GB2344996A

GB2344996A - A solid stable aggregate formed from a pyruvate component and a carbohydrate component

Info

Publication number: GB2344996A
Application number: GB9930382A
Authority: GB
Inventors: Ivo Pischel
Original assignee: SKW Trostberg AG
Current assignee: Evonik Operations GmbH
Priority date: 1998-12-23
Filing date: 1999-12-22
Publication date: 2000-06-28
Also published as: GB9930382D0

Abstract

Solid, stable aggregates are formed from pyruvic acid or its salts in combination with a carbohydrate component, preferably maltodextrin. The constituents are present in a weight ratio of from 0.01 to 100 : 1 of pyruvate to carbohydrate. The carbohydrate component which is, in effect, a polyhydroxyaldehyde or polyhydroxyketone may be a sugar such as glucose or lactose, a polysaccharide, such as maltodextrin or a sugar alcohol such as used in anhydrous form, as hydrates or as moist products. The pyruvic acid is preferably used as anhydrous acid, in aqueous, alcoholic or organic solution or it may be generated in-situ as an intermediate, from the reaction of sodium pyruvate with an inorganic acid. The aggregates may be prepared by reacting the carbohydrate component, in the form of a solution, suspension or as a solid substance with a pyruvic acid or pyruvate solution at a temperature from -20 to +20 {C. Subsequent treatment of the mixture of pyruvic acid and carbohydrate produced may involve a liquid phase separation step, a thermal treatment, treatment with ultrasound or microwaves. The product obtained consists of an aggregate of pyruvic acid and carbohydrate aggregates which may be used for increasing endurance and strength in sport, for weight and body fat reduction, in the health sector, as a food supplement additive and as an animal feed.

Description

2344996 Solid, stable pyruvic acid/carbohydrate(-derivative) aggregates

and hydrates thereof and methods for their preparation

Description

The present invention relates to solid, stable pyruvic acid/carbohydrate(dehvative) aggregates and hydrates thereof, methods for their preparation and use thereof.

It is known that pyruvic acid and its salts, the pyruvates, have valuable physiological, therapeutic and dietetic properties. Pyruvates are used, for example, to increase endurance and strength in sport, for weight and body fat reduction and as a protective substance for body cells and body tissues, especially cardiovascular, hepatic, renal, peritoneal and neuronal tissue, as a substance for inhibiting free-radical formation and as a free-radical scavenger in body cells and body tissues (including synovial tissue), in addition in the health sector and as food supplements.

Pyruvates are also suitable as wound healing compositions and for treating kidney disorders (acute kidney failure, nephrolithiasis).

Free pyruvic acid itself is a very unstable compound, which makes it insufficiently storage-stable for use as a therapeutic (free-radical scavenger, cytoprotection, in obesity etc.) or as a food supplement. This is because during storage, inter alia, di-meric, polymeric and cyclic compounds are formed which can be toxic. During storage pyruvi acid also has a tendency to form above its melting point of 16 'C large amounts of decomposition products based on the formation of acyclic or cyclic dimers or polymers by aldol addition reactions or aldol condensation reactions of pyruvic acid or of the pyruvate ions.

Typical acyclic compounds are para-pyruvic acid (4-hydroxy-4-methyl-2oxoglutaric acid) and its salts and the long chain aldol addition products. In addition, oxal succinic acid and methyl succinic acid can also be formed as by-products. The acyclic pyruvic acid polymers, formed by lactonization reactions, ketalization reactions and other reactions, can form cyclic compounds, for example 2- hydroxy-2 methyl-4-oxoglutaric 5-lactone or trimesic, isophthalic and pyrantricarboxylic acid derivatives (Beilstein, Basic Series Vol. 3, pp. 608-613; 1 st Supplementary Series, "1 2 pp. 217-219; 2nd Supplementary Series, pp. 393-401; 3rd Supplementary Series, pp.

1146-1156; 4th Supplementary Series, pp. 1505-1510). These abovementioned acyclic and cyclic by-products and decomposition products of pyruvic acid and its salts can be physiologically incompatible or toxic.

Hitherto, only the salt formation has been used for stabilizing the unstable pyruvic acid. However, this type of stabilization has proved to be highly problematic, since sodium pyruvate and potassium pyruvate are unsuitable for many physiological applications because of their sodium ion and potassium ion contents.

The object of this invention was therefore to provide a solid and storagestable pyruvic acid in pure and readily meterable form and a method for its preparation.

This object is achieved by providing solid stable aggregates comprising pyruvic acid and a carbohydrate component and hydrates thereof which comprise the constituents, pyruvic acid and carbohydrate (-d e rivative) in a weight ratio from 0.0 1 to 100: 1 and preferably from 0.01 to 1.0: 1.

Surprisingly, these pyruvic acid/ca rbohyd rate aggregates, in addition to the required stability and solid form, are distinguished in that they are completely free from by-products and physiologically unsuitable constituents and, in addition, are very readily meterable, which, in comparison with the liquid pyruvic acid, overall gives the f61.1owing unexpected advantages:

The claimed aggregates have a high purity and are completely free from byproducts; they are thermally stable and therefore have a high storage stability; they are available in the solid state and are thus readily meterabie. In sum they can be processed into solid formulations and can therefore also be used as solid acidulants.

Ail these advantages have not been predictable to this extent.

In practice, of the claimed aggregates, those which have proved very suitable are especially those whose constituents pyruvic acid and ca rbo hydrate (d e rivative)s are in a weight ratio from 0.05 to 0.75: 1 and very particularly preferably in a weight ratio of 0.5: 1.

3 The term pyruvic acid for the purposes of the present invention means both the 2-oxopropionic acid form and the 2,2-dihydroxypropionic acid form.

Preferred variants of the claimed aggregates have a water content from 1 to 30 % by weight. To stabilize pyruvic acid, in principle all carbohydrates, for example polyhydroxyaldehydes (aldoses) and polyhydroxyketones (ketoses), and derivatives 10 thereof can be used. However, according to the present invention particularly the aldohexoses and ketohexoses and the oligosaccharides or polysaccharides derived therefrom and 0-glycosidic derivatives thereof have proved to be useful. In particular, mono-saccharides, for example glucose, fructose and sorbitol, and cyclic and open-chain oligohexoses having from 2 to 10 monomer units, such as sucrose, 15 lactose, arabino-galactan and maltose, but also polysaccharides having from 11 to 106 monomer units, for example insulin, maltodextrins, starch and glycogen, are to be preferred. It is of importance that the carbohydrates can also be used in any desired mixtures. 20 In addition to the solid stable aggregates, the invention also provides methods for the preparation thereof. For this purpose, firstly, the ca rbo hydrate (derivative)s can be reacted in the form of solutions, suspensions or as solid substance with pyruvic acid (solutions) in the temperature range from -20 to +120 OC and preferably between +10 and +90 'C, whereupon the resultant solution is, if appropriate, finally freed from the 25 liquid phases. This can preferably be carried out by solid/liquid separation, distillation, evaporation and/or concentration respectively in vacuum, spray-drying and/or freezedrying, or by any other suitable separation method. Alternatively, a mixture consisting of pyruvic acid (solutions) and solid carbohydrate (derivatives) is subjected to a thermal treatment in the temperature range from -20 to +120 "C, a treatment with 30 ultrasound or microwaves, which can also be performed in vacuum, and leads to the formation of homogeneous aggregates. All these reactions can be performed in the presence of a solvent or diluent or else in the absence of solvent. Suitable solvents or diluents for the claimed preparation 4 method proved to be all customary solvents such as water, alcohols, ethers, ketones, esters, organic acids, aliphatic and aromatic hydrocarbons and mixtures thereof.

According to the invention the carbohydrate (derivatives) can be used in anhydrous form, as hydrates or as moist products. Pyruvic acid can be used as anhydrous acid, in aqueous solution or dissolved in one of the abovementioned alcoholic or organic solvents or diluents, or else formed as an intermediate. Formed as an intermediate means that the pyruvic acid can be generated in situ, for which the invention provides, in p articular the reaction of sodium pyruvate with an inorganic acid such as hydrochloric acid or sulphuric acid in the temperature range from -20 to + 90 "C and preferably from -10 to +60"C, which, if appropriate, can also take place in the presence of a solvent or diluent and for which then again all the abovementioned customary solvents are suitable. A direct reaction of pyruvic acid with the carbohydrate(dedvative)s in the absence of solvents is also possible according to the present invention. All claimed reaction variants can be performed in the known chemical engineering apparatuses such as in kneaders, mixers, blade dryers, agitated vessels or spray dryers. The pyruvic acid/carbohydrate(derivative) aggregates of the invention are obtained in high yield and purity according to the present invention without further necessary purification steps.

The present invention thus provides that either both starting components are used in solid or liquid form or that one component is solid and the other is liquid. It is only necessary to 6hsure that, to prepare the aggregates of the invention with or without hydrate contents, the pyruvic acid and the carbohydrate(dedvative)s are always reacted within the claimed weight ratios.

Because of their excellent properties, the aggregates of the invention are used to increase endurance and strength in the field of sports, for weight and body fat reduction and as a protective substance for body cells and body tissues, particularly cardiovascular, hepatic, ophthalmic, renal and neuronal tissue and also transplanted tissue, and as a substance for inhibiting free-radical formation and as free-radical scavenger in body cells and body tissues (including synovial tissue), in the health sector, in the treatment of obesity and overweight and as a food supplement additive.

Use of the aggregates in animal feeding is also provided according to the invention.

In this context the invention also takes into account use of the aggregates of the invention in pharmaceutical formulations such as tablets, powders, coated tablets, drinks and gelatin capsules, the number of which can be increased as desired and where effervescent tablets and/or effervescent powders are of particular interest.

The present invention is thus an important advance in the use of pyruvic acid in the therapeutic and dietetic sectors and in sports medicine. This is because on the basis of the prior ar t it could not be expected that solid storage-stable pyruvic acid/carbohyd rate (derivative) aggregates are accessible by simple methods and lead to readily meterabie products.

Furthermore it has been found that the pyruvic acid in the preparation variants of the invention does not undergo, or undergoes only very slight, condensation and decomposition reactions with formation of aldol adducts. In addition, the novel preparation of the claimed pyruvic acid/ca rbohyd rate aggregates also succeeds using pyruvic acid generated as an intermediate and without subsequent work-up being necessary. Aqueous pyruvic acid solutions or solvents can also be used, pyruvic acid/carbohyd rate aggregates having defined water of crystallization contents being accessible.

The examples below show the advantages of the present invention.

Examples

1 Preparation of pyruvic acid/maltodextrin aggregates 1.1 10 g of maltodextrin (Cerestar Dry MD 0158) were dissolved at 20 "C in 30 g of water. 2.55 g of pyruvic acid were added to the solution and after a stirring time of 1 hour it was frozen at -35 T. The mixture was then lyophilized, yielding 12.5 g of the pyruvic acid/maltodextrin aggregate having a pyruvic acid content of approximately 21 % by weight.

6 Elemental analysis calculated: C 41.9 %, H 6.3 found: C 42.1 %, H 6.1 %; mp. 140 'C; IR (KBr) [l/cm]: 1023, 1159, 1638, 1736, 2927,3436.

1.2 10 g of maltodextrin (Cerestar Dry MD 0158) were dissolved at 20 'C in 30 g of water. 5.1 g of pyruvic acid were added to the solution and after a stirring time of 1 hour it was frozen at -35 "C. The mixture was then lyophilized, yielding 15 g of the pyruvic acid/maltodextrin aggregate having a pyruvic acid content of approximately 34 % by weight.

mp. - 130 "C; R (KBr) [1 /em] 1023, 1159, 1638, 1736, 2927, 3436.

1.3 10 g of maltodextrin (Cerestar Dry MD 0158) were suspended at40 C in a mixture of 50 mi of ethyl acetate and 5 mi of water. 5 g of pure pyruvic acid were added to the suspension and after a stirring time of 1 hour the suspension was concentrated in vacuo. The product, to remove the residual moisture, was then dried in vacuo (15 mbar) at 50 "C, as a result of which a pyruvic acid-lca rbohyd rate aggregate having a pyruvic acid content of approximately % was obtained.

Elemental analysis calculated: C 41.9 %, H 6.3 %, found: C 42.2 %, H 6.2 %; mp. 140 Q IR (KBr) [l /em]: 1023, 1159, 1638, 1736, 2927, 3436.

2. Preparation of pyruvic acid/maltodextrin-glucose aggregates g of maltodextrin (Cerestar Dry M D 0 158) and 5 g of glucose were dissolved at 20 'C in 30 g of water. 2.55 g of pyruvic acid were added to the solution and after a stirring time of 1 hour it was frozen at -35 "C. The mixture was then lyophilized, yielding 12.4 g of the pyruvic acid/maltodextrin-glucose aggregate having a pyruvic acid content of approximately 21 % by weight.

mp. - 120 'C; IR (KBr) [l/em]: 772, 1023, 1159, 1377, 1638, 1736, 2927, 3392, 3436.

7 3. General preparation instructions for pyruvic acid/carbohyd rate aggregates Method A:

10 g of any desired carbohydrate are to be dissolved at 20 "C in from 30 to g of water. From 2.55 to 10 g of pyruvic acid are added to the solution and after a stirring time of 1 hour the mixture shall be frozen at -35 "C. The mixture is then to be Iyophilized, yielding a pyruvic acid/carbohydrate aggregate having a pyruvic acid content of from 20 to 50 % by weight.

Method B:

g of any desired carbohydrate are to be suspended at 40 "C in a mixture of from 10 to 50 mi of ethyl acetate and from 1 to 10 g of water. From 2.55 to to g of pyruvic acid are added to the suspension and after a stirring time of 1 hour the mixture shall be concentrated in vacuo. The product, to remove residual moisture, is then to be dried at from 20 to 50 OC in vacuo (from 1 to 100 mbar), yielding a pyruvic acid/ carbohydrate aggregate having a pyruvic acid.content of from 20 to 50 % by weight. 20 Method C:

1.. 1 From 2.55 to 10 g of pyruvic acid are to be added at 20 "C to 10 g of any ', 1 1 desired carbohydrate and after 1 hour the mixture, with addition of from 0.5 to mi of water, shall be mixed in a laboratory kneader. The product, to remove residual moisture, is then to be dried at from 20 to 50 C in vacuo (from 1 to 100 mbar), yielding-a pyruvic acid/ca rbohyd rate aggregate having a pyruvic acid content of from 20 to 50 % by weight.

All pyruvic acid/ca rbohyd rate aggregates produced by these methods are obtained as white crystalline powders, the hygroscopicity of the aggregates increasing with increasing pyruvic acid contents.

The table below presents some of the pyruvic acid/carbohyd rate aggregates obtainable according to the methods described in Example 3.

8 Carbohydrate Pyruvic acid Method used M.P. PC] IR (KBr) used content (at 20 % [I/CMI [0/0 wt.] conten) Maltodextrin max. 50 A, B, C -140 1023,1159, 1638, 1736, 2927,3436 Glucose max. 20 A, C hygroscopic Fructose max. 20 A, C hygroscopic Sucrose max. 20 A, B hygroscopic Sorbitol max. 20 A, C hygroscopic Inulin max. 50 A, B, C -105 937,1033, 1137,1282, 1638,1737, 2936,3425 Lactose max. 50 A, B, C -135 567,632, 779,877, 900,1034, 1262,1456, 1656,1737, 2934,3382 Starch max. 50 A, C - 160 (d) 1164,1655, 1736,3435 a-Cyclodextrin max. 30 A,B - 240 (d) 1029,1155, 1298,1639, 1736,2932, - 3392 P-Cyclodextrin max. 40 A, B - 270 (d) 1029,1158, 1736,2927, 3392 -y-Cyclodextrin max. 40 A, B - 250 (d) 1028,1158, 1353,1637, 1736,2932, 3415 Arabinogalactan' max. 40 A, B -120 1081,1397, 1636,1734 (d): decomposes 4. Formulations comprising pyruvic acid/maltodextrin aggregates 4.1 Effervescent (tablet/powder) formulation containing alkali metal hydrogen carbonate or carbonates or alkaline earth metal hydrogen carbonate or carbonates g of a pyruvic acid (34 % by weight)lmaltodextrin aggregate were highly intimately mixed with 3 g of sodium hydrogen carbonate, if appropriate with addition of flavourings, aromatizing ingredients, minerals and sweeteners, vitamins, sugars and pharmaceutical and/or dietetic ingredients. When placed in from 100 to 200 ml of water, the pyruvic acid/maltodextrin aggregate developed an acidic action and caused the mixture to foam, the additive-free formulation giving a clear solution which, in addition to maltodextrin, also contained sodium pyruvate.

4.2 Formulation containing an amino acid 10gofapyruvic acid (34 % byweight)/maltodextrin aggregate were highly intimately mixed with 3 g of glycine', if appropriate with addition of flavourings, aromatizing ingredients, minerals and sweeteners, vitamins, sugars and pharmaceutical and/or dietetic ingredients. When placed in from 100 to 200 ml of water the pyruvic acid/maltodextrin aggregate developed an acidic action and generated in-situ a stable "glycine pyruvate", which, in contrast, was very unstable when the individual compounds pyruvic acid and glycine were combined. The additive-free formulation gave a clear solution which, in addition to maltodextrin, also contained "glycine pyruvate".

Claims

1 Solid stable aggregates comprising a pyruvic acid component and a carbohydrate component or hydrates thereof, which aggregates comprise the constituents pyruvic acid and carbohydrate in a weight ratio of from 0.01 to 100: 1.

2. Aggregates according to Claim 1, characterized in that the components pyruvic acid and carbohydrate are present in a weight ratio of from 0.01 to 1.0: 1, preferably in a weight ratio of from 0.05 to 0.75: 1, particularly preferably in a weight ratio of 0.5: 1.

3. Aggregates according to one of Claims 1 or 2, characterized in that the aggregates comprise from 1 to 30 % by weight of water.

4. Aggregates according to one of Claims 1 to 3, characterized in that the carbohydrate component compdses polyhydroxyaldehydes and/or polyhydroxyketones.

5. Aggregates according to one of Claims 1 to 4, characterized in that the carbohydrate component comprises aldohexoses and/or ketohexoses, in particular oligosaccharides, polysaccharides and/or O-glycosidic derivatives thereof.

6. Aggregates according to one of Claims 1 to 5, characterized in that the carbohydrate component comprises mo nosaccha rides, for example, glucose, fructose and sorbitol, cyclic and open-chain oligohexoses having from 2 to 10 monomer units, for example sucrose, lactose, arabino-galactan and maltose, and/or polysaccharides having from 11 to 106 monomer units, for example inulin, maltodextrins, starch or glycogen.

7. Method for preparing the aggregates according to one of Claims 1 to 6, characterized in that the carbohydrate component is reacted in the form of a solution or suspension or as a solid substance with pyruvic acid (solutions) in the temperature range from -20 to +120 OC, preferably between +10 and +90 "C, and if appropriate the liquid phases are then removed.

8. Method according to Claim 7, characterized in that the liquid phases are removed by solid[liquid separation, distillation, evaporation and/or concentration in each case in vacuo, spray drying and/or freeze drying.

9. Method for preparing the aggregates according to one of Claims 1 to 6 by thermal treatment, treatment with ultrasound or microwave of mixtures consisting of pyruvic acid (solutions) and a solid carbohydrate component in the temperature range from -20 to +1 20T.

10. Method according to Claim 9, characterized in that the treatment is carried out undervacuum.

11. Method according to one of Claims 7 to 10, characterized in that the carbohydrate component is used in anhydrous form, as hydrate or as moist product.

12. Method according to one of Claims 7 to 11, characterized in that the pyruvic acid is used as anhydrous acid, in aqueous, alcoholic or organic solution.

13. Method acording to one of Claims 7 to 12, characterized in that the pyruvic acid is generated in situ.

14. Method according to Claim 13, characterized in that sodium pyruvate is reacted with an inorganic acid, preferably hydrochloric acid or sulphuric acid in the temperature range from -20 to +90 "C, preferably between -10 and 60 T, if appropriate in the presence of a solvent.

15. Method according to one of Claims 7 to 14, characterized in that the solvents used are water, alcohols, ethers, ketones, esters, organic acids and aliphatic or aromatic hydrocarbons and mixtures thereof.

12

16. Method according to one of Claims 7 to 15, characterized in that it is carried out in kneaders, mixers, blade dryers, stirred vessels or spray dryers.

17. Use of the aggregates according to one of Claims 1 to 5 for increasing endurance and strength in sport, for weight reduction and body fat reduction and as protective substance for body cells and body tissues, particularly cardiovascular, hepatic, ophthalmic, renal and neuronal tissue and also transplanted tissue, and as a substance for inhibiting free-radical formation and as free-radical scavenger in body cells and body tissues (including synovial tissue), in the health sector, in the treatment of obesity and overweight, as a food supplement additive and in animal feeding.

18. Use of the aggregates according to one of Claims 1, to 5 in pharmaceutical formulations such a tablets, powders, coated tablets, drinks and gelatin capsules.

19. Solid stable aggregates comprising a pyruvic acid component and a carbohydrate component or hydrates thereof substantially as hereinbefore described with reference to any one of Eles 1.1, 1.2, 1.3, 2, 3, 4.1, or 4.2.

20. A Mthod for producing solid stable aggregates =prising a Pyruvic acid ccrpowent and a carbohydrate c nent or hYdraties' thereof substantially as hereinbefore described with reference to any one of Examples 1.1, 1.2, 1.3, 2, 3, 4.1 or 4.2.