20, 25, 30 or 35% to about 40, 45, 50 or 55%, based on the weight of the amino-nitrogen source, hereinafter referred to as the composition of the invention.

The term "amino-nitrogen source" as used herein refers to amino acids, such as essential amino acids, conditionally essential amino acids (conditional essential amino acids) or non-essential amino acids, alone or in combination, in free or salt form, for example also including whole proteins.

The term "intact protein" as used herein refers to proteins, e.g. hydrolysed, e.g. partially hydrolysed, and peptides, e.g. amino acids, in non-free or salt form.

According to the present invention, the "intact protein" may be selected from at least one of casein, whey protein, soy protein, collagen, or wheat protein.

In one aspect, the compositions of the invention are provided wherein the leucine in free and/or salt form is present in an amount of at least about 10 to about 35%, such as about 11, 12, 13, 14 or 15 to about 20, 25 or 30%, such as at least about 14 or 15% by weight based on the total amino acid weight.

Another aspect of the invention provides a composition of the invention, wherein leucine is in free and/or salt form in an amount of at least about 20 to about 80%, such as about 20 to about 65%, such as about 25, 30 or 35% to about 40, 45, 50 or 55%, such as about 65% by weight, based on the weight of the amino acid in free and/or salt form.

The term "amino acid" as used herein, unless otherwise indicated, refers to an amino acid in free and/or salt form, selected from at least one of the following amino acids: essential amino acids such as isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, or histidine; conditionally essential amino acids, such as tyrosine, cysteine, arginine or glutamine; or a non-essential amino acid, such as glycine, alanine, proline, serine, glutamic acid, aspartic acid, asparagine, taurine or carnitine.

In another aspect, there is provided a composition of the invention, wherein leucine is in free form and/or in salt form in an amount of at least about 20 to about 95%, such as about 25, 30, 35, 40 or 45% to about 50, 55, 60, 65, 70, 75, 80, 85 or 90%, such as about 95% by weight, based on the weight of essential amino acids in free form and/or in salt form.

The term "essential amino acid" (EAA), as used herein, refers to an essential amino acid, in free and/or salt form, selected from at least one of the following amino acids, unless otherwise specified: isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and histidine. It is to be understood that "leucine" as used herein refers to leucine in free form and/or in salt form, unless otherwise indicated.

The term "total leucine" or "total amino acids, such as essential or conditionally essential or non-essential amino acids" as used herein refers to leucine or amino acids in free and/or salt form as well as leucine or amino acids derived from or bound to the intact protein.

In another aspect, the composition of the invention is provided, wherein the total leucine, i.e. the sum of leucine in free and/or salt form and leucine derived from an intact protein is at least about 10 to about 40%, such as at least about 15 to about 35%, such as at least about 20 to about 30, such as about 21, 22, 23, 24 or 25%, such as about 22% by weight based on the total amino acid weight. The total leucine content in the compositions of the invention may be from about 25 to about 45, such as from about 30 to about 40%, such as about 36% of the total essential amino acids. The compositions of the invention may comprise leucine in free and/or salt form to leucine in intact protein form in a ratio of about 3:1 to about 1:3, e.g. about 2: about 1. In one aspect, the invention provides a composition of the invention comprising total leucine in a ratio of about 3:1 to about 1:3, for example about 1.5: 1: leucine in free and/or salt form.

In another aspect, the invention provides a composition of the invention wherein the amount of leucine, e.g. total leucine, is at most 3 times higher than the maximum amount of any other essential amino acid, e.g. total essential amino acid.

The invention also relates to such compositions, which further comprise branched chain amino acids, such as valine, leucine, isoleucine or mixtures thereof, in free and/or salt form and/or in intact protein form, in an amount of about 30-60%, such as about 35-55%, such as about 30 or 35-45% by weight, based on the weight of the amino-nitrogen source, such as total amino acids.

In a further aspect of the invention, the present composition is provided with a reduced amount of tryptophan or hydroxytryptophan in free and/or salt form and/or in intact protein form, e.g. in an amount of less than about 5%, e.g. less than about 3% by weight based on the weight of the amino-nitrogen source, e.g. total amino acids.

The invention also relates to compositions according to the invention which further comprise threonine in free and/or salt form and/or in intact protein form in an amount of about 3% or 5% to about 11% by weight, based on the weight of the amino-nitrogen source, e.g. total amino acids.

In another aspect, the present invention relates to a composition according to the invention further comprising valine in free and/or salt form and/or in intact protein form in an amount of from about 6 to about 16%, such as from about 8 to about 10% by weight based on the weight of the amino-nitrogen source, such as based on the total amino acids.

In another aspect of the present invention, the composition of the present invention may further comprise conditionally essential amino acids in free and/or salt form and/or in intact protein form selected from at least one of arginine, glutamine, casein and cysteine.

In a preferred embodiment of the invention, the composition of the invention comprises arginine in free form and/or in salt form, e.g. in an amount of about 5% or 10% to about 40%, e.g. about 15% to about 25%, 30% or 35%, e.g. about 15 to 20% by weight, based on the weight of the amino-nitrogen source, e.g. total essential and conditionally essential amino acids. In another aspect, free arginine comprises from about 5% to about 10%, e.g., about 7%, of the total amino acids of the present compositions.

In another embodiment of the invention, the composition of the invention, e.g. a pharmaceutical or nutritional composition, based on the amino-nitrogen source, e.g. total amino acid weight, may have the following amino acid composition: leucine 20-35%, e.g. 30%; isoleucine 3-6%, e.g., 3-4%; valine 5-15%, e.g., 8-12%; methionine 0.5-7%, e.g. 2-5%; 8-12%, e.g., 9-10% phenylalanine; lysine 10-14%, e.g. 12-13%; threonine 8-12%, e.g. 9-11%; histidine 8-12%, e.g. 8-11%; 5-15% of arginine. In another aspect, the compositions of the invention may include the following concentration ranges of amino acids (on a mole% basis): leucine 20-40%, e.g., about 35-40%; isoleucine 3-10%, e.g., about 7%; valine 5-15%, e.g., about 10%; methionine 0.5-7%, e.g., about 5%; phenylalanine 5-12%, e.g., about 5%; lysine 8-20%, e.g., about 9%; threonine 6-12%, e.g., about 6%; histidine 3-8%, e.g., about 3%; tryptophan 0-4%, e.g., about 1%; arginine 5-15%, e.g., about 13%. The amino acids may be in free and/or salt form and/or in the form of the intact protein, e.g. in free form or predominantly in free form. The compositions of the invention may in particular comprise arginine, leucine and methionine in free form and/or in salt form, for example in amounts of about 5% to about 15% arginine, about 10% to about 30% leucine and about 0.5% to about 5% methionine by weight, based on the weight of the amino-nitrogen source, for example of the total amino acids. In another aspect, the compositions of the present invention may comprise arginine leucine methionine in free form and/or salt form in a ratio of about 0.1 to about 5: about 0.5 to about 10: about 0.01 to about 1, e.g., about 0.5: about 1: about 0.05.

In another aspect of the invention, the composition of the invention may further comprise glutamine, such as glutamine peptide, for example in an amount of about 4-9g per daily dose.

In another aspect of the present invention, the composition of the present invention further comprises intact proteins, such as at least one protein selected from casein, whey protein, soy protein, collagen or wheat protein, preferably whey protein and/or soy protein and/or casein may be used. For example, the present invention provides a composition comprising leucine in free and/or salt form and intact protein, wherein the leucine in free and/or salt form is present in an amount of about 10%, 15% or 20% to about 25%, 30% or 35%, such as about 15% to about 20%, such as about 18% by weight, based on the weight of intact protein. The composition of the invention may comprise the intact protein leucine in free and/or salt form in a ratio of about 10:1 to about 1:10, such as about 5:1 to about 1:5, such as about 5: 1. The ratio of total amino acids to total leucine may be from about 3:1 to about 6:1, for example from about 4 to 5: 1.

In one aspect, the inventors have discovered that high levels of essential and optionally conditionally essential amino acids can be provided using compositions comprising, in combination:

a) essential and optionally conditionally essential amino acids in free and/or salt form; and

b) intact protein of which

The ratio of total essential and optional conditionally essential amino acids to total amino acids is from about 0.4 to about 0.95, e.g., from about 0.45, 0.5, 0.55 or 0.6 to about 0.7, 0.75, 0.8 or 0.9, e.g., about 0.65. In one aspect, the compositions of the invention provide a ratio of total essential and optional conditionally essential amino acids to total non-essential amino acids of about 0.65 to about 0.45. In another aspect, the compositions of the present invention comprise from about 40 to about 95%, such as about 45, 50, 55 or 60% to about 70, 75, 80 or 90%, such as about 65% by weight of total essential and optionally conditionally essential amino acids, based on total amino acid weight.

In another particular embodiment of the invention, the composition of the invention comprises a mixture of essential amino acids only in free form and/or in salt form, such as leucine only in free form and/or in salt form, and at least one essential amino acid only in free form and/or in salt form.

According to the invention, the composition of the invention may be in the form of a dietary product, such as a supplement or a nutraceutical, such as a health food (dietary food) or a beverage product, such as a complete diet, a partial diet, as a food additive or in the form of a dissolved powder, or in the form of a pharmaceutical preparation, such as a tablet, pill, sachet or capsule.

In a further aspect the invention provides a nutraceutical or beverage product, dietary supplement or nutraceutical or pharmaceutical formulation comprising a composition of the invention.

The composition of the invention in the form of a dietary product, for example a supplement or a pharmaceutical preparation, may consist solely of the composition of the invention and optionally a pharmaceutically or nutritionally acceptable carrier.

The compositions of the present invention may be in the form of a health food or beverage product, for example in the form of a dissolvable powder. The powder may be combined with a liquid, e.g., water, or other liquid such as milk or juice, e.g., in a powder to liquid ratio of about 1 to about 5, to provide a ready-to-use composition, e.g., a ready-to-drink composition or an instant beverage.

Optionally, the compositions of the present invention may be nutritionally complete, i.e., may include vitamins, minerals, trace elements, and nitrogen, carbohydrates, and fat and/or fatty acid sources, such that they may be used as the sole source of nutrition, providing substantially all of the daily required amounts of vitamins, minerals, carbohydrates, fat and/or fatty acids, proteins, and the like. Thus, the composition of the invention may have a nutritionally balanced complete dietary form, e.g. a form suitable for oral or tube feeding, e.g. by nasogastric, nasoduodenal, esophageal stoma, gastrotomy or jejunostomy tube administration, or a peripheral or total parenteral nutrition form. Preferably the composition of the invention is for oral administration.

Surprisingly and unexpectedly, the present inventors have found that: particularly useful compositions for promoting muscle protein synthesis or controlling tumor-induced weight loss, such as cachexia, e.g., cancer cachexia, can be obtained by combining a mixture of essential amino acids, in free form and/or in salt form, alone or in combination with intact proteins as described above, with n-3 polyunsaturated fatty acids, including but not limited to alpha-linolenic acid (LNA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alone or in combination with each other. The effect of such a combination is greater than the effect obtainable with any type of single combination partner in the combination, i.e. greater than the effect of a nutritional therapy using only the essential amino acid mixture in free form and/or in salt form or the n-3 fatty acids as defined herein, alone or in combination with intact proteins.

Thus, in one aspect, the invention further relates to a combination, e.g. for use in promoting muscle protein synthesis or controlling tumor-induced weight loss, such as cachexia, e.g. cancer cachexia, comprising:

(a) essential amino acid mixtures in free and/or salt form, wherein leucine, e.g., total leucine, is at least about 10 to about 40%, e.g., at least about 15 to about 35%, e.g., at least about 20 to about 30, e.g., about 15% to about 25%, e.g., about 22% by weight, based on the amino-nitrogen source, e.g., total amino acid weight; and

(b) at least one n-3 fatty acid selected from the group consisting of alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid;

wherein leucine may be present in a combination of leucine in free and/or salt form and leucine derived from intact proteins, and n-3 fatty acids may be present in free or oil or fat form.

Such combinations are preferably combined preparations or pharmaceutical or nutritional compositions.

Preferably the present composition may comprise EPA and DHA, e.g. in a ratio of EPA and DHA of from about 2:1 to about 1:2, e.g. about 1.5: 1.

In another aspect of the invention, the compositions of the invention may comprise EPA and DHA, alone or in combination, for example EPA alone, in an amount of at least about 600mg to about 2g, for example about 1.5g to about 1.8g, per serving of diet. When combined, the content of EPA may be from about 500mg to about 1.5g, e.g. about 1g, and the content of DHA may be from about 250mg to about 1.5g, e.g. from about 500mg to about 750mg, e.g. about 650mg per serving of diet.

In another aspect of the invention, the composition of the invention may comprise a mixture of n-6, e.g. linoleic acid and n-3 polyunsaturated fatty acids, e.g. selected from linolenic acid, EPA and DHA, e.g. with a ratio of n-6: n-3 polyunsaturated fatty acids of from about 0.1:1 to about 1:0.1, e.g. from about 0.2, 0.5 or 0.8 to about 1, 1.2 or 1.5, e.g. about 1.1: 1.

In another aspect, the compositions of the invention may comprise from about 2g or 2.5g to about 3.5g, for example from about 2.5g or 3g, per serving of diet of monounsaturated fatty acids (MUFA) and from about 3g or 3.5g to about 4g or 6g, for example from about 4.5g or 5g, per serving of diet of polyunsaturated fatty acids (PUFA).

Nutraceuticals, such as health food or beverage products, comprising the composition of the invention comprise, in addition to the mixture of essential amino acids and optionally n-3 fatty acids, in free and/or salt form, other nutritional ingredients, such as fat and/or carbohydrate. Edible oils may be used to prepare the nutritional compositions of the present invention. Edible oils include, but are not limited to, canola oil, Medium Chain Triglycerides (MCT), fish oil, soybean lecithin, corn oil, safflower oil, sunflower oil, high oleic safflower oil, olive oil, borage oil, blackcurrant oil, evening primrose oil, and linseed oil. Fish oils may preferably be used, such as oils containing about 45% EPA and about 10% DHA, such as are known and describedOil available under the trade name Pronova Biocare, Norway; or concentrated fish oil containing, for example, about 70% EPA.

The dosage of edible oil, for example in the form of fish oil, per serving may contain, for example, from about 0.5g to about 3g, for example from about 1.5g to about 2g, of n-3 polyunsaturated fatty acids.

A dose of edible oil per serving of diet may contain, for example, from about 2.5g, 3.5g or 4.5g to about 5.5g, 6.5g or 7.5g, for example about 5.5g, of fish oil and/or from about 0.5g, 1g, 1.5g, 2g or 2.5g to about 3g, 3.5g, 4g, 4.5g or 5g, for example from about 1g to about 3g, for example about 1g of Medium Chain Triglycerides (MCT).

According to the invention, up to 5 or 6, e.g. about 2-3, servings of diet may be administered per day.

In another aspect of the invention, the composition of the invention, e.g. a nutritional composition, may further comprise soluble fibres, such as agar, alginate, carobin, pectin and derivatives thereof, such as pectin from fruits and cooked vegetables and more preferably from citrus fruits and apples; beta-glucans, such as oat beta-glucan; carrageenans, such as kappa, gamma and iota carrageenans; furcellaran (furcellaran); inulin; arabinogalactans; cellulose and its derivatives; scleroglucan; psyllium, such as psyllium husk, mucilage and gums. According to the invention, the gums and mucilages are preferably plant exudates. In particular, the term "gum" as used herein refers to commonly available gums and, more specifically, to konjac (konjac) gum, xanthan gum, guar gum (guar gum), locust bean gum, tara bean gum (tara bean gum), tragacanth gum, acacia gum, karaya gum, ghatti gum, gellan gum and other related sterculia gum, alfalfa, clover, fenugreek, tamarind powder. Natural and modified, e.g. hydrolysed, soluble fibres may be used in the present invention. According to the invention, preferably guar gum, for example hydrolysed guar gum, can be used.

The composition of the invention may further deliver from about 5g to about 15g per day, for example about 9g per day of soluble fibre, for example in the form of inulin and hydrolysed guar gum, for example in 3 servings of a diet each containing about 3 g.

In one embodiment of the invention, the daily amount of the amino-nitrogen source delivered may be at least about 10g to about 60g, such as about 15g to about 55g, such as about 20g to about 50g, such as about 44g to about 54 g. Most preferably, at least about 6g to about 18g, e.g. about 10g to about 12g, of total amino-nitrogen source per daily dose of amino acid in free form and/or in salt form. At least about 3g to about 15g, such as about 6g, 7.5g, 8g or 8.5g to about 12g, such as about 8g, of total amino-nitrogen source per daily dose of essential amino acids in free form and/or in salt form. For example a daily dose of about 15g of amino acid, e.g. in free and/or salt form, may be administered 3 times a day, e.g. in 3 meals each containing about 5g of amino acid, with the same effect. In one aspect, the daily delivery of leucine in free and/or salt form can be from about 5g to about 10g, e.g., about 8 g. The total leucine delivered per day may be from about 10g to about 20g, such as from about 12g to about 15g, such as about 12 g. In one aspect of the invention, the total essential amino acids and optionally the conditionally essential amino acids may be delivered at about 6 to about 21g per serving, such as about 6 to about 12g per serving.

The daily delivery of the optional nutrients referred to above varies with the individual's weight, sex, age and/or medical condition. Accordingly, all proportions referred to above are to be understood as being indicative of preferred or individual inventive teachings only, but not limiting the invention in its broadest aspect.

In another embodiment of the invention, the nutritional product provides at least 100%, e.g. 100%, of the u.s.rda required vitamins and minerals per daily dose.

The present inventors have found that: particularly high amounts of vitamin E can be used in the compositions described above to promote muscle protein synthesis or to control tumor-induced weight loss such as cachexia, e.g., cancer cachexia.

Thus, the present invention in a further aspect relates to a composition according to the invention further comprising tocopherol and/or tocotrienol, e.g. vitamin E (alpha-tocopherol), in an amount of about 50mg to about 400mg, e.g. about 100mg or 200mg to about 300, e.g. about 150, 240mg or 300mg per daily dose, e.g. in 3 parts, each containing about 50 or 100 mg.

The thermogenic density of the present compositions, e.g., nutritional compositions, may be about 1.5kcal/mL, e.g., about 600 to about 1500 kcal/day, e.g., about 720 to about 900 kcal/day, in the form of about 2 to about 5 or 6 meals/day, e.g., in 3 portions, each about 310 kcal. Suitable amounts per serving may range from about 20 to about 500ml, preferably from about 50 to about 250ml, e.g. about 200 or 240 ml. The compositions of the present invention may provide the benefit of using as little as, for example, 2 parts per day. The level of amino-nitrogen source, e.g. intact protein or amino acids, e.g. essential amino acids or fatty acids or carbohydrates, per liter is not critical as long as the recommended amount of the invention is provided in a reasonable volume. Typical nutritional compositions useful according to the invention have a caloric distribution of from about 12 to about 24%, such as about 23%, from a source of amino nitrogen, such as a protein, a combination of amino acids, such as in free and/or salt form, and intact protein; about 40 to about 65%, for example about 46%, from carbohydrate, e.g. maltodextrin and sucrose forms; and about 10 to about 35%, for example about 30%, from fat, e.g. fish oil and vegetable oil forms.

The nutritional compositions of the invention may be prepared as a nutraceutical or beverage product, e.g., in the form of an oral nutritional product, e.g., a nutraceutical beverage such as a ready-to-use beverage, optionally a soft drink, including juices used in bars, frozen milk, yogurt drinks, smoothie or soy-based beverages; or dispersing the nutritional composition of the invention in any kind of food product such as bakery products, cereal bars, snacks, soups, breakfast cereals, muesli, candies, pop-top cans, cookies, biscuits, crackers (such as crisp rice crackers) and dairy products.

Preferably, the composition of the invention is administered as a nutraceutical, e.g. as part of a food, e.g. in the form of a health drink, e.g. a ready-to-use beverage.

The nutritional composition of the invention may be administered in the form of a single composition containing all ingredients, such as essential amino acids, fatty acids and/or soluble fibers; or each ingredient may be administered separately. For example, a liquid nutritional product, such as a syrup, suspension, emulsion or solution form, if any, may contain all ingredients except essential amino acids, e.g., except branched chain amino acids and/or glutamine, e.g., glutamine peptides. For example, if branched chain amino acids and/or glutamine, e.g., glutamine peptide, are present, they can be administered in the form of a solid oral dosage form, e.g., a capsule, pill, tablet, dragee, or sachet.

Solid oral dosage forms are prepared in a manner known per se, for example by means of conventional mixing, granulating, shaping, dissolving or lyophilizing processes.

For example, a composition for oral administration can be obtained by: combining the active ingredient with a solid carrier; optionally granulating the resulting mixture and processing the mixture or granules, if desired or necessary after addition of suitable excipients, into tablet or dragee cores.

Suitable physiologically acceptable carriers may be, inter alia: fillers, such as sugars, for example lactose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, for example starch pastes made using corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone; and if desired a disintegrating agent such as the above-mentioned starches and carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. In one aspect of the invention, the composition of the invention may be free of lactose. Further excipients may be, in particular, flow regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate; and/or polyethylene glycol. Dragee cores may be provided with suitable coating layers, using in particular concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or lozenge coating, for example, for the purpose of identifying or indicating different dosages of the active ingredient.

Other orally administrable compositions may be in the form of hard gelatin capsules or soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Hard gelatin capsules may contain the compositions of the invention in particulate form, for example in admixture with: fillers such as lactose; binders such as starch; and/or glidants such as talc or magnesium stearate; and if desired, stabilizers. In soft capsules, the compositions according to the invention are preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oils or liquid polyethylene glycols, to which stabilizers may likewise be added.

Conventional additives may be included in the compositions of the present invention, including any additive selected from the group consisting of: a preservative; a chelating agent; a penetrant; a buffering agent or pH adjusting agent; an effervescent agent; sweeteners, such as artificial sweeteners; a flavoring agent; a colorant; taste masking agents; an acidifying agent; an emulsifier; a stabilizer; a thickener; a suspending agent; a dispersing or wetting agent; an antioxidant; an acidifying agent; a tissue forming agent; defoaming agents, and the like.

In addition to the above, the present invention also provides a process for the preparation of a composition as defined above, such as a nutraceutical or pharmaceutical preparation, comprising the steps of: the ingredients of the composition are mixed into an intimate mixture and the resulting composition is mixed into a food or beverage product, such as a ready-to-use beverage, or formulated in a unit dosage form, such as by filling the composition into capsules, if desired.

In another aspect, the invention provides a method of controlling tumor-induced weight loss, such as cachexia, e.g., cancer cachexia, e.g., treating or preventing or ameliorating the effects of cachexia, e.g., cancer cachexia, and/or anorexia, comprising enterally administering to a human in need of such treatment any of the compositions disclosed herein.

In another aspect, the present invention provides a method of promoting or stimulating muscle protein synthesis or ameliorating sarcopenia in a human comprising enterally administering to a human in need of such treatment a composition of the present invention.

In another aspect, the invention provides a method of preventing catabolism and increasing protein synthesis in a subject undergoing metabolic stress comprising administering to a human in need of such treatment a composition of the invention.

The invention further provides the use of a composition as described herein for dietary modulation of malnutrition, for example protein-energy malnutrition.

The present invention provides in a further aspect the use of a composition of the invention for the preparation of a medicament for the treatment and/or prevention of tumor-induced weight loss such as cachexia, e.g. cancer cachexia and/or anorexia, amelioration of the effects of cachexia, e.g. cancer cachexia and/or anorexia, stimulation of muscle protein synthesis or amelioration of sarcopenia in a human.

The treatment methods or uses as described herein are applicable to tumor-induced weight loss such as cancer cachexia or anorexia in human patients with different cancers, for example liver, breast, lung, prostate, gastrointestinal or pancreatic cancer. Cachexia or anorexia may be associated with the disease itself or with therapeutic effects.

The therapeutic method or use of the invention may be used in combination with pharmacological and optionally/complementary drug therapy and/or with educational intervention, for example for the treatment and control of physical and emotional symptoms associated with cachexia, such as cancer cachexia and/or anorexia. For example, the compositions of the present invention may be used in combination with anti-cancer agents, such as 5-fluorouracil, mitomycin-C, doxorubicin, chloroethyl nitrosoureas and methotrexate. In another aspect, the composition may be used in combination with interleukin-15.

In a further aspect, the present invention provides a combination pharmaceutical formulation for simultaneous, separate or sequential use in the treatment or prevention of cachexia, e.g. cancer cachexia and/or anorexia, comprising a composition of the invention and one or more anticancer agents.

Depending on the form of use of the composition of the invention, i.e. as a complete food, a food component, a food additive, a drink, a sachet, a tablet or a capsule, the composition of the invention may be administered from 1 to 5-6 times per day. For patients using the composition of the present invention as a normal dietary supplement, the daily dose may be 2 parts per day. For patients receiving the composition of the invention as a total daily nutritional intake, up to 6 meals per day may be recommended. The use of the composition of the invention is not limited to a specific time of day, and may for example be taken with a staple food, preferably between meals.

The composition of the present invention may be administered under the supervision of a medical professional, or the composition of the present invention may be self-administered.

For the treatment of tumor-induced weight loss such as cachexia, e.g. cancer cachexia and/or anorexia under clinical supervision, it is possible to combine nutritional means with conventional drug therapies such as anticancer drugs. The anti-cancer agent may conveniently be co-formulated with the composition of the invention into standard pharmaceutical dosage forms. In another aspect of the invention, the compositions of the invention may be formulated as a kit for separate, sequential or simultaneous administration with one or more anticancer agents.

Most preferably, the compositions of the invention, e.g., nutritional compositions or dietary supplements, may be consumed during patient care and treatment, e.g., until the patient's weight is restored or lean body mass is increased. Because these preparations can be safely consumed, cachexia or anorexia patients can continue to take these supplements as long as they need them, e.g., until normal or lean body mass is restored. Early intervention may be a critical success factor for improving the outcome of patients with cachexia, such as cancer cachexia.

Any person considered to be at risk of tumor-induced weight loss, e.g. cachexia and/or anorexia, or a subject already suffering from cachexia, e.g. cancer cachexia and/or anorexia, may benefit from ingesting a composition of the invention. The compositions of the present invention may be particularly suitable for use in patients with solid tumors that have cachexia or are at risk of developing it. By stimulating the anabolism of muscle proteins, the compositions of the present invention may have the following capabilities: reversing tumor-induced weight loss, e.g., cachexia or reducing the proportion thereof; promoting weight gain; stimulating muscle growth; improving the immune function; restoring metabolic balance; maintaining increased resistance to infection, improving tolerance to cancer therapy, enhancing response to cancer therapy; the morbidity is reduced; improving symptoms related to life quality, such as weakness, fatigue, gastrointestinal stress, sleep/wake disorder, pain, listlessness, short breath, lethargy, depression, and discomfort.

According to the presently claimed invention, natural compounds that do not exhibit any serious side effects can be used to effectively improve symptoms and conditions associated with tumor-induced weight loss, such as cachexia and/or anorexia. Furthermore, the method of the invention is well tolerated, e.g. does not cause any discomfort or nausea and is convenient to use.

The use of all compositions of the invention can be observed in standard clinical trials, e.g. in indications and standard animal models as described above, e.g. for mammals, e.g. adults, using a dose of the amino acids in free form and/or in salt form in the range of from about 0.05 to about 0.3g/kg body weight/day, preferably from about 0.085 to about 0.25g/kg body weight/day, more preferably from about 0.1 or 0.15 to about 0.2g/kg body weight/day; or a dose of total essential amino acids in an amount ranging from about 6 to about 12g or up to about 21g per serving of diet; or from about 36 to about 72g total essential amino acids per day. The effect of the composition of the invention in the prevention and treatment of tumor-induced weight loss, e.g. cachexia, such as changes in food intake, body weight, anthropometric measures, serum levels of lipids, fatty acids, amino acids, serum markers, 5-hydroxytryptamine, C-active protein, TNF α, IL-1 levels, tumor morphology can be monitored by any method known to the person skilled in the art.

A human clinical trial can be performed as follows:

a randomized double blind study comparing the composition of the invention with a standard nutritional supplement was performed in patients with advanced pancreatic cancer: for example, a dosage of the amino acid in free form and/or in salt form is used in an amount ranging from about 0.05 to about 0.3g/kg body weight/day, preferably from about 0.085 to about 0.25g/kg body weight/day, more preferably from about 0.1 or 0.15 to about 0.2g/kg body weight/day; and a dose of n-3 polyunsaturated fatty acid in the range of about 0.05 to about 0.3g/kg body weight/day, preferably about 0.06 to about 0.2g/kg body weight/day, more preferably about 0.06 to about 0.13 or 0.15g/kg body weight/day; or using a dose of total essential amino acids in an amount ranging from about 6 to about 12g or up to about 21 g/serving or from about 36 to about 72g total essential oxyacids per day for the purpose of comparing effects on lean body mass, assessing effects on serum and urine mediators, pro-inflammatory cytokines and muscle metabolism and assessing changes in behavioral state, quality of life and viability. 125 patients were tested per treatment group, for example, to evaluate the following parameters: change in lean body mass, body weight, nutrient intake and fatty acid analysis between baseline and week 12. In addition, for a subset of 40 patients, a baseline-3 week study can be performed as follows: a urolytic protein inducing factor; acute phase protein response (C-active protein concentration); and pro-inflammatory cytokines, ubiquitin metabolism (muscle biopsies performed in 15 patients); as well as the acceptability of the product, such as taste and compliance with a treatment regimen.

The invention will now be further illustrated by the following examples.

Example 1

Experiments were performed in healthy elderly subjects (x ═ 71 ± 2 years) to determine whether non-essential amino acids in the amino acid mixture, i.e. amino acids synthesized in vivo in sufficient proportions to provide daily requirements, were required to stimulate muscle protein synthesis. The response of muscle protein metabolism over a 3 hour period to either 18g of Essential Amino Acids (EAA) or 40g of balanced amino acids (BAA, EAA +22g of non-essential amino acids) administered orally was compared. Use of L-²H₅Phenylalanine infusion, bone arterial and venous cannulation, and muscle biopsy to determine the basal status and muscle protein metabolism during oral amino acids. The exact amino acid mixtures tested are shown in table 1.

TABLE 1 amino acid content in two supplements administered to two groups of elderly subjects

Supplements were prepared from the amino acid crystals and dissolved in 540ml water containing sugarless flavours.

Results

In both groups, net muscle protein synthesis (reflected by phenylalanine kinetics) starts from basal levels (p)<0.01) similarly increased (BAA: -16 ± 5 to 16 ± 4); EAA: -18. + -. 5-14. + -. 13nmol^-1100ml leg^-1) This is due to similar muscle protein synthesis (BAA: 43 +/-67 +/-11; EAA: 62 +/-6-75 +/-10 nmol min^-1100mlleg^-1) Increase (p)<0.01) and no decomposition change. The results indicate that only essential amino acids can lead to amino acid-induced stimulation of muscle protein anabolism.

Example 2

The effect of the free essential amino acid mixture on stimulation of muscle protein synthesis was compared with the effect of the same amount of protein. Older volunteers (n ═ 5) were given 15g of free essential amino acids (leucine, isoleucine, methionine, phenylalanine, histidine, lysine and threonine) in one group, and 15g of whey protein in the other group. The results are shown in FIGS. 1 and 2. Use was made of a mixture of peptides such as Biolo et al, journal of physiology in the United states (Am J Physi0l)267 (39): the A-V equilibrium technique and stable isotope tracers described in E467-474, 1994, which is incorporated herein by reference, determine the net muscle protein synthesis, i.e. the equilibrium between protein synthesis and breakdown. Although whey protein is a rapidly absorbed protein compared to other proteins such as casein, the change in plasma phenylalanine concentration (representative of all EAAs) is moderate and transient (figure 1). In contrast, phenylalanine concentrations peaked rapidly and reached extremely high concentrations after ingestion of EAA (fig. 2). The response of the net protein synthesis is also shown in FIGS. 1 and 2. The net equilibrium pattern is comparable to the change in concentration. The overall response to EAA beverages was more than 2-fold that of intact protein, while the amount of N ingested was comparable (figure 3).

The results show that: ingestion of EAA in elderly individuals in non-stressed states is more effective at stimulating net muscle protein synthesis than ingestion of a comparable amount of intact protein.

Figure 1 shows the response of plasma phenylalanine concentration and net balance (reflecting net protein synthesis) to the intake of 15g whey protein.

FIG. 2 shows the response of phenylalanine concentration and net equilibrium to 15g of essential amino acid solution (EAA).

Figure 3 shows a comparison of net muscle protein synthesis versus EAA versus overall response to whey protein. Significant difference, p < 0.001.

Example 3

To investigate the optimal free amino acid mixture for stimulating the synthesis of net muscle protein, a series of studies were performed in new zealand white rabbits weighing about 4.5 kg. By comparison with a library such as Biolo et al, J ParentEnteral Nutr, 16: 305-315, 1992 for quantification of net muscle protein balance using similar techniques as used in human studies, which is incorporated herein by reference, except that a flow probe is used to measure leg blood flow. This animal model was designed to represent the surgically induced stress model required by the collection of samples and is therefore considered a good model for critically ill cancer patients. Rabbits were infused with different amino acid mixtures and muscle response was quantified.

The groups were as follows:

control group: without amino acids

Group AA: equilibrium AA solution (10%) containing all amino acids

(27.3μmol·kg^-1·min^-1)

EAA group: only essential amino acids (27.3. mu. mol. kg)^-1·min^-1)

Leu (25%) + AA group: leucine was added to the equilibrium AA solution to 25% of the total nitrogen and

general infusionNitrogen was the same as in the other groups (27.3. mu. mol. kg)^-1·min^-1)

Leu (35%) + group AA: the same as above, but Leu accounts for 35% of the total

Leu alone: leucine of only 8.3. mu. mol. kg. min

The amino acid composition in each mixture is shown in table 2.

TABLE 2 amino acid composition in 100ml infusion solution

Table 3 compares the amount of leucine infused relative to total N

Table 3.

(1) Leucine infusion

Data are in μmol kg^-1·min^-1Mean of the counts. + -. SEM. P compared with control group<0.05. No statistical analysis was performed in the EAA group.

The results are shown in Table 4.

TABLE 4 protein dynamics in muscle

Data are in μmol kg^-1·min^-1Mean of the counts. + -. SEM. P compared with control group<0.05。

Neither the equilibration solution nor the EAA solution stimulated net muscle synthesis at the indicated doses. In contrast, when the mixture is rich in leucine, a stimulating effect on the synthesis is observed.

Example 4

An EAA + arginine mixture for a nutritional supplement effective in ameliorating sarcopenia in a cancer patient. Values are% of total amino acids (on a molar basis).

4.14.24.34.4 range

Leucine 303038.825-40

Isoleucine 347.43-10

Valine 9810.45-10

Methionine 354.61-5

Phenylalanine 1095.55-12

Lysine 13129.48-20

Threonine 9116.46-12

Histidine 8113.43-8

Arginine 151013.010-15

Tryptophan-1.21-4

100 100 100 62-115

Example 5

A cancer supplement in the form of a ready-to-drink composition.

Example 5A

Percentage of Diet of gram per portion

Water 66.6667176.667

Canola oil 1.85674.920

MCT oil 1.04112.759

4510 (Fish oil) 1.18783.148

DHA(algae oil) 0.35110.930

Casein acid Ca 6.890018.259

1.6978 4.499

Arginine 0.69441.840

Leucine 0.55111.460

Valine 0.29780.789

Methionine 0.03000.080

Phenylalanine 0.24560.651

Sucrose 7.608920.164

Corn syrup (25DE) 9.434425.001

Potassium citrate 0.18890.501

Sodium citrate 0.18890.501

Lactic acid 0.04440.118

Fragrance 0.39891.057

Sucrolose 0.0700 0.186

Sodium chloride 0.04000.106

Mono-and diglycerides 0.13220.350

Defoaming agent 0.00220.006

Ascorbic acid sodium 0.03000.080

Vitamin/mineral premix 0.35110.930

100.000 265.000

In total (per 100g)

A total of 265 g (per diet)

Example 5B

The method comprises the following steps: heating water to 160F and adding water4510、DHAPerfume, sucralose, sodium chloride, sodium ascorbate, and lactic acid. The mixture was cooled to below 100F and the pH was adjusted to 6.5 with lactic acid. The mixture was heated to 140F with stirring and homogenized at 2500psi after a 5 minute hold time. Adding the remaining groupsThe mixture was pre-heated to 150F, heated at 290F for 4 seconds and homogenized at 2500 psi.

As vitamin/mineral premixture, the following composition can be used:

maltodextrin powder 10DE 37.404155

Dipotassium phosphate 35.701500

Magnesium oxide 8.330400

Vitamin E acetate 7.168900

Tricalcium phosphate 4.760200

Ferrous sulfate 1.387600

Zinc sulfate 1.042500

Biotin, 1% Producer 0.933000

Nicotinamide (B3) 0.761600

Palmitic acid vitamin A0.606900

Calcium pantothenate 0.430800

Copper gluconate 0.380800

Vitamin K0.297500

Cyanocobalamin (B12) 0.202300

Minerals: manganese sulfate (monohydrate), USP, KOSHER 0.172860

Vitamin D30.119000

Pyridoxine hydrochloride (B6) 0.095200

Potassium iodide 10% 0.055258

Thiamine hydrochloride (B1) 0.054700

Riboflavin (B2) 0.054700

Minerals: chromium acetate (monohydrate) KOSHER 0.015480

Pure folic acid 0.015333

Minerals: sodium molybdate (dihydrate)

(ACS reagent grade) KOSHER 0.005160

Minerals: sodium selenite (anhydrous) KOSHER 0.004154

Total 100.000000

Canola oil is from Columbus Foods, US

MCT oil from Stepan Company

4510 (Fish oil) from Pronova Biocare, Lysake, Norway

DHA(algal oils) from Martek, Columbia, Maryland

Casein acid Ca from New Zealand Milk Products

From Novartis Nutrition Corporation

Arg, Leu, Val, Met, Phe from Ajinomoto, JP

Corn syrup (25DE) from Cargill

Vanilla flavor as a flavorant

Vitamin/mineral premix from Fortitech

Mono-and diglycerides from American Ingredients

Antifoam from Dow Corning

Example 6

A cancer supplement in the form of a ready-to-drink composition. The composition was prepared according to the method described in example 5.

An equivalent composition can be obtained using 0.0327g vitamin E per 100 ml.

This example illustrates a composition for example for the following purposes when administered daily, for example, 1-6 parts of a 200ml diet: providing a source of amino acids to combat protein energy malnutrition; optimizing protein synthesis and muscle building capacity; help to recover and maintain muscle mass and weight; it is possible to improve the response to cancer therapy and improve the quality of life.

Claims (17)

1. Composition comprising a source of amino nitrogen, wherein the source of amino nitrogen comprises intact protein, leucine in free and/or salt form and at least one of isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine or histidine, wherein the total leucine content is between 20 and 35 wt% based on the total amino acid weight.

2. The composition according to claim 1, further comprising 5 to 40 wt. -% arginine in free and/or salt form and/or 0.5 to 5 wt. -% methionine in free and/or salt form based on the total amino acid weight.

3. A composition according to claim 1 or 2, further comprising an n-3 polyunsaturated fatty acid.

4. A composition according to claim 3, wherein the n-3 polyunsaturated fatty acid is selected from at least one of α -linolenic acid, eicosapentaenoic acid and docosahexaenoic acid.

5. Composition according to claim 4, comprising at least 1g eicosapentaenoic acid per serving diet or at least 2g eicosapentaenoic acid per daily dose.

6. The composition according to claim 1, further comprising a tocopherol and/or a tocotrienol.

7. A composition according to claim 6 comprising at least 50mg vitamin E per serving or at least 150mg vitamin E per daily dose.

8. Composition according to claim 1, comprising 6g to 18g amino acids in free and/or salt form per daily dose.

9. Composition according to claim 1, comprising 5 to 10g leucine in free and/or salt form per daily dose.

10. Composition according to claim 2, comprising 5 to 10g leucine in free and/or salt form per daily dose.

11. A composition according to claim 1 comprising 6 to 21g total essential and optionally conditionally essential amino acids per serving.

12. A pharmaceutical or nutritional composition or dietary supplement comprising a composition according to any one of claims 1 to 11 and a pharmaceutically or nutritionally acceptable carrier.

13. A kit comprising a composition according to any one of claims 1 to 11 or a pharmaceutical or nutraceutical composition or dietary supplement according to claim 12 for separate, sequential or simultaneous administration with one or more anticancer agents.

14. Use of a composition according to any one of claims 1 to 11 for the preparation of a medicament or nutraceutical for controlling tumor-induced weight loss and/or anorexia, stimulating muscle protein synthesis or ameliorating muscle loss or dietary modification of malnutrition in a human.

15. The use according to claim 14, wherein said tumor-induced weight loss is cachexia.

16. Use according to claim 14, wherein the composition is a composition according to any one of claims 2, 8 or 10.

17. Use according to claim 15, wherein the composition is a composition according to any one of claims 2, 8 or 10.