OA13061A

OA13061A - Rehydrating formulation.

Info

Publication number: OA13061A
Application number: OA1200400128A
Authority: OA
Inventors: Roderick Frederick Gerardus Joseph King; Simon Edmund George Lester
Original assignee: Galactogen Products Ltd
Priority date: 2001-11-07
Filing date: 2002-11-04
Publication date: 2006-11-10
Also published as: EA200400636A1; BR0213942A; MXPA04004339A; JP2005508984A; CA2466278A1; CN1582157A; EP1441741A1; GB0126746D0; ZA200403278B; AP2004003051A0

Description

013061 -1-

REHYDRATING FORMULATION

The présent invention relates to an aqueous formulation for combattingdéhydration comprising a low concentration of galactose and a source of sodium ions (eg asodium sait).

There are a nurnber of circumstances in which a subject may suffer déhydrationand associated defîciencies such as îoss of minerai salts. For example, exercise acts todeplete the body of fuel stores and increases the rate of perspiration causing loss of waterand minerai salts. These losses can be significant if exercise is prolonged and particularlyif ambient températures are moderate or high. Other circumstances which may lead todéhydration include excessive températures, nutritional deprivation, fever, diarrhoea andvomiting excess as a resuit of (for example) enterotoxin effects (eg choiera typically in thethird world), viral effects (eg rotavirus typically in the developed world) or post surgicalrest (eg when GI rest is important). Altematively, the circumstances which may lead todéhydration may be seîf-induced (eg through alcohol consumption). In extreme cases, lossof fluid and/or electrolytes may be clinically important or even life threatening, inparticular in children and the elderly.

Humans do not fonction efficiently when dehydrated or when they are suffering anelectrolyte imbalance. Rehydrating drinks containing inorganic salts and/or high sugar (egglucose) content are well established in combatting these disorders. However theadministration of glucose may lead to exaggerated insulin responses.

Galactose is a naturally occurring hexose for which worldwide demand isnegligible and reported uses scarce. Prior publications relating to galactose include: (1) WO-A-01/28360 (Marathade Ltd) discloses high energy multi-saccharide food productscontaining 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 isprimarily galactose; 013061 -2- (3) WO-A-96/18313 (University ofNottingham) discloses formulations for increasingcreatine uptake comprising creatine, insulin and a simple carbohydrate such as galactose; (4) WO-A-98/06418 (Mannatech, Inc) discloses dietary suppléments comprising galactosefor nutritional support and treating varions disorders; 5 (5) US-A-5843921 (Childrens Hospital of Los Angeles) discloses formulations for treatment of diabètes comprising less than 3g per unit of simple sugars including galactose; (6) WO-A-96/08979 (Quadrant Holdings Cambridge Ltd) discloses sports beveragescomprising trehalose and galactose; (7) WO-A-90/02494 (Svenska Mejeriemas Riksforening Ekonomi AB) discloses a sports10 drink comprising galactose originating from a desalinated and hydrolised whey concentrate; (8) EP-A-349712 (Biodyn Ag) discloses foodstuffs containing atooth protecting amount ofgalactose in the form of lactose hydrosylate; and (9) EP-A-184121 (Biodyn Ag) discloses anti-caries additives for sucrose foodstuffs15 comprising galactose I. US-A-5780094 (Marathade Limited) discloses a rehydrating sports drinkcontaining a high concentration of galactose and a proportion of glucose. The absorption ofwater in the intestine is efficient and effective when driven by sodium co-transportinvolving a high concentration of galactose and glucose. Galactose advantageously effects *•0 more rapid intestinal uptake of water than does glucose.

The présent invention is based on the récognition that being physiologicallyadapted to effectively métabolisé galactose and glucose (the two constituent sugars oflactose in milk) children are able to exploit sodium co-transport for effective rehydrationusing a low concentration of galactose. In particuîar, the présent invention relates to an 25 improved rehydrating aqueous formulation comprising a low concentration of galactoseand a sodium sait to combat déhydration resulting from (for example) diarrhoea.

Thus viewed from one aspect the présent invention provides an aqueousformulation for combatting déhydration comprising galactose at a concentration in therange 25 to 135mM, a source of sodium ions and water. 01306 1 -3-

The aqueous formulation of the invention is generally more effective than aconventional glucose-containing rehydrating solution in treating extreme déhydrationwhich might otherwise be fatal to a child. Moreover galactose (unlike glucose) does notelicit a primary insulin response. 5 In a preferred ernbodiment, the concentration of galactose in the aqueous formulation is in the range 25 to 130mM, preferably 37 to 120mM, more preferably 40 to120mM, especially preferably 45 to 90mM.

The source of sodium ions in the aqueous formulation of the invention is typicallya sodium sait. Any physiologically tolerable sodium sait will suffice. Examples include 10 sodium lactate, sodium chloride, sodium citrate, trisodium citrate, sodium hydrogenphosphate, disodium hydrogen phosphate and sodium bicarbonate. The counterion (eg chloride, bicarbonate, phosphate, hydrogenphosphate or citrate) may providestability and buffering capacity and sodium citrate is advantageous for acidosis associatedwith diarrhoea of spécifie aetiology (eg viral). Sodium chloride is preferred. 15 The concentration of sodium ions may be adapted to facilitate sodium co-transport and replacement of electrolyte loss. In a preferred ernbodiment, the concentration ofsodium ions in the aqueous formulation is in the range 25 to lOOmM, preferably 30 to90mM, particularly preferably 35 to 90mM, more preferably 45 to 90mM, yet morepreferably 60 to 90mM. For combatting déhydration as a symptom of severe diarrhoea (eg 20 caused by enterotoxin effects), higher sodium concentrations are preferred (eg 80-90mMsuch as about 90mM). For combatting déhydration as a symptom of less severe diarrhoea(eg caused by viral effects or when hypematraemia is a risk), lower sodium concentrationsare preferred.

An ernbodiment of the aqueous formulation further comprises one or more sources 25 of additional ions (eg potassium, magnésium, calcium or zinc) to advantageously achievereplacement of minerais which hâve been lost as a symptom of (for example) diarrhoea.

The source of an additional ion is typically a sait (eg a minerai sait) such as a chloride. 013061 -4-

Preferably the aqueous formulation comprises a source of potassium ions (eg apotassium sait such as potassium chloride). The potassium sait serves to replace elecirolyteloss. In a preferred embodiment, tire concentration of potassium ions in the aqueousformulation is in the range 5 to 35mM, preferably 10 to 30mM, particularly preferably 15 5 to 25mM, more preferably about 20 to 25mM.

An embodiment of the aqueous formulation of the invention further comprises oneor more additional carbohydrates. In an embodiment of the invention, the one or moreadditional carbohydrates may be a digestible saccharide such as a digestible saccharideselected from one or more of the group consisting of monosaccharides, disaccharides, 10 oligosaccharides and polysaccharides. These may be natural or synthetic saccharides. Forexample, the one or more additional carbohydrates may be selected from the groupconsisting of glucose, sucrose, dextrose, fructose, lactose and maltose. Preferably theadditional carbohydrate is a monosaccharide, particularly preferably glucose. In situationswhere the osmolality of the aqueous formulation is important (eg where hyperosmolar or Î5 isomolar solutions are contra indicated), maltodextrin or higher oligosaccharide may beused in place of glucose.

In a preferred embodiment, the galactose and optionally one or more additionalcarbohydrates of the aqueous formulation are présent in a total amount sufficient to meetthe carbohydrate requirements of sodium co-transport for effective rehydration. In a 20 preferred embodiment, the total concentration of carbohydrate is in the range 50 to 300mM,preferably 50 to 200mM, particularly preferably 55 to 175mM, more preferably 60 to135mM, especially preferably 90 to 130mM.

In a preferred embodiment of the formulation, galactose and glucose are présent ina total amount sufficient to meet the carbohydrate requirements of sodium co-transport in 25 effective rehydration. Typically the ratio of molar concentration of galactose and glucose isin the range 0.6:1 to 1:0.6, preferably 0.8:1 to 1:0.8, particularly preferably 0.9:1 to 1:0.9,more preferably the molar concentration ratio is about 1:1. 013061

In a preferred embodiment, the concentration of glucose in the aqueousformulation is in the range 30 to 135mM, preferably 35 to 130mM, particularly preferably37 to 120mM, more preferably 40 to IOOmM, especialiy preferably 45 to 80mM.

In situations where the osmoiality of the aqueous formulation is important (eg5 where hyperosmolar or isomolar solutions are contra indicated), maltodextrin or higher oligosaccharide is preferably used in place of glucose. Thus the ranges of preferred glucoseconcentration may be satisfied by a concentration of an oligosaccharide with an appropriatechain length. For exampie. in place of glucose at 60mM, a maltodextrin of average chainlength six could be used at lOmM. 10 A general purpose formulation might typically hâve a ratio of sodium ion concentration: carbohydrate concentration of about 1:2 eg a concentration of sodium ions ofabout 60mM and galactose and glucose présent at a total concentration of 120mM. Such aformulation would be useftil where the circumstance leading to déhydration is diarrhoea asa resuit of post surgical rest (eg when GI rest is important) or the circumstance leading to 15 déhydration is self-induced (eg through alcohol consumption).

The aqueous formulation of the invention may be administered by any convenientroute. Preferably the aqueous formulation is adapted for oral administration. For example,the aqueous formulation may be palatable and for this purpose may further comprisenatural or synthetic flavourings such as fruit flavourings (eg blackcurrant, strawberry, 20 apple, citrus, Iemon, lime, orange or cranberry) or caffeine and sweeteners.

The aqueous formulation of the invention may further comprise physiologicallytolerable stabilisers, anti-oxidants (eg ascorbic acid) and preservatives (eg sodium benzoateor sorbic acid) as desired.

The administration dosage generally dépends on the level of déhydration and the25 size and âge of the subject. Generally it is advisable for the dose to be équivalent to or slightly greater than the actual or expected ioss of bodily water and to be administered at 013061 -6- appropriate intervals. Typically a dose of aqueous formulation is in the range 100 to 250ml.

Citric acid may be added to the aqueous formulation for partial or totalreplacement of citrate ion and for buffering purposes (typically to maintain pH in the range2 to 6). Where the source of sodium or other ions is a citrate sait and/or citric acid is added,tire concentration of citrate ion in the aqueous formulation may be in tlie range 5 to 30mM,preferably 10 to 25mM, particularly preferably 10 to 15mM. A phosphate sait may be usedas an alternative buffering agent.

Where the source of sodium (and optionally additional ions) is a chloride sait, theconcentration of chloride 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.For combatting déhydration as a symptom of severe diarrhoea, higher chlorideconcentrations are preferred (eg 70-80mM such as about 80mM).

The aqueous formulation of the invention may be an aqueous solution, aqueousdispersion or aqueous suspension. Preferably the aqueous formulation is an aqueoussolution. Preferably the aqueous formulation (eg solution) is a reconstituent aqueousformulation (eg solution). For example, a reconstituent aqueous formulation of theinvention may be reconstituted by the end user at the point of use from a compositioncomprising galactose and a source of sodium ions (and optionally one or more sources ofadditional ions and one or more additional carbohydrates) by addition of a suitable volumeof aqueous solvent (eg water).

Viewed from a forther aspect the présent invention provides a compositionformulable (eg dissolvable) in water to form an aqueous formulation as hereinbeforedefined, said composition comprising galactose, a source of sodium ions, optionally anadditional carbohydrate and optionally a source of additional ions. For example, thecomposition comprises galactose in an amount sufficient to form a concentration in therange 25 to 135mM in a specified volume of aqueous solvent (eg water) and a source ofsodium ions. 013061 -7-

The composition of the invention may be provided in any suitable soiid or liquidform. For example, the composition may be provided in soiid form such as powdered (egeffervescent or non-effervescent powdered) or tablet form or in liquid form such as gel orliquid concentrate form. 5 Viewed from a yet further aspect the présent invention provides the use of galactose and a source of sodium ions for the préparation of (A) an aqueous 25 to 135mMgalactose formulation for combatting (eg treating or preventing) déhydration or (B) amédicament formulable (eg dissolvable in water) into an aqueous 25 to 135mM galactoseformulation for combatting (eg treating or preventing) déhydration,

10 In a preferred embodiment ofthe use of the invention, the aqueous 25 to I35mM galactose formulation is as hereinbefore defîned.

In a preferred embodiment of the use of the invention, the médicament is acomposition as hereinbefore defîned.

In a preferred embodiment, the présent invention provides the use of galactose and15 a source of sodium ions for the préparation of (A) an aqueous 25 to 135mM galactose formulation for combatting déhydration and associated deficiencies or (B) a médicamentformulable into an aqueous 25 to 135mM galactose formulation for combattingdéhydration and associated deficiencies. The associated deficiencies may be minerai loss,electrolyte imbalance, etc. 20 Jn a preferred embodiment, the présent invention provides the use of galactose and a source of sodium ions for the préparation of (A) an aqueous 25 to 135mM galactoseformulation for combatting déhydration in children (eg infants) or (B) a médicamentformulable into an aqueous 25 to 135mM galactose formulation for combattingdéhydration in children (eg infants). 25 Preferabiy the déhydration and (where présent) associated deficiencies are symptoms of diarrhoea . The diarrhoea may be a resuit of (for example) enterotoxin effects 013061 -S- (eg choiera typically in the third world), virai effects (eg rotavirus typically in thedeveloped world) or post surgical rest (eg when GI rest is important). The concentration ofeach component may be tailored to optimise treatment of déhydration and associateddeficiencies caused by mild, moderate or severe diarrhoea. For combatting déhydration as a 5 symptom of severe diarrhoea, higher sodium and chloride concentrations are prefeired.Altematively, the circumstances which may iead to déhydration may be self-induced (egthrough alcohol consumption).

In a preferred embodiment of the use of the invention, the déhydration orassociated deficiencies are Iife threatening. 10 Viewed from a still yet further aspect the présent invention provides a method for combatting déhydration in a subject comprising the step of: administering an effective dose of an aqueous formulation as hereinbefore deiïned to thesubject.

Viewed from an even still further aspect the présent invention provides a method 13 for combatting déhydration and associated deficiencies in a subject comprising the step of:administering an effective dose of an aqueous formulation as hereinbefore defined to thesubject.

Although the subject may be any âge, preferably the subject is a child (eg aninfant). Preferably the déhydration and (where présent) associated deficiencies are 2© symptoms of dianhoea (eg severe diarrhoea). The diarrhoea may be a resuit of (for example) enterotoxin effects (eg choiera typically in the third world), viral effects (egrotavirus typically in the developed world) or post surgicai rest (eg when GI rest isimportant). Altematively, the circumstances which may lead to déhydration may be self-induced (eg through alcohol consumption). 23 The présent invention will now be described in a non-limitative sense with reference to the following Example. 013061 -9-

Example

Nine reconstituent aqueous formulations A, Al and B-H were prepared which hadthe components and concentrations after reconstitution in water shown in Table 1 :

Table 1

Substance > Concentration mM A(A1) B C D E F G H Galactose 45(90) 60 80 40 45 45 75 55 Glucose 45(0) 60 80 40 45 45 75 55 Sodium Chloride 45 70 25 30 35 20 25 60 Potassium Chloride 25 20 20 15 20 25 20 20 Trisodium Citrate/ Citric Acid 10 10 10 10 15 13.3/ 6.7 0 10 Sucrose 0 0 0 80 20 0 0 0 Fructose 0 0 0 1 2 0 0 0 Sodium bicarbonate 0 0 0 0 0 0 15 0 A solid mixture of pre-weighed components was prepared such that the specified5 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 beup to 1000ml. Typically 250ml would be appropriate and a single dose may be made up ofone, two or three 250ml unit volumes administered at appropriate intervals. Each aqueousformulation may be flavoured to be palatable as desired using lemon, lime, blackcurrant, 10 orange, citrus or eranberry. 013061 -10-

The sodium concentration for compositions F, G and H are 60,40 and 90mMrespectively and the chloride concentrations are 45, 45 and SOmM respectively, Higher sodium and chloride concentrations are désirable for effective treatment of severediarrhoea. Thus compositions F, G and H are useful in the treatment of moderate, mild andsevere diarrhoea respectively.

General puipose formulations I, J, K, L, M and N are shown in Table 2.

Table 2

Substance ? Concentration mM, I J K L M N Galactose 120 120 60 60 60 60 Glucose - - 60 60 - - Sodium Chloride 60 30 60 30 60 30 Potassium Chloride 20 20 20 20 20 20 Trisodium Citrate/ Citric Acid 13.3/ 6.7 13.3/ 6.7 13.3/ 6.7 Maltodextrin (chain 6) 0 0 0 0 10 10

Claims

013061 CLAIMS

1. An aqueous formulation for combatting déhydration comprising galactose at aconcentration in the range 25 to 135mM, a source of sodium ions and water.
2. An aqueous formulation as claimed in claim 1 wherein the concentration ofgalactose in the aqueous formulation is in the range 25 to 130mM, preferably in therange 37 to 120mM, particularly preferably in the range 40 to 120mM.
3. An aqueous formulation as claimed in claim 1 or 2 wherein the source of sodiumions is sodium chloride optionally together with sodium citrate.
4. An aqueous formulation as claimed in any preceding claim wherein theconcentration of sodium ions in the aqueous formulation is in the range 25 to lOOmM,preferably in the range 30 to 90mM, particularly preferably in the range 35 to 90mM,more preferably in the range 45 to 90mM, especially preferably in the range 60 to90mM.
5. An aqueous formulation as claimed in any preceding claim further comprising asource of potassium ions at a concentration in the aqueous formulation in the range 20to 25mM.
6. An aqueous formulation as claimed in any preceding claim further comprising oneor more additional carbohydrates selected from the group consisting of glucose,sucrose, dextrose, fructose, lactose and maltose.
7. An aqueous formulation as claimed in any preceding claim wherein the totalconcentration of carbohydrate is in the range 50 to 300mM, preferably in the range 50to 200mM, particularly preferably in the range 55 to 175mM, more preferably in therange 60 to 135mM, most preferably in the range 90 to 130mM. 013061 -12-
8. An aqueous formulation as claimed in either of daims 6 or 7 wherein galactoseand glucose are présent in a total amount sufïicient to meet the carbohydraterequirements of sodium co-transport in effective rehydration and the ratio of molar 5 concentration of galactose and glucose is in the range 0.6:1 to 1:0.6, preferably in therange 0.8:1 to 1:0.8, especially preferably in the range 0.9:1 to 1:0.9, more preferablyis about 1:1.
9. An aqueous formulation as claimed in any of daims 6 to 8 wherein theconcentration of glucose in the aqueous formulation is in the range 30 to 135mM, îq preferably in the range 35 to 130mM, especially preferably in the range 37 to 120mM,more preferably in the range 40 to lOOmM, most preferably in the range 45 to 80mM.
10. An aqueous formulation as claimed in any preceding daim wherein theconcentration of glucose is satisfied at least in part by a glucosidic oligosaccharide.
11. An aqueous formulation as claimed in daim 10 wherein the glucosidicoligosaccharide is maltodextrin. 15
12. A composition formulable in water to form an aqueous formulation as defined inany preceding daim, said composition comprising galactose, a source of sodium ions,optionally an additional carbohydrate and optionally a source of additional ions.
13. Use of galactose and a source of sodium ions for the préparation of (A) an2Q aqueous 25 to 135mM galactose formulation for combatting déhydration or (B) a médicament formulable into an aqueous 25 to 135mM galactose formulation forcombatting déhydration.
14. Use as claimed in daim 13 of galactose and a source of sodium ions for thepréparation of (A) an aqueous 25 to 135mM galactose formulation for combatting 25 déhydration in children or (B) a médicament formulable into an aqueous 25 to135mM galactose formulation for combatting déhydration in children.
15. Use as claimed in daim 13 or 14 wherein the déhydration is a symptom ofdiarrhoea. 013061 -13-
16. Use of an aqueous formulation as defined in any of daims 1 to 11 in themanufacture of a médicament for combatting déhydration.
17. A use as claimed in claim 16 wherein the subject is a child.