WO2004004740A1

WO2004004740A1 - Aqueous formulation comprising digestible saccharides to reduce the tendency to cardiovascular disease in a subject

Info

Publication number: WO2004004740A1
Application number: PCT/GB2003/002914
Authority: WO
Inventors: Roderick Frederick Gerardus Joseph King; Simon Edmund George Lester
Original assignee: King Roderick Frederick Gerard; Simon Edmund George Lester
Priority date: 2002-07-05
Filing date: 2003-07-07
Publication date: 2004-01-15
Also published as: AU2003281195A1

Abstract

The present invention relates to an aqueous formulation for satisfying at least a part of the dietary carbohydrate requirements of a subject, said aqueous formulation comprising digestible saccharides such as galactose with beneficial effects on a tendency to cardiovascular disease, and to uses of digestible saccharides therapeutically.

Description

AQUEOUS FORMULATION COMPRISING DIGESTIBLE SACCHARIDES TO REDUCE THE TENDENCY TO CARDIOVASCULAR DISEASE IN A SUBJECT

Cardiovascular disease (including coronary events and stroke) is a major worldwide concern which effects individuals of any age. It involves significant mortality and has associated widespread economic and clinical implications.

It is known that poor oral hygiene, an imbalanced diet or nutritional deprivation is behind various dental diseases (Nutrition Science News: Oral Health, M Sterling, December 1999). For example, dental cavities arise from the acidic environment created when bacteria feed on food debris in the teeth. These bacteria together with acid, carbohydrates and bacteria form plaque which accumulates further bacteria and holds acid close to the tooth from where it erodes enamel. Bacteria are also responsible for gum disease such as periodontitis and gingivitis. In serious cases of dental disease, bacteria may penetrate into the vascular system leading to an increased tendency to cardiovascular disease.

Conventional foodstuffs for satisfying the dietary carbohydrate requirements of a subject rely heavily on specific sugar content. Oral bacteria are known to thrive on certain sugary foodstuffs.

Galactose is a naturally occurring hexose for which worldwide demand is negligible and reported uses scarce. Prior publications relating to galactose include:

(1) WO-A-01/28360 (Marathade Ltd) discloses high energy multi-saccharide food products containing galactose and creatine for use in sport or to combat hunger or fatigue;

(2) EP-A-0340491(Biodyn Ag) discloses a foodstuff in which the saccharide component is primarily galactose; (3) WO-A-96/18313 (University of Nottingham) discloses formulations for increasing creatine uptake comprising creatine, insulin and a simple carbohydrate such as galactose;

(4) WO-A-98/06418 (Mannatech, Inc) discloses dietary supplements comprising galactose for nutritional support and treating various disorders;

(5) US-A-5843921 (Childrens Hospital of Los Angeles) discloses formulations for treatment of diabetes comprising less than 3g per unit of simple sugars including galactose;

(6) WO-A-96/08979 (Quadrant Holdings Cambridge Ltd) discloses sports beverages comprising trehalose and galactose;

(7) WO-A-90/02494 (Svenska Mejeriernas Riksforening Ekonomi AB) discloses a sports drink comprising galactose originating from a desalinated and hydrolised whey concentrate;

(8) EP-A-349712 (Biodyn Ag) discloses foodstuffs containing a tooth protecting amount of galactose in the form of lactose hydrosylate; and

(9) EP-A-184121 (Biodyn Ag) discloses anti-caries additives for sucrose foodstuffs comprising galactose I.

It is reported by Desnick et al, The New England Journal of Medicine, 345, July 2001, 9-16, 25-32 and 55-57 that the cardiac variant of the genetic metabolic disorder Fabry's disease which leads to heart disease may be reversed using chaperone therapy in which galactose or recombinant α-galactosidase is administered to the subject by intravenous infusion.

The present invention is based on the recognition that by exercising careful control of carbohydrate nutrition, it may be possible to reduce the tendency to cardiovascular disease. In particular, the present invention relates to an aqueous formulation which essentially satisfies the dietary carbohydrate requirements of a subject in a manner which reduces a tendency to cardiovascular disease.

Thus viewed from one aspect the present invention provides an aqueous formulation for satisfying at least a part of the dietary carbohydrate requirements of a subject, said aqueous formulation comprising: one or more digestible saccharides at a concentration sufficient to satisfy at least a part of the dietary carbohydrate requirements and water, optionally together with one or more sources of mineral ions selected from the group consisting of sodium, potassium, calcium, zinc, copper, manganese and magnesium ions, wherein at least one of said digestible saccharides is present at a concentration sufficient to reduce the tendency to cardiovascular (eg heart and stroke) disease in the subject.

The one or more digestible saccharides may be present at a concentration sufficient to satisfy a major proportion of the dietary carbohydrate requirements (eg to substantially fully (preferably wholly) satisfy the dietary carbohydrate requirements) of the subject.

In a preferred embodiment, the at least one of said digestible saccharides is present at a concentration sufficient to stabilise or activate an enzyme or enzyme system, said enzyme or enzyme system being capable of reducing the tendency to cardiovascular (eg heart and stroke) disease in the subject. Preferably said enzyme or enzyme system is capable either (1) of eliminating a factor associated with the tendency to cardiovascular (eg heart or stroke) disease or (2) of promoting a factor associated with reducing the tendency to cardiovascular (eg heart or stroke) disease.^'

In an embodiment of the invention, the one or more digestible saccharides may be selected from the group consisting of digestible monosaccharides, disaccharides, oligosaccharides and polysaccharides. These may be natural or synthetic digestible saccharides. For example, the one or more digestible saccharides may be selected from the group consisting of galactose, glucose, sucrose, dextrose, fructose, lactose, maltodextrin, starch (soluble) and maltose. Preferably the one or more digestible saccharides includes a digestible monosaccharide, particularly preferably galactose. Preferably the one or more digestible saccharides are galactose and glucose, particularly preferably is galactose (ie alone).

Galactose may be present in an amount sufficient to stabilise an enzyme or enzyme system, said enzyme or enzyme system being capable of reducing the tendency to cardiovascular (eg heart and stroke) disease in the subject. Preferably the enzyme is α- galactosidase A. Enzymes stabilised in this manner are more effective in promoting normal metabolism.

In a preferred embodiment, the total concentration of carbohydrate is in the range 50 to 350mM (broadly corresponding to a carbohydrate concentration of 1-25% w/v depending on the chain length of any carbohydrate higher than a monomer eg 1-15% w/v for maltodextrin or soluble starch), preferably 50 to 310mM, particularly preferably 55 to 250mM, more preferably 60 to 175mM, especially preferably 70 to 160mM.

In a preferred embodiment, galactose and glucose are present in a total amount sufficient to satisfy at least a part of the dietary carbohydrate requirements and the ratio of molar concentration of galactose to glucose is in the range 1 :1 to 1 :0.1, preferably 1 : 1 to 1 :0.15, particularly preferably 1 :1 to 1:0.2, more preferably 1 :1 to 1 :0.4.

In a preferred embodiment, the concentration of galactose in the aqueous formulation is in the range 50 to 300mM, preferably 70 to 250mM, more preferably 80 to 200mM.

In a preferred embodiment, the concentration of glucose in the aqueous formulation is in the range 10 to lOOmM, preferably 20 to 80mM, particularly preferably 40 to 60mM.

The source of sodium ions in the aqueous formulation of the invention is typically a sodium salt. Any physiologically tolerable sodium salt will suffice. Examples include sodium lactate, sodium chloride, sodium citrate, trisodium citrate, sodium hydrogenphosphate, disodium phosphate and sodium bicarbonate. The counter ion (eg chloride, bicarbonate, phosphate, hydrogenphosphate or citrate) may provide stability and buffering capacity.

In a preferred embodiment, the concentration of sodium ions in the aqueous formulation is in the range 1 to lOOmM, preferably 5 to 85mM, particularly preferably 10 to 75mM, more preferably 15 to 45mM, yet more preferably 25 to 40mM. The sodium ions assist co-transport of galactose in the gut.

A preferred embodiment of the aqueous formulation comprises one or more sources of mineral ions selected from the group consisting of sodium, potassium and magnesium ions. The source of a mineral ion is typically a salt such as a chloride, phosphate or citrate.

Preferably the aqueous formulation comprises a source of potassium ions (eg a potassium salt such as potassium chloride or potassium hydrogenphosphate or potassium citrate). In a preferred embodiment, the concentration of potassium ions in the aqueous formulation is in the range 1 to 35mM, preferably 10 to 25mM, particularly preferably 15 to 20mM. The potassium ions are useful in the metabolism of carbohydrates.

Preferably the aqueous formulation comprises a source of magnesium ions (eg a magnesium salt such as magnesium chloride). In a preferred embodiment, the concentration of magnesium ions in the aqueous formulation is in the range 1 to lOmM, preferably 2 to 8mM, particularly preferably 3 to 7mM, more preferably about 5mM.

Preferably the aqueous formulation comprises a source of soluble fibre. In a preferred embodiment, the concentration of fibre in the aqueous formulation is in the range 1 to 10% w/v, preferably 2 to 8% w/v, particularly preferably 4 to 6% w/v, more preferably about 5% w/v.

Preferably the aqueous formulation is adapted for oral administration. The aqueous formulation of the invention may be administered as a consumable (eg a foodstuff, drink or nutritional supplement) or as a medicament. The aqueous formulation is conveniently palatable and for this purpose may further comprise natural or synthetic flavourings such as fruit flavourings (eg blackcurrant, strawberry, apple, citrus, lemon, lime, orange or cranberry) or caffeine and sweeteners. The aqueous formulation of the invention may further comprise physiologically tolerable stabilisers, anti-oxidants (eg ascorbic acid) and preservatives (eg sodium benzoate or sorbic acid) as desired for the safety, palatability and acceptability of the aqueous formulation.

Citric acid may be added to the aqueous formulation for partial or total replacement of any citrate ion and for buffering purposes (typically to maintain pH in the range 2 to 6). Where the source of sodium or other ions is a citrate salt and/or citric acid is added, the concentration of citrate ion in the aqueous formulation may be in the range 5 to 30mM, preferably 10 to 25mM, particularly preferably 10 to 15mM.

Where the source of mineral ions is a chloride salt, the concentration of chloride ion in the aqueous formulation may be in the range 20 to lOOmM, preferably 30 to 90mM, more preferably 40 to 85mM, especially preferably 50 to 80mM.

Where the source of ions is a phosphate salt, the concentration of phosphate ion in the aqueous formulation may be in the range 10 to lOOmM, preferably 30 to 90mM, more preferably 40 to 85mM, especially preferably 45 to 80mM. The phosphate ions are useful in the metabolism of carbohydrates and may act as a buffer.

The administration dosage generally depends on the dietary carbohydrate requirements of the subject and reflects the size and age of the subject. Generally it is advisable for the volume dose to be sufficient to provide the carbohydrate requirements of the subject and to be administered at appropriate intervals. Typically a dose of aqueous formulation is in the range 100 to 200ml.

The aqueous formulation of the invention may be an aqueous solution, aqueous dispersion or aqueous suspension. Preferably the aqueous formulation is an aqueous solution. Preferably the aqueous formulation (eg solution) is a reconstituent aqueous formulation (eg solution). For example, a reconstituent aqueous formulation of the invention may be reconstituted by the end user at the point of use from a composition comprising one or more digestible saccharides and optionally one or more sources of mineral ions by addition of a suitable volume of aqueous solvent (eg water).

Viewed from a further aspect the present invention provides a composition formulable (eg dissolvable) in aqueous solvent (eg water) to form an aqueous formulation as hereinbefore defined, said composition comprising one or more digestible saccharides in an amount sufficient to satisfy at least a part of the dietary carbohydrate requirements of a subject, optionally together with one or more sources of mineral ions selected from the group consisting of sodium, potassium, calcium, zinc, copper, manganese and magnesium ions, wherein at least one of said digestible saccharides is present in an amount sufficient to reduce the tendency to cardiovascular (eg heart and stroke) disease in the subject.

The composition of the invention may be provided in any suitable solid or liquid form. For example, the composition may be provided in solid form such as powdered (eg effervescent or non-effervescent powdered) or tablet form or in liquid form such as gel or liquid concentrate form.

From a further patentable viewpoint, the present invention seeks to improve the treatment of cardiovascular disease using certain digestible saccharides.

Viewed from a yet further aspect the present invention provides the use of one or more digestible saccharides (and optionally one or more sources of mineral ions selected from the group consisting of sodium, potassium, calcium, zinc, copper, manganese or magnesium ions) for the preparation of a medicament for reducing the tendency of a subject to cardiovascular disease, wherein at least one of the one or more digestible saccharides is present in the medicament in an amount sufficient to reduce the tendency to cardiovascular (eg heart and stroke) disease in the subject.

The medicament may be administered by any convenient route (eg orally or by injection). Preferably the medicament is administered orally. It may be in a solid or liquid form and may be administrable as a foodstuff (eg a bar), nutritional supplement or drink or as a tablet or powder. The one or more digestible saccharides may be present at a concentration sufficient to satisfy at least a part of the dietary carbohydrate requirements of the subject. The one or more digestible saccharides may be present at a concentration sufficient to satisfy a major proportion of the dietary carbohydrate requirements (eg to substantially fully (preferably wholly) satisfy the dietary carbohydrate requirements) of the subject.

In a preferred embodiment, the at least one of said digestible saccharides is present at a concentration sufficient to stabilise or activate an enzyme or enzyme system, said enzyme or enzyme system being capable of reducing the tendency to cardiovascular (eg heart and stroke) disease in the subject. Preferably said enzyme or enzyme system is capable either (1) of eliminating a factor associated with the tendency to cardiovascular (eg heart or stroke) disease or (2) of promoting a factor associated with reducing the tendency to cardiovascular (eg heart or stroke) disease.

Preferably the medicament is or comprises (A) an aqueous formulation or (B) a composition formulable (eg dissolvable in water) into an aqueous formulation as hereinbefore defined.

Preferably the one or more digestible saccharides include galactose (preferably alone).

Viewed from an even still further aspect the present invention provides a method for reducing the tendency of a subject to cardiovascular disease comprising the step of: administering an effective dose of an aqueous formulation, composition or medicament as hereinbefore defined to the subject.

The present invention will now be described in a non-limitative sense with reference to the following Examples (by w/v is meant g per 100ml solution).

Example 1 Five reconstituent aqueous formulations A-E were prepared which had the following components and concentrations after reconstitution in water:

A solid mixture of pre- weighed components was prepared such that the specified concentrations were obtained when a certain proportion was dissolved in a specified volume of water. The unit volume of water added to reconstitute the composition may be up to 1000ml. Typically 250ml would be appropriate and a single dose may be made up of one, two or three 250ml unit volumes administered at appropriate intervals. Each aqueous formulation may be flavoured to be palatable as desired using lemon, lime, blackcurrant, orange, citrus or cranberry.

Examples C, D and E (at least) may be particularly useful in reducing the tendency to cardiovascular (eg heart or stroke) disease.

Example 2

Examples F, G, H, I & J correspond respectively to A, B, C, D & E of the fibre-free formulations specified in Example 1. Examples F, G, H, I & J correspond respectively to A, B, C, D & E in terms of their respective use (Examples ABD are equivalent to FGI and Examples CDE are equivalent to HIJ).

Claims

1. An aqueous formulation for satisfying at least a part of the dietary carbohydrate requirements of a subject, said aqueous formulation comprising: one or more digestible saccharides at a concentration sufficient to satisfy at least a part of the dietary carbohydrate requirements and water, optionally together with one or more sources of mineral ions selected from the group consisting of sodium, potassium, calcium, zinc, copper, manganese and magnesium ions, wherein at least one of said digestible saccharides is present at a concentration sufficient to reduce the tendency to cardiovascular disease in the subject.

2. An aqueous formulation as claimed in claim 1 wherein the one or more digestible saccharides are present at a concentration sufficient to satisfy a major proportion of the dietary carbohydrate requirements .

3. An aqueous formulation as claimed in claim 1 or 2 wherein the one or more digestible saccharides is present at a concentration sufficient to satisfy wholly the dietary carbohydrate requirements of the subject.

4. An aqueous formulation as claimed in any preceding claim wherein at least one of said digestible saccharides is present at a concentration sufficient to stabilise or activate an enzyme or enzyme system, said enzyme or enzyme system being capable of reducing the tendency to cardiovascular disease in the subject.

5. An aqueous formulation as claimed in claim 4 wherein said enzyme or enzyme system is capable either (1) of eliminating a factor associated with the tendency to cardiovascular disease or (2) of promoting a factor associated with reducing the tendency to cardiovascular disease.

6. An aqueous formulation as claimed in any preceding claim wherein the one or more digestible saccharides are selected from the group consisting of digestible monosaccharides, disaccharides, oligosaccharides and polysaccharides.

7. An aqueous formulation as claimed in claim 6 wherein the one or more digestible saccharides are selected from the group consisting of galactose, glucose, sucrose, dextrose, fructose, lactose, maltodextrin, starch (soluble) and maltose.

8. An aqueous formulation as claimed in claim 6 or 7 wherein the one or more digestible saccharides includes galactose.

9. An aqueous formulation as claimed in claim 8 wherein the one or more digestible saccharides is galactose alone.

10. An aqueous formulation as claimed in claim 8 or 9 wherein the galactose is present in an amount sufficient to stabilise an enzyme or enzyme system, said enzyme or enzyme system being capable of reducing the tendency to cardiovascular disease in the subject.

11. An aqueous formulation as claimed in claim 10 wherein the enzyme is α-galactosidase A.

12. An aqueous formulation as claimed in any preceding claim wherein the total concentration of carbohydrate is in the range 50 to 350mM, preferably 50 to 310mM, particularly preferably 55 to 250mM, more preferably 60 to 175mM, especially preferably 70 to l60mM.

13. An aqueous formulation as claimed in claim 8 wherein the concentration of galactose in the aqueous formulation is in the range 50 to 300mM, preferably 70 to 250mM, more preferably 80 to 200mM.

14. An aqueous formulation as claimed in any preceding claim wherein galactose and glucose are present in a total amount sufficient to satisfy at least a part of the dietary carbohydrate requirements and the ratio of molar concentration of galactose to glucose is in the range 1 :1 to 1 :0.1, preferably 1 :1 to 1 :0.15, particularly preferably 1 :1 to 1 :0.2, more preferably 1 :1 to 1 :0.4.

15. An aqueous formulation as claimed in any preceding claim wherein the concentration of glucose in the aqueous formulation is in the range 10 to lOOmM, preferably 20 to 80mM, particularly preferably 40 to 60mM.

16. An aqueous formulation as claimed in any preceding claim adapted for oral administration.

17. An aqueous formulation as claimed in any preceding claim being a reconstituent aqueous formulation.

18. A composition formulable in aqueous solvent to form an aqueous formulation as defined in any preceding claim, said composition comprising one or more digestible saccharides in an amount sufficient to satisfy at least a part of the dietary carbohydrate requirements of a subject, optionally together with one or more sources of mineral ions selected from the group consisting of sodium, potassium, calcium, zinc, copper, manganese and magnesium ions, wherein at least one of said digestible saccharides is present in an amount sufficient to reduce the tendency to cardiovascular disease in the subject.

19. Use of one or more digestible saccharides (and optionally one or more sources of mineral ions selected from the group consisting of sodium, potassium, calcium, zinc, copper, manganese or magnesium ions) for the preparation of a medicament for reducing the tendency of a subject to cardiovascular disease, wherein at least one of the one or more digestible saccharides is present in the medicament in an amount sufficient to reduce the tendency to cardiovascular disease in the subject.

20. Use as claimed in claim 19 wherein the one or more digestible saccharides are present at a concentration sufficient to satisfy at least a part of the dietary carbohydrate requirements of the subject.

21. Use as claimed in claim 20 wherein the one or more digestible saccharides are present at a concentration sufficient to satisfy a major proportion of the dietary carbohydrate requirements.

22. Use as claimed in any of claims 19 to 21 wherein the one or more digestible saccharides are present at a concentration sufficient to substantially fully satisfy the dietary carbohydrate requirements of the subject.

23. Use as claimed in any of claims 19 to 22 wherein the one or more digestible saccharides are present at a concentration sufficient to satisfy wholly the dietary carbohydrate requirements of the subject.

24. Use as claimed in any of claims 19 to 23 wherein the medicament is administered orally.

25. Use as claimed in any of claims 19 to 24 wherein the medicament is or comprises an aqueous formulation as defined in any of claims 1 to 16 or a composition as defined in claim 17.

26. Use as claimed in any of claims 19 to 25 wherein the at least one of said digestible saccharides is present at a concentration sufficient to stabilise or activate an enzyme or enzyme system, said enzyme or enzyme system being capable of reducing the tendency to cardiovascular disease in the subject.

27. Use as claimed in claim 26 wherein said enzyme or enzyme system is capable either (1) of eliminating a factor associated with the tendency to cardiovascular disease or (2) of promoting a factor associated with reducing the tendency to cardiovascular disease.

28. Use as claimed in any of claims 19 to 27 wherein the one or more digestible saccharides is galactose alone.