NL1037643C2

NL1037643C2 - Nutritional product comprising a biguanide.

Info

Publication number: NL1037643C2
Application number: NL1037643A
Authority: NL
Inventors: Karel Paul Bouter
Original assignee: Karel Paul Bouter
Priority date: 2010-01-22
Filing date: 2010-01-22
Publication date: 2011-07-25

Description

r' . --s t

Nutritional product comprising a biguanide 5 The invention is directed to a nutritional product comprising a biguanide. The invention is further directed to a nutritional product comprising a biguanide for specific uses.

Changes in societies throughout the world, like reduction in exercise - e.g. as a result of increasing automation - and changes in dietary 10 habits, contribute to a growing part of the population suffering from so called ‘disorders of civilisation’ (also known as ‘Western diseases’). Examples of such disorders include in particular obesity, (weight-related) hypertension, hypercholesterolemia, insulin resistance, metabolic syndrome and diabetes type II.

15 Programs aimed at reducing the risk of developing such disorders by promoting a more healthy life-style are partially successful and have not been able to reduce the number of new patients with diabetes.

However there is not only a need for methods of treatment of subjects directed at preventing the occurrence of such disorders, there is 20 also a need for methods of treatment of subjects already suffering form such a disorder, in order to cure the subject or at least to reduce the risk of developing complications or to reduce the risk of developing a further disorder of civilisation (which may be a more severe disorder).

It is an object of the invention to provide a product for use in a 25 prophylactic or therapeutic treatment of a disorder of civilisation.

It is the inventor’s finding that this object is met by a nutritional product comprising a specific active compound.

Accordingly, the present invention relates to a nutritional product comprising a biguanide (as an active ingredient) for use in the treatment of 30 a disorder of civilisation.

1037643 < ; i 2

In particular, the present invention relates to a nutritional product comprising a biguanide (as an active ingredient) for use in the treatment of obesity. Such treatment may in particular be directed at reducing visceral fat content of a subject.

5 In particular, the present invention relates to a nutritional product comprising a biguanide (as an active ingredient) for use in the treatment of a subject to reduce the risk of developing hypertension or for use in the treatment of a subject to reduce the risk of developing hypercholesterolemia.

In particular, the present invention relates to a nutritional product 10 comprising a biguanide (as an active ingredient) for use in the treatment of a subject to reduce the risk of developing insulin resistance, for use in the treatment of metabolic syndrome or for use in the treatment of a nondiabetic subject to reduce the risk of developing diabetes type II.

Further, the invention relates in particular to a nutritional product 15 comprising a biguanide, usually in a concentration of 25 to 2000 mg per 100 g, based on total weight of the nutritional product, in particular in a concentration of 100-1500 mg per 100 g, based on total weight of the nutritional product, more in particular in a concentration of 250-1000 mg/ 100 g, based on total weight of the nutritional product. A preferred 20 concentration may be selected depending on the type of product and the desired daily dosage. For example, in a product that is typically consumed in a relatively low amount per dosage the concentration can be relatively high, in particular above 1000 mg/100 g, based on total weight of the nutritional product. An example of such a product is a cookie. A product that is typically 25 consumed in a relatively high amount, for example a dairy product such yoghurt or the like, the concentration may be relatively low, in particular 500 mg/100 g or less, based on total weight of the nutritional product.

Usually, the nutritional product further comprises at least one dietary component selected from the group of (i) digestible carbohydrates, 30 (ii) amino acid sources, such as proteins, peptides, free amino acids

I I

3 including salts of free amino acids, (iii) lipids and (iv) dietary fibre. In particular, at a least a digestible carbohydrate and an amino acid source may be present. A nutritional product according to the invention is particularly suitable for use in any one or more of the above mentioned 5 treatments.

Further, the invention relates to a method of treating a subject, the method comprising orally administering a nutritional product (for use) according to the invention.

The term “or” as used herein means “and/or” unless specified 10 otherwise.

The term “a” or “an” as used herein means “at least one” unless specified other wise.

When referring to a noun (e.g. a compound, an additive, etc.) in the singular, the plural is meant to be included. Thus, when referring to a 15 specific moiety, e.g. "compound", this means "at least one" of that moiety, e.g. "at least one compound", unless specified otherwise.

The term ‘treatment’ as used herein includes prophylactic treatments and therapeutic treatments, unless specified otherwise.

It is observed that biguanides are known pharmaceutically active 20 compounds that can be used for instance for the therapeutic treatment of diabetes.

As used herein, the term ‘biguanides’ generally encompasses compounds represented by the formula:

Ri NH NH

\ I I

N—C—N—C—R3 / |

R2 A

25 and salts thereof that are suitable for use in a food or pharmaceutical application. Suitable salts include the chloride salt (biguanide HC1).

4

Herein R1 and R2 independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycle, and alkenyl group, an aryl group, an aralkyl group, an aryloxyalkyl group or a heteroaryl group, or R1 and R2 taken together, represent an alkylene, which may comprise one or more 5 hetero atoms.

R3 represents a primary, secondary or tertiary amine. R3 may in particular be a primary amine. In case R3 represents a secondary or tertiary amine, the substituents for the hydrogens may in particular be a C1-C7 alkyl.

10 Such compounds have, e.g. been described in US patent 7,199,159.

Said alkyl group may in particular be a C1-C7 alkyl, such as methyl, ethyl or propyl.

Said cycloalkyl group may in particular be a C3-C7 cycloalkyl, such as cyclohexyl.

15 Said heterocycle may in particular contain a ring structure of 3 to 7 carbons and at least one heteroatom selected from O, S and N. The alkenyl group may in particular be a C2-C7 alkenyl, such as vinyl or allyl.

Said aryl group may in particular be an aromatic hydrocarbon ring, such as a phenyl group, which is unsubstituted or substituted with a 20 substituent selected from C1-C7 alkyl groups, C2-C7 alkenyl groups, Cl, I,

Br and F. The aryl is either directly attached to the remainder of the compound or by a linker, such as an —NH-, an alkyl (in which case the group may be referred to as aralkyl) or an oxyalkyl (in which case the group may be referred to as aryloxy).

25 Said aralkyl group may in particular be an aryl, as mentioned above, linked to the remainder of the compound via a -(CH2)n- with n being an integer of 1 to 7.

Said aryloxyalkyl group may in particular be an aryl, as mentioned above, linked to the remainder of the compound via a -0-(CH2)n- 30 with n being an integer of 1 to 7 5

Said heteroaryl group may in particular be an unsubstituted or substituted aromatic ring, such as a six-membered aromatic ring, comprising at least one heteroatom selected from S, O and N. The substituents may in particular be as specified for the aryl.

5 If R1 and R2 taken are together, they may in particular form a C2-C7 alkylene which may comprise one or more heteroatoms selected from O and S.

In a preferred embodiment, the biguanide is selected from biguanides wherein R1 and R2 independently represent a methyl, an ethyl 10 or a propyl.

In a specifically preferred embodiment, the biguanide in a nutritional product of the invention is metformin (also known as N,N-dimethylimidodicarbonimidic diamide or 1,1-dmethylbiguanide).

In principle, a product according to the invention may be used by 15 any animal. A product according to the invention is in particular suitable for treatment of humans or other mammals.

A product according to the invention is in particular suitable for male adults, female adults, male adolescents or female adolescents. For humans, the term ‘adults’ is used herein for humans having an age of 18 20 years or more. For humans, the term ‘adolescents’ is used herein for nonadults having an age of at least 11 years.

A human subject preferably meets one or more of the following criteria: - the subject having a body mass index (BMI) of more than 25, in particular 25 of 25.6 or more, more in particular of 30 or more, even more in particular of 35 or more. BMI equals body weight (in kg) divided by length squared (in m2).

- for adults: the subject having a waist size of over 94 cm for males or of over 80 cm for females.

6 ' - the subject-having one or more relatives (first, second or third degree) with diabetes type II, in particular at least one relative of the first degree with diabetes type II.

- the subject having diabetes II, and treated with insuline (this criterion is of 5 course not relevant for a treatment directed at preventing diabetes) - subjects with insulin resistance - subjects with polycysteus ovary syndrome - the subject being non-diabetic.

Specific effects that are indicators for an effective treatment in 10 accordance with the invention may in particular include one or more of the following: - a reduction in waist girth (without a change in daily caloric intake) - a reduction in body weight - a reduction in visceral fat 15 - a reduction in systolic blood pressure - a reduction in diastolic blood pressure - a reduction in fasting blood-glucose level - a reduction in average blood-glucose level (as determined by measuring the glycated haemoglobin (HbAlc) level) 20 - a decrease in blood-triglyceride level - an increase in Hdl-cholesterol (all changes compared to the situation just before the start of the treatment) A composition for use in accordance with the invention is usually administered at least three times per week, preferably - on average - at 25 least once a day, e.g. up to three times a day.

The (average) daily dosage is usually chosen lower than generally dosed when using the biguanide for a therapeutic treatment of a diabetic patient. The (average) daily dosage is usually below 850 mg. Preferably, the (average) daily dose is 500 mg or less, in particular 450 mg or less or 350 mg 7 or less. The (average) daily dosage usually is at least 50 mg, in particular at least 150 mg, more in particular at least 200 mg or at least 250 mg.

In a specific embodiment that dosage is a dosage that is effective in providing a metformin concentration in whole blood in the range of 1,0-5 4,0 mg/1, within about 1 to about 4 hours after consumption, in particular within about 2 to about 4 hours after consumption.

A treatment according to the invention may be continued for a prolonged period, usually for at least 6 weeks, in particular for at least 3 months and may be continued for up to a year or for more than a year, e.g.

10 for the rest of the subject’s life. In case the subject has a high BMI (> 25) or a high waist size (>92 cm for human males or >88 for human females), the treatment may be discontinued after the BMI and/or waist girth has been reduced below said values. Alternatively the treatment may prophylactically be continued, e.g. to avoid the subject becoming obese (again).

15 Besides the biguanide, such as metformin, a nutritional product (for use) according to the invention in general comprises one or more nutritional ingredients, notably one or more nutritional ingredients selected from the group of (i) digestible carbohydrates, (ii) amino acid sources, such as proteins, peptides, free amino acids including salts of free amino acids, 20 (iii) lipids and (iv) dietary fibre. Further, one or more components selected from the group of minerals, trace elements, vitamins and further micronutrients, e.g. antioxidants, may be present. Further, the product may comprise any food additive, in particular one or more food additives selected from the group of colourants, flavours, aroma’s, acids, preservatives, 25 stabilisers, thickening agents and the like.

In an advantageous embodiment, the product comprises juice of a citrus fruit, such as lemon juice. This has been found advantageous with respect to neutralising the taste of the biguanide, which may be experienced as unpleasantly bitter. Another possibility to achieve this is to provide the 30 product with one or more food-grade organic acids, which may be selected 8 from the group of citric acid, malic acid and tartaric acid. The organic acid or fruit juice are usually present in an effective amount to neutralise the taste of the biguanide. An effective amount may be determined empirically, depending on the amount of biguanide and the composition of the product.

5 Further a nutritional product according to the invention may comprise one or more probiotics, e.g. selected from the group of lactic acid bacteria and bifidobacteria.

In general, the nutritional ingredients of a nutritional product according to the invention may be selected from known nutritional 10 ingredients for a specific product.

For instance, the biguanide may be blended with an existing food product, made in a conventional way, for instance a liquid or semi-liquid nutritional product, or be blended with raw materials or intermediate materials which blend is subsequently used for the preparation of a known 15 food product. E.g. the biguanide may be blended with dough (or the materials for forming a dough), after which the dough is used for preparing a baked food product.

In an advantageous embodiment the nutritional product according to the invention, is selected from the group of fermented milk 20 products, unfermented milk products, fermented milk-substitute products, and unfermented milk-substitute products.

As used herein, the term ‘milk-substitute product’ is in particular used for products that are made from vegetable materials and can be used to emulate or replace a dairy product, such as soy-milk, rice milk, almond milk 25 etc.

Preferred examples of fermented products in particular include yoghurts and drinks comprising fermented milk or yoghurt (in the art also referred to as yoghurt drinks), e.g. kefir, lassi or ayran.

9 A preferred example of a non-fermented milk product respectively substitute thereof is butter respectively margarine, in particular butter respectively margarine for use as a spread on bread.

In a further advantageous embodiment, the nutritional product is 5 a cereal product, in particular a baked cereal product, such as a product selected from cookie, cakes and granola bars.

In a specific embodiment, the nutritional product has a lipid content of less 0-6 wt. %, in particular 3 wt. % or less, more in particular 1 wt. % or less. Obviously, such product will not be butter or margarine.

10 The nutritional product may in principle comprise any edible lipid. Usually, unless the nutritional product is lipid-free, it comprises a mixture of lipids. A lipid in a product of the invention may be of vegetable or animal origin. Examples of lipid-mixtures of vegetable origin are vegetable oils (from which fractions may be used). Suitable oils include corn 15 oil, cottonseed oil, canola oil, olive oil, peanut oil, safflower oil, soybean oil, sunflower oil, oils from nuts and oils from fruit seeds. Suitable lipids from animal origin include milk-fat and fractions thereof.

The nutritional product may in particular comprise one or more in triglycerides. A triglyceride in a product according to the invention may be 20 saturated, mono-unsaturated or poly-unsaturated. Preferred polyunsaturated fatty acids include omega-3 and omega-6 polyunsaturated fatty acids. Examples of omega-3 polyunsaturated fatty acids include include alpha-linolenic acid (ALA), eicosopentaenoic acid (EPA) docosapentaenoic acid (DPA), and docosahexanoic acid (DHA)..

25 In a specific embodiment, 50-100 wt. %, in particular 60-98 wt. %, more in particular 70-95 wt. % of the lipids in a product according to the invention is formed by saturated and mono-unsaturated triglycerides.

If present, the polyunsaturated fatty acid content may in particular be in the range of 1-50 wt. %, more in particular in the range of 2-30 40 wt. % or in the rang of 5-30 wt. %.

I f 10

In a specific embodiment, the digestible carbohydrate content is relatively low, in particular less than 50 wt. % based on total compounds contributing to caloric value of the product (i.e. digestible carbohydrates, proteins, peptides and amino acids, lipids), more in particular less than 40 5 wt. % or less, e.g. 1-30 wt.%, based on total compounds contributing to caloric value of the product.

Advantageously, the nutritional product is packaged in a unit-dose packaging, preferably a sealed packaging. Preferably, the nutritional product in the unit-dose package contains 50-500 mg, in particular 150-350 10 mg, more in a particular 200-250 mg biguanide.

The invention will now be illustrated by the following examples.

Example 1: cookie comprising metformin 15 A cookie dough was prepared comprising 1000 mg fine-ground metformin per 100 g conventional cookie dough, by mixing fine-ground metformin into the dough. 40 droplets of lemon juice per 100 g dough were added to the dough comprising the metformin, in order to neutralise the bitter taste of the metformin. Thereafter, the dough was divided in pieces of 20 25 g, from which pieces cookies were baked in a conventional way.

Two human volunteers each consumed one cookie (providing 250 mg metformin) on an empty stomach. Blood samples were taken before consumption, 1 hour after consumption, 2 hours after consumption and 4 hours after consumption. Glucose levels, lipid levels and metformin levels in ! 25 the samples were determined. In the glucose levels and in the lipid levels no significant changes were observed. The results for metformin are shown | in the following table: j 30 r 4 11

Table 1: metformin concentration (mg/1) in blood samples Time subject 1 subject 2 before consumption <0.5 <0.5 1 hr after consumption <0.5 <0.5 2 hrs after consumption 0.7 <0.5 4 hrs after consumption 0.8 0.6

These results show that metformin included in a food product (a product of which the production comprises a severe heating step), is 5 absorbed by subjects consuming the food product to the extent that significant metformin levels are found in blood of said subjects.

During the experiment, no negative side-effect were observed.

Example 2: yoghurt comprising metformin 10 A yoghurt containing metformin is made by mixing fine-ground metformin is mixed into fat-free yoghurt in an amount of 450 mg metformin per 100 ml yoghurt. 10 droplets of lemon juice per 100 ml yoghurt are added to neutralise the metformin taste.

15 The yoghurt is consumed on an empty stomach by human volunteers for a period of 6 weeks in a daily amount of 100 ml per volunteer. The human volunteers have a body mass index of more than 25.6. Before administration of the first dosage also waist-size, body weight and blood pressure are determined.

20 Blood samples are taken before consumption, 1 hour after consumption, 2 hours after consumption and 4 hours after consumption of the first daily dosage (1st day). Glucose levels, glycated haemoglobin (HbAic) levels, lipid levels and metformin levels in the samples are determined.

On the 14th day ,blood glucose levels are determined again, in 25 blood samples taken on an empty stomach.

* » 12

On the 42nd day, blood glucose, glycated haemoglobin (HbAic), lipid and metformin levels are determined again, in blood samples taken on an empty stomach. Further, waist-size, body weight and blood pressure are determined again.

5 103 7 6 43

Claims

A foodstuff comprising a biguanide for use in the treatment of obesity.

A food according to claim 1, wherein the product is intended to reduce an individual's visceral fat content.

3. A foodstuff comprising a biguanide for use in the treatment of an individual for reducing the risk of developing hypertension or for use in the treatment of an individual for reducing the risk of developing hypercholesterolemia.

4. A foodstuff comprising a biguanide for use in the treatment of an individual for reducing the risk of developing insulin resistance, for use in the treatment of metabolic syndrome or for use in the treatment of an individual not suffering from diabetes suffers to reduce the risk of developing type II diabetes.

A foodstuff for use according to one or more of the preceding claims for treatment of an individual who has a body mass index of 25.6 kg / m2 or more, in particular of at least 30 kg / m2.

6. A food according to one or more of the preceding claims for the treatment of an individual who does not suffer from diabetes.

A foodstuff for use according to one or more of the preceding claims, wherein the foodstuff is intended for administration in an amount that provides a daily dose of the biguanide in the range of 50-500 mg, in particular in the range of 150-450 mg.

A foodstuff for use according to one or more of the preceding claims, wherein the biguanide is metformin.

9. A foodstuff comprising a biguanide in a concentration of 25-2000 mg per 100 g, based on the total weight of the foodstuff, which foodstuff further comprises at least one food constituent selected from the group of (i) digestible carbohydrates, (ii) amino acid sources, such as, proteins, peptides, free amino acids including salts of free amino acids, (iii) lipids and (iv) dietary fiber.

A foodstuff according to claim 9, wherein the biguanide is metformin.

A food according to claim 9 or 10, wherein the lipid content is 0-6 wt. %, in particular 3% by weight or less, more in particular 1 wt. % or less.

A foodstuff according to one or more of claims 9-11, wherein the product is packaged in a unit dose package.

A food according to claim 12, wherein the food in the unit dose package contains 50-500 mg, in particular 150-450 mg biguanide.

14. A food according to any one of claims 9-13 wherein the food is selected from the group of fermented milk products, unfermented milk products, unfermented milk substitute products, fermented milk substitute products and baked cereal products, in particular from the group of, yogurts, yogurt substitutes, yoghurt drinks, butter, butter substitutes, cookies, cakes, pies, pastries and muesli bars.