CA1119517A - Oral formulations for human use - Google Patents
Oral formulations for human useInfo
- Publication number
- CA1119517A CA1119517A CA000318507A CA318507A CA1119517A CA 1119517 A CA1119517 A CA 1119517A CA 000318507 A CA000318507 A CA 000318507A CA 318507 A CA318507 A CA 318507A CA 1119517 A CA1119517 A CA 1119517A
- Authority
- CA
- Canada
- Prior art keywords
- composition
- monosaccharide
- composition according
- amino acid
- citric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
A unit-dose pharmaceutical composition adapted for administration to humans, which composition comprises 40 to 80% of an actively absorbed mono-saccharide, 7.5 to 30% of an actively absorbed naturally occuring amino acid, and 0.5 to 10% of citric acid, or a salt thereof; is useful in the treatment of diarrhoea in humans by oral rehydration.
A unit-dose pharmaceutical composition adapted for administration to humans, which composition comprises 40 to 80% of an actively absorbed mono-saccharide, 7.5 to 30% of an actively absorbed naturally occuring amino acid, and 0.5 to 10% of citric acid, or a salt thereof; is useful in the treatment of diarrhoea in humans by oral rehydration.
Description
lll9S~7 Oral Formulations for Human Use This invention relates to a pharmaceutical composition for use in the treatment of diarrhoea in humans.
In adults diarrhoea is an unpleasant but usually self limiting condition, and the objective of therapy is simply to eliminate the symptoms in the shortest period of time.
In babies and young children however diarrhoea can be much more serious and indeed can be fatal.
Therapies typically used for the treatment of diarrhoea include :
(a) adsorbant powders, such as kaolin or pectin, (b) opium derivatives, such as morphine, which have the action of reducing peristalsis in the bowel, and (c) anticholinergic drugs, such as atropine or propantheline, which act by decreasing gastro-intestinal motility and tone.
Combinations of different active ingredients are also frequently used, for example kaolin plus morphine.
Antibiotics, such as neomycin or sulphonamides, are also included in many ~anti-diarrhoeal' preparations, but medical opinion is now generally against such usage, partly because there is little evidence of efficacy, but more importantly, because there is a possibility that emergence of resistant strains may be encouraged.
111~517 In severe cases of diarrhoea, dehydration of the patient is a major problem, and so replacement of lost fluids becomes a primary aim of the therapy.
Although diarrhoea due to any cause can become "severe", particularly if the illness is prolonged, the most significant categories of severe diarrhoea are infantile gastro-enteritis and cholera.
We have now discovered a composition which provides effective therapy of diarrhoea in humans, severe or otherwise, by oral rehydration.
It should perhaps be pointed out that our own West German Offenlegungs-~schrift No. 2,712,786 describes veterinary compositions for the treatment of diarrhoea in animals, which compositions comprise specified proportions of an actively absorbed monosaccharide, an actively absorbed naturally occurring amino acid, and an agent which is citric acid or a salt thereof. However, nowhere in the Offenlegungsschrift are the compositions of this invention disclosed or suggested.
Accordingly, the present invention provides a pharmaceutical composi-tion in unit dosage form of which each unit dose has less than 20 g of active inqredients, for administration to humans for the treatment of diarrhoea by oral rehydration, which composition comprises 40 to 80~ of an actively absorbed monosaccharide, 7.5 to 30% of an actively absorbed naturally occurring amino 20 acid, 0.5 to 10% of citric acid, or a salt thereof, or both, and 1 to 5% of flavours, the composition being sterilized and the ingredients conforming to international standards.
All percentages used herein are calculated on a weight/total weight basis.
Active absorption (or active transport) is well known to the skilled man, as are the monosaccharides and amino acids which are actively absorbed. In this regard, the reader is referred to standard text books such as "Medicinal Physiology" by Guyton (published by W.B. Saunders and Company) 4th Edition, pages 769 to 771. Of course, ~1~95~7 whether or not a particular monosaccharide or amino acid is actively absorbed may also readily be determined by experiment as for example described in Wilson T.~.
1962 Intestinal Absorption (Saunders, Philadelphia).
To be actively absorbed, monosaccharides must have (a) at least six carbon atoms in their chain (b) a D-pyranose ring structure and (c) an intact hydroxyl group at carbon 2. Thus suitable examples of monosaccharides for use in this invention include the naturally occurring D-pyranoses such as dextrose and galactose. Other examples of suitable monosacc-harides include naturally occurring D-pyranoses that have been chemically modified whilst retaining the necessary structural features (a), (b) and (c).
Examples of such modified monosaccharides include C2 7 acylated and Cl 4 alkylated derivatives, such as acetyl, methyl, ethyl and n- and iso-propyl derivatives. Specific examples include ~-methyl glucoside,3-Omethyl glucose and 6-deoxygalactose.
Preferably the monosaccharide will be dextrose (either the anhydrous or monohydrate form) or galactose.
More preferably the monosaccharide is dextrose.
Suitable examples of actively absorbed naturally occurring amino acids include neutral amino acids such as glycine and alanine and basic amino acids such as arginine. Preferably the amino acid is glycine.
The pharmaceutical compositions of the invention will normally contain 10 to 25% electrolytes. Suitable electrolytes for such inclusion includes salts containing ions such as sodium, potassium, calcium, chloride, phosphate, gluconate, sulphate, bicarbonate, carbonate and the like. Specific examples of such electrolytes for inclusion in the compositions include potassium di-hydrogen phosphate, dipotassium hydrogen phosphate, tri-potassium phosphate, potassium chloride and the like with potassium dihydrogen phosphate being particularly suitable.
One particularly preferred electrolyte for inclusion in the composition of the invention is sodium chloride which will normally account for 2 to 2~/o of the composition, for example 2 to 10% of the composition.
The monosaccharide is defined as representing 40 to 80% of the composition. M~re suitably it will represent 50 to 75%, for example 60 to 75% of the composition. Often the monosaccharide will represent at least 65% of the composition. Similarly while the amino acid in the composition can represent 7.5 to 30/O of the composition, more suitably it will represent 7.5 to 20% of the composition, for example 8 to 15% of the composition. 8 to 12% has been found to be a particularly suitable inclusion range for the amino acid.
The citric acid or salt thereof represents 0.5 to 10% of the composition. More suitably the acid or its salt will represent 0.5 to 5%, preferably 0~5 to 2%, for examp]e 0.6 to 1.2% of the composition. Often the composition will contain both the acid and a salt thereof, in which case combined the acid and salt will not represent more than 10h of the composition. In such cases the salt may represent 0.1 to 5%, more suitably 0.1 to 0.5% of the composition, and the acid 0.5 to 5%, more suitably 0.5 to 2%, for example 0.6 to 1.2% of the composition.
Suitable examples of the salts include sodium or potassium salts such as mono, di- or tri-sodium, or mono, di or tri-potassium citrate.
Particularly preferred compositions contain citric acid and a salt thereof.
If desired the compositions of this invention can contain other substances such as vitamins, minerals, buffers, excipients or the like in conventional manner.
~19Si~7 From the aforesaid it will be seen that one particularly suitable pharmaceutical ccmposition of the invention will oomprise 50 to 75% dextrose or galactose, 7.5 to 20% of glycine, alanine or arginine, 0.5 to 10% citric acid, or a salt thereof, and 2 to 20% of sodium chloride.
Preferably in such compositions the citric acid or salt thereof will represent 0.5 to 5% of the aomposition.
Often, such cQmpositions will aontain 0.5 to 5% citric acid, and 0.1 to 5% of a salt thereof.
Preferably such compositions contain dextrose as the mono-saccharide and glycine as the amino acid.
A particularly preferred aomposition of the invention comprises 60 to 75% de~trose, 8 to 15~ glycine, 0.5 to 2% citric acid and 0.1 to 0.5% of a salt thereof, and 2 to 20% sodium chloride. Such aompositions often include 5 to 10% of potassium dihydrogen phosphate.
The pharmaceutical ccmpositions of this inv~ntion are in unit dose fonm, that is that they contain an effective weight of ingredients to give relief to a diarrhoea sufferer.
Accordingly the compositions will not contain more than 20 g. of active ingredients, suitably 4 to 18 g., for example 8 g. and 16 g.
The oompositions are also of course adapted for administratiQn to humans. This may merely mean that the conpositiQns are provided in the correct weights to give unit doses for humans, and are associated with instructions as to how these compositions are to be administered (for example printed on the unit-dose containers and/or on the bulk packaging for these unit-dose contaLners).
However the cQ~pOSitiQnS of this invention also contain flavours, such as citrus flavours e.g. orange and lenon flavours, artificial sweetners, and . 5 -the like. The oompositions of this invention include 1 to 5% of such flavours for example 3%. Of course the skilled man will realise that as flavours are norm~lly volatile liquids, they are conveniently used in the form of dry solids in which the flavour is incorporated into a solid base material such as dextroseor starch. In such cases the weight of flavours present in the ccmpositions, taking the flavours as their dry weight including base material, is suitably 5 to 40%, re suitably 15 to 25%, for example 20%. ~hen the mano-saccharide in the ccmposition is dextrose then preferably the flavours are dextrose-based, thereby removing extraneous material that would have been incorporated had the fLavours been, for example, starch based.
Also, the major ingredients of the composition, namely the mono-saccharide, the amino acid, the citric acid or salt thereof, and the electro-lytes (when present) will be of a purity meeting the internationally accepted standards, such as those set by the British, European and U.S. Pharmacopoeias.
m e oompositions are rendered sterile prior to administration. This can be done by r- irradiation of the packaged composition. More simply, an advantageous effect can be obtained by dissolving the ingredients in boiling water. This latter course of action is particularly suitable when the compo-sition is to be administered to babies.
The unit dose compositions of this invention may be presented in any suitable ContainRr~ such as bottles, cans and more preferably sachets. It has been found that the stability of the compositions is enhan oe d if the no-saccharide oomponent thereof, and any mono-saccharide based flavours, is packaged separately from the other components. This may of course simply and neatly be achieved by presen~ing the compositions in twin packs, twin sachets or the like.
lll9Sl'7 The compositions of this invention may be prepared by mixing together the ingredients and filling them into suitable containers at the required unit dose fill rate (optlonally as described above the mono-saccharide may be kept separate in this operation and separately filled into its own portion of the container).
In order to improve the uniformity of filling of the containers, and also of course the uniformity of the compositions emptied from the containers for administration, in view of the small weights involved, the major ingredients of the compositions may be used in granular form. In such cases the citric acid and/or salt thereof may suitably be milled to provide a very fine powder which we have found mixes very well with the granules of the major ingredients to give a uniform fill mix. Due to the difficulty of obtaining granular dextrose commercially, ordinary powdered dextrose may be used in the presence of a glidant, such as for example colloidal silicon dioxide. If present such a glidant will represent no more than 0.5% of the composition, for example 0.1 or 0.2%.
It will be appreciated that suitably with the twin pack presentation one portion of the pack will contain powdered dextrose and glidant, and the other portion will contain granular amino acid, electrolytes ~`when present) and finely milled citric acid or a salt thereof.
By way of illustration, granular ingredients suitably have a particle size of 200 to 600 ~, more 30 suitably 300 to 500 ~; powdered ingredients suitably have a particle size of 50 to 200 ~; and finely milled powders suitably have a particle size of less than 50~, for example 25 to 45 ~ (particle sized when used herein are expressed as geometric mean sizes by weight).
Preferably the granular ingredients will have substantially the same particle size.
As will have been appreciated the compositions of this invention are administered to the diarrhoea sufferer in aqueous solution. Accordingly in a further aspect this invention provides the unit-dose pharmaceutical composition adapted for administration comprising the aforedefined ingredients, when in aqueous solution.
~ ormally the unit-dose compositions of this invention will be dissolved in 250 mls. or 500 mls.
of water to provide these solutions. With babies 250 ml, is particularly convenient as this is the conventional volume of their feed bottles.
Of course the volume of solution administered to the sufferer per day will depend on the severity of the diarrhoea and on his bodyweight. For babies and young children 100 to 500 ml/kg/day is a suitable quantity. For adults, except in cases of extremely severe diarrhoea when higher quantities may be needed, 25 to 100 ml/kg~day should be sufficient.
The solution may be administered in one, two, three or four or more doses per day, or by any other similar conventional regime.
From a further aspect this invention provides a method of treating diarrhoea in humans which method comprises administering to the sufferer a solution of this invention.
The unit-dose compositions of this invention are easy to formulate, palatable, have useful stability and are readily soluble in waterO
The following Examples illustrate the invention:
5~7 E _ 15 g of the.following composition was prepared by mixing together the ingredients in dry powder form :
Dextroæ (anhydrous) 72% by weight Glycine : 12% by weight Sodium Chloride : 7% by weight Potassium Dihydrogen Phosphate : 7% by weight Citric Acid : 2% by weight an9 e 4/a~vr The resultant unit-dose composition was then dissolved in 500 ml of water.
8 g of the following composition was prepared by mixing together the ingredients in dry powder form :
Dextrose (anhydrous) 67% by weight Glycine 10.3% by weight Sodium Chloride 14.3% by weight Potassium dihydrogen phosphate 6.8% by weight Citric Acid 0.8% by weight Tripotassium citrate 0.2% by weight ng e ~/~ v~
The resultant unit-dose composition was then dissolved in 250 ml of water.
EX~MPLE 3 The procedures of ExEmples 1 ancl 2 were repeated, but prior to dis-solution in water the ingredients were filled into a twin sachRt with the dextr~se in one part of the sachet and all the other ingredients in the other part of the sachet.
EX~MæLE 4 -Each of Examples 1 to 3 was repeated with otherwise identical compositions but contai m ng a lemon flav~ur.
Twin sachets were filled with the following ingredients:
Sachet A
ngredient Weight g. Particle Size Glycine U.S.P. 0.7725 500 Citric acid (anhydr~us) 0.0600 370 Ph. Eur.
Potassium dihydrogen phosEhate N.F. 0.5100 350 Potassium citrate Ph.Eur. 0.0150milled to C 50 Soclium chloride Ph. Eur. 1.0725 365 Tbtal Weight 2,4300 g.
.. . . . . .. . ... . . .
~119~17 Sachet B
Inaredient weiqht a Dextrose monohydrate B.P. 4.2315 B Aerosil 200 (colloidal 0.0059 Silicon Dioxide N.F.) Orange dry flavour, 0.9960 dextrosebased, containing 75% dextrose as mono-hydrate Lemon dry flavour, 0.6628 dextrose based, containing 90X dextrose as mono-hydrate Total Weight : 5.8962 g.
Total dextrose monohydrate weight is 5.5750 g.
The twin sachets thus formed were then opened and their contents dissolved in 250 ml. of water.
~r~d~
In adults diarrhoea is an unpleasant but usually self limiting condition, and the objective of therapy is simply to eliminate the symptoms in the shortest period of time.
In babies and young children however diarrhoea can be much more serious and indeed can be fatal.
Therapies typically used for the treatment of diarrhoea include :
(a) adsorbant powders, such as kaolin or pectin, (b) opium derivatives, such as morphine, which have the action of reducing peristalsis in the bowel, and (c) anticholinergic drugs, such as atropine or propantheline, which act by decreasing gastro-intestinal motility and tone.
Combinations of different active ingredients are also frequently used, for example kaolin plus morphine.
Antibiotics, such as neomycin or sulphonamides, are also included in many ~anti-diarrhoeal' preparations, but medical opinion is now generally against such usage, partly because there is little evidence of efficacy, but more importantly, because there is a possibility that emergence of resistant strains may be encouraged.
111~517 In severe cases of diarrhoea, dehydration of the patient is a major problem, and so replacement of lost fluids becomes a primary aim of the therapy.
Although diarrhoea due to any cause can become "severe", particularly if the illness is prolonged, the most significant categories of severe diarrhoea are infantile gastro-enteritis and cholera.
We have now discovered a composition which provides effective therapy of diarrhoea in humans, severe or otherwise, by oral rehydration.
It should perhaps be pointed out that our own West German Offenlegungs-~schrift No. 2,712,786 describes veterinary compositions for the treatment of diarrhoea in animals, which compositions comprise specified proportions of an actively absorbed monosaccharide, an actively absorbed naturally occurring amino acid, and an agent which is citric acid or a salt thereof. However, nowhere in the Offenlegungsschrift are the compositions of this invention disclosed or suggested.
Accordingly, the present invention provides a pharmaceutical composi-tion in unit dosage form of which each unit dose has less than 20 g of active inqredients, for administration to humans for the treatment of diarrhoea by oral rehydration, which composition comprises 40 to 80~ of an actively absorbed monosaccharide, 7.5 to 30% of an actively absorbed naturally occurring amino 20 acid, 0.5 to 10% of citric acid, or a salt thereof, or both, and 1 to 5% of flavours, the composition being sterilized and the ingredients conforming to international standards.
All percentages used herein are calculated on a weight/total weight basis.
Active absorption (or active transport) is well known to the skilled man, as are the monosaccharides and amino acids which are actively absorbed. In this regard, the reader is referred to standard text books such as "Medicinal Physiology" by Guyton (published by W.B. Saunders and Company) 4th Edition, pages 769 to 771. Of course, ~1~95~7 whether or not a particular monosaccharide or amino acid is actively absorbed may also readily be determined by experiment as for example described in Wilson T.~.
1962 Intestinal Absorption (Saunders, Philadelphia).
To be actively absorbed, monosaccharides must have (a) at least six carbon atoms in their chain (b) a D-pyranose ring structure and (c) an intact hydroxyl group at carbon 2. Thus suitable examples of monosaccharides for use in this invention include the naturally occurring D-pyranoses such as dextrose and galactose. Other examples of suitable monosacc-harides include naturally occurring D-pyranoses that have been chemically modified whilst retaining the necessary structural features (a), (b) and (c).
Examples of such modified monosaccharides include C2 7 acylated and Cl 4 alkylated derivatives, such as acetyl, methyl, ethyl and n- and iso-propyl derivatives. Specific examples include ~-methyl glucoside,3-Omethyl glucose and 6-deoxygalactose.
Preferably the monosaccharide will be dextrose (either the anhydrous or monohydrate form) or galactose.
More preferably the monosaccharide is dextrose.
Suitable examples of actively absorbed naturally occurring amino acids include neutral amino acids such as glycine and alanine and basic amino acids such as arginine. Preferably the amino acid is glycine.
The pharmaceutical compositions of the invention will normally contain 10 to 25% electrolytes. Suitable electrolytes for such inclusion includes salts containing ions such as sodium, potassium, calcium, chloride, phosphate, gluconate, sulphate, bicarbonate, carbonate and the like. Specific examples of such electrolytes for inclusion in the compositions include potassium di-hydrogen phosphate, dipotassium hydrogen phosphate, tri-potassium phosphate, potassium chloride and the like with potassium dihydrogen phosphate being particularly suitable.
One particularly preferred electrolyte for inclusion in the composition of the invention is sodium chloride which will normally account for 2 to 2~/o of the composition, for example 2 to 10% of the composition.
The monosaccharide is defined as representing 40 to 80% of the composition. M~re suitably it will represent 50 to 75%, for example 60 to 75% of the composition. Often the monosaccharide will represent at least 65% of the composition. Similarly while the amino acid in the composition can represent 7.5 to 30/O of the composition, more suitably it will represent 7.5 to 20% of the composition, for example 8 to 15% of the composition. 8 to 12% has been found to be a particularly suitable inclusion range for the amino acid.
The citric acid or salt thereof represents 0.5 to 10% of the composition. More suitably the acid or its salt will represent 0.5 to 5%, preferably 0~5 to 2%, for examp]e 0.6 to 1.2% of the composition. Often the composition will contain both the acid and a salt thereof, in which case combined the acid and salt will not represent more than 10h of the composition. In such cases the salt may represent 0.1 to 5%, more suitably 0.1 to 0.5% of the composition, and the acid 0.5 to 5%, more suitably 0.5 to 2%, for example 0.6 to 1.2% of the composition.
Suitable examples of the salts include sodium or potassium salts such as mono, di- or tri-sodium, or mono, di or tri-potassium citrate.
Particularly preferred compositions contain citric acid and a salt thereof.
If desired the compositions of this invention can contain other substances such as vitamins, minerals, buffers, excipients or the like in conventional manner.
~19Si~7 From the aforesaid it will be seen that one particularly suitable pharmaceutical ccmposition of the invention will oomprise 50 to 75% dextrose or galactose, 7.5 to 20% of glycine, alanine or arginine, 0.5 to 10% citric acid, or a salt thereof, and 2 to 20% of sodium chloride.
Preferably in such compositions the citric acid or salt thereof will represent 0.5 to 5% of the aomposition.
Often, such cQmpositions will aontain 0.5 to 5% citric acid, and 0.1 to 5% of a salt thereof.
Preferably such compositions contain dextrose as the mono-saccharide and glycine as the amino acid.
A particularly preferred aomposition of the invention comprises 60 to 75% de~trose, 8 to 15~ glycine, 0.5 to 2% citric acid and 0.1 to 0.5% of a salt thereof, and 2 to 20% sodium chloride. Such aompositions often include 5 to 10% of potassium dihydrogen phosphate.
The pharmaceutical ccmpositions of this inv~ntion are in unit dose fonm, that is that they contain an effective weight of ingredients to give relief to a diarrhoea sufferer.
Accordingly the compositions will not contain more than 20 g. of active ingredients, suitably 4 to 18 g., for example 8 g. and 16 g.
The oompositions are also of course adapted for administratiQn to humans. This may merely mean that the conpositiQns are provided in the correct weights to give unit doses for humans, and are associated with instructions as to how these compositions are to be administered (for example printed on the unit-dose containers and/or on the bulk packaging for these unit-dose contaLners).
However the cQ~pOSitiQnS of this invention also contain flavours, such as citrus flavours e.g. orange and lenon flavours, artificial sweetners, and . 5 -the like. The oompositions of this invention include 1 to 5% of such flavours for example 3%. Of course the skilled man will realise that as flavours are norm~lly volatile liquids, they are conveniently used in the form of dry solids in which the flavour is incorporated into a solid base material such as dextroseor starch. In such cases the weight of flavours present in the ccmpositions, taking the flavours as their dry weight including base material, is suitably 5 to 40%, re suitably 15 to 25%, for example 20%. ~hen the mano-saccharide in the ccmposition is dextrose then preferably the flavours are dextrose-based, thereby removing extraneous material that would have been incorporated had the fLavours been, for example, starch based.
Also, the major ingredients of the composition, namely the mono-saccharide, the amino acid, the citric acid or salt thereof, and the electro-lytes (when present) will be of a purity meeting the internationally accepted standards, such as those set by the British, European and U.S. Pharmacopoeias.
m e oompositions are rendered sterile prior to administration. This can be done by r- irradiation of the packaged composition. More simply, an advantageous effect can be obtained by dissolving the ingredients in boiling water. This latter course of action is particularly suitable when the compo-sition is to be administered to babies.
The unit dose compositions of this invention may be presented in any suitable ContainRr~ such as bottles, cans and more preferably sachets. It has been found that the stability of the compositions is enhan oe d if the no-saccharide oomponent thereof, and any mono-saccharide based flavours, is packaged separately from the other components. This may of course simply and neatly be achieved by presen~ing the compositions in twin packs, twin sachets or the like.
lll9Sl'7 The compositions of this invention may be prepared by mixing together the ingredients and filling them into suitable containers at the required unit dose fill rate (optlonally as described above the mono-saccharide may be kept separate in this operation and separately filled into its own portion of the container).
In order to improve the uniformity of filling of the containers, and also of course the uniformity of the compositions emptied from the containers for administration, in view of the small weights involved, the major ingredients of the compositions may be used in granular form. In such cases the citric acid and/or salt thereof may suitably be milled to provide a very fine powder which we have found mixes very well with the granules of the major ingredients to give a uniform fill mix. Due to the difficulty of obtaining granular dextrose commercially, ordinary powdered dextrose may be used in the presence of a glidant, such as for example colloidal silicon dioxide. If present such a glidant will represent no more than 0.5% of the composition, for example 0.1 or 0.2%.
It will be appreciated that suitably with the twin pack presentation one portion of the pack will contain powdered dextrose and glidant, and the other portion will contain granular amino acid, electrolytes ~`when present) and finely milled citric acid or a salt thereof.
By way of illustration, granular ingredients suitably have a particle size of 200 to 600 ~, more 30 suitably 300 to 500 ~; powdered ingredients suitably have a particle size of 50 to 200 ~; and finely milled powders suitably have a particle size of less than 50~, for example 25 to 45 ~ (particle sized when used herein are expressed as geometric mean sizes by weight).
Preferably the granular ingredients will have substantially the same particle size.
As will have been appreciated the compositions of this invention are administered to the diarrhoea sufferer in aqueous solution. Accordingly in a further aspect this invention provides the unit-dose pharmaceutical composition adapted for administration comprising the aforedefined ingredients, when in aqueous solution.
~ ormally the unit-dose compositions of this invention will be dissolved in 250 mls. or 500 mls.
of water to provide these solutions. With babies 250 ml, is particularly convenient as this is the conventional volume of their feed bottles.
Of course the volume of solution administered to the sufferer per day will depend on the severity of the diarrhoea and on his bodyweight. For babies and young children 100 to 500 ml/kg/day is a suitable quantity. For adults, except in cases of extremely severe diarrhoea when higher quantities may be needed, 25 to 100 ml/kg~day should be sufficient.
The solution may be administered in one, two, three or four or more doses per day, or by any other similar conventional regime.
From a further aspect this invention provides a method of treating diarrhoea in humans which method comprises administering to the sufferer a solution of this invention.
The unit-dose compositions of this invention are easy to formulate, palatable, have useful stability and are readily soluble in waterO
The following Examples illustrate the invention:
5~7 E _ 15 g of the.following composition was prepared by mixing together the ingredients in dry powder form :
Dextroæ (anhydrous) 72% by weight Glycine : 12% by weight Sodium Chloride : 7% by weight Potassium Dihydrogen Phosphate : 7% by weight Citric Acid : 2% by weight an9 e 4/a~vr The resultant unit-dose composition was then dissolved in 500 ml of water.
8 g of the following composition was prepared by mixing together the ingredients in dry powder form :
Dextrose (anhydrous) 67% by weight Glycine 10.3% by weight Sodium Chloride 14.3% by weight Potassium dihydrogen phosphate 6.8% by weight Citric Acid 0.8% by weight Tripotassium citrate 0.2% by weight ng e ~/~ v~
The resultant unit-dose composition was then dissolved in 250 ml of water.
EX~MPLE 3 The procedures of ExEmples 1 ancl 2 were repeated, but prior to dis-solution in water the ingredients were filled into a twin sachRt with the dextr~se in one part of the sachet and all the other ingredients in the other part of the sachet.
EX~MæLE 4 -Each of Examples 1 to 3 was repeated with otherwise identical compositions but contai m ng a lemon flav~ur.
Twin sachets were filled with the following ingredients:
Sachet A
ngredient Weight g. Particle Size Glycine U.S.P. 0.7725 500 Citric acid (anhydr~us) 0.0600 370 Ph. Eur.
Potassium dihydrogen phosEhate N.F. 0.5100 350 Potassium citrate Ph.Eur. 0.0150milled to C 50 Soclium chloride Ph. Eur. 1.0725 365 Tbtal Weight 2,4300 g.
.. . . . . .. . ... . . .
~119~17 Sachet B
Inaredient weiqht a Dextrose monohydrate B.P. 4.2315 B Aerosil 200 (colloidal 0.0059 Silicon Dioxide N.F.) Orange dry flavour, 0.9960 dextrosebased, containing 75% dextrose as mono-hydrate Lemon dry flavour, 0.6628 dextrose based, containing 90X dextrose as mono-hydrate Total Weight : 5.8962 g.
Total dextrose monohydrate weight is 5.5750 g.
The twin sachets thus formed were then opened and their contents dissolved in 250 ml. of water.
~r~d~
Claims (10)
1. A pharmaceutical composition in unit dosage form of which each unit dose has less than 20 g of active ingredients, for administration to humans for the treatment of diarrhoea by oral rehydration, which composition comprises 40 to 80% of an actively absorbed monosaccharide, 7.5 to 30% of an actively absorbed naturally occurring amino acid, 0.5 to 10% of milled citrate salt or milled citrate salt and citric acid, 1 to 5% of flavours and, if required, one or more electrolytes, the composition being sterilized and the ingredients conforming to international standards, the amino acid and any electrolytes being present in granular form and having the same particle size.
2. A composition according to claim 1, wherein the monosaccharide is dextrose.
3. A composition according to claim 1 or 2, wherein the monosaccharide represents 60 to 75% of the composition.
4. A composition according to claim 1 or 2, wherein the amino acid is glycine.
5. A composition according to claim 1, wherein the amino acid represents 8 to 12% of the composition.
6. A composition according to claim 1, additionally comprising 2 to 20% sodium chloride.
7. A composition according to claim 1 or 2 containing citric acid and tripotassium citrate, the citric acid representing 0.5 to 5% and the tripotassium citrate 0.1 to 5% of the composition.
8. The composition of claim 6, wherein the monosaccharide is dextrose in an amount of 60 to 75%, the amino acid is glycine in an amount of 8 to 15%, citric acid is present in an amount of 0.5 to 2%, and tripotassium citrate is present in an amount of 0.1 to 0.5%.
9. A composition according to claim 1, wherein prior to use the monosaccharide is physically separated. from the other ingredients of the composition to form a composition of enhanced stability, the monosaccharide also containing a glidant.
10. A composition according to claim 1, dissolved in water to form an aqueous solution ready for oral administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB53875/77 | 1977-12-23 | ||
| GB5387577 | 1977-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1119517A true CA1119517A (en) | 1982-03-09 |
Family
ID=10469271
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000318507A Expired CA1119517A (en) | 1977-12-23 | 1978-12-22 | Oral formulations for human use |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS54101437A (en) |
| AU (1) | AU4282278A (en) |
| BE (1) | BE872647A (en) |
| CA (1) | CA1119517A (en) |
| CH (1) | CH644017A5 (en) |
| DE (1) | DE2854281A1 (en) |
| FR (1) | FR2412313A1 (en) |
| GB (1) | GB2012163B (en) |
| IE (1) | IE47698B1 (en) |
| IT (1) | IT1111383B (en) |
| NL (1) | NL7812403A (en) |
| NZ (1) | NZ189122A (en) |
| OA (1) | OA06135A (en) |
| PH (1) | PH14262A (en) |
| ZA (1) | ZA786856B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0059057A1 (en) * | 1981-02-20 | 1982-09-01 | Beecham Group Plc | Treatment of diarrhoea |
| US4542123A (en) * | 1982-01-11 | 1985-09-17 | Massachusetts Institute Of Technology | Composition and method for increasing brain tyrosine levels |
| EP0112061A3 (en) * | 1982-11-20 | 1985-08-14 | Beecham Group Plc | Pharmaceutical or veterinary compositions containing guanoxabenz |
| CA1217723A (en) * | 1983-01-13 | 1987-02-10 | Robert W. Phillips | Oral energy rich therapy for diarrhea in mammals |
| GB8528307D0 (en) * | 1985-11-18 | 1985-12-24 | Beecham Group Plc | Veterinary compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ183492A (en) * | 1976-03-27 | 1980-04-28 | Beecham Group Ltd | Veterinary rehydration compositions containing monosaccharide amino acid and citric acid or citrate |
-
1978
- 1978-12-06 ZA ZA00786856A patent/ZA786856B/en unknown
- 1978-12-07 NZ NZ189122A patent/NZ189122A/en unknown
- 1978-12-08 BE BE192233A patent/BE872647A/en unknown
- 1978-12-13 PH PH21944A patent/PH14262A/en unknown
- 1978-12-15 DE DE19782854281 patent/DE2854281A1/en not_active Withdrawn
- 1978-12-15 FR FR7835352A patent/FR2412313A1/en active Granted
- 1978-12-20 JP JP15908578A patent/JPS54101437A/en active Pending
- 1978-12-20 IE IE2515/78A patent/IE47698B1/en unknown
- 1978-12-21 CH CH1304478A patent/CH644017A5/en not_active IP Right Cessation
- 1978-12-21 AU AU42822/78A patent/AU4282278A/en active Pending
- 1978-12-21 IT IT52414/78A patent/IT1111383B/en active
- 1978-12-21 GB GB7849575A patent/GB2012163B/en not_active Expired
- 1978-12-21 NL NL7812403A patent/NL7812403A/en not_active Application Discontinuation
- 1978-12-22 OA OA56691A patent/OA06135A/en unknown
- 1978-12-22 CA CA000318507A patent/CA1119517A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IE47698B1 (en) | 1984-05-30 |
| JPS54101437A (en) | 1979-08-10 |
| CH644017A5 (en) | 1984-07-13 |
| FR2412313A1 (en) | 1979-07-20 |
| BE872647A (en) | 1979-06-08 |
| GB2012163B (en) | 1982-09-22 |
| OA06135A (en) | 1981-06-30 |
| GB2012163A (en) | 1979-07-25 |
| PH14262A (en) | 1981-04-23 |
| IT7852414A0 (en) | 1978-12-21 |
| IE782515L (en) | 1979-06-23 |
| NL7812403A (en) | 1979-06-26 |
| DE2854281A1 (en) | 1979-07-05 |
| ZA786856B (en) | 1979-11-28 |
| NZ189122A (en) | 1980-12-19 |
| AU4282278A (en) | 1979-06-28 |
| IT1111383B (en) | 1986-01-13 |
| FR2412313B1 (en) | 1982-06-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |