Title: Pourable alginate compositions
United States Patent: 6,395,307
Inventors: Banning; Douglas (London, GB); Dettmar; Peter William (Patrington, GB); Jolliffe; Ian Gordon (Cottingham, GB); Hampson; Frank Chadwick (Hedon, GB); Onsoyen; Edvar Jarle (Drammen, NO); Field; Paul Frederick (Hull, GB); Craig; Duncan Quinell MacKenzie (Belfast, IE); Kristensen; Ase Hanne (Oslo, NO)Assignee: Reckitt Benckiser (UK) Limited (Slough, GB)
Appl. No.: 403217Filed: December 17, 1999
PCT Filed: April 23, 1998PCT NO: PCT/GB98/01188
371 Date: December 17, 1999102(e) Date: December 17, 1999
PCT PUB.NO.: WO98/48814PCT PUB. Date: November 5, 1998
Foreign Application Priority Data: Apr 30, 1997[GB] (9708772); Apr 30, 1997[GB] (9708773)
An aqueous pourable liquid composition comprising a high concentration of sodium alginate and an alkali metal bicarbonate, wherein the sodium alginate has an average mannuronic acid residue to guluronic acid residue ratio of at least 0.6:1. In addition, an alginate or alginic acid for forming a protective coating on gastrointestinal mucosal tissue, use of and compositions including the same are provided.
SUMMARY AND DETAILED DISCLOSURE OF THE INVENTIONThe inventors have now unexpectedly found that the thickening problems relating to the pourable product may be alleviated by using particular forms of sodium alginate.
Sodium alginate mainly comprises the sodium salt of alginic acid which is a mixture of polyuronic acids composed of residues of D-mannuronic and L-guluronic acids as previously described. It may be obtained from algae belonging to the order Phaeophycae.
Generally alginates having high proportions of guluronic acid resides have been preferred in prior art liquid alginate products. Typically materials having mannuronic to guluronic acid residue ratios of approximately 0.4:1 (i.e. 4 mannuronic acid residues to 10 guluronic acid residues) have been used.
In the compositions described above for the treatment of reflux oesophagitis it has been considered important to form a gelatinous carbonated foam or raft of the highest strength. An important factor in the raft strength has been the cross-linking of the alginates through the presence of a polyvalent ion, such as through the inclusion of calcium carbonate in the above described composition.
Cross-linking via the polyvalent ion occurs to the greatest extent between the guluronic acid residues in the alginate chains and for this reason raft-forming compositions of the above described type have comprised alginates rich in G units. These are also known as "high G" alginates. (Similarly alginates rich in M units are known as "high M" alginates.) Typically, the high G alginates will have a mannuronic acid residue to guluronic acid residue ratio (hereinafter M/G value) of 2/3 or less.
The inventors have now surprisingly found that the thickening problems described above may be alleviated by using sodium alginates having higher mannuronic acid residue to guluronic acid residue ratios than have previously been used in liquid products.
Therefore, according to a first aspect to the present invention there is provided an aqueous pourable liquid composition comprising a high concentration of sodium alginate and an alkali metal bicarbonate, wherein the sodium alginate has an average mannuronic acid residue to guluronic acid residue ratio of at least 0.6:1. Such compositions are preferably suitable for use as pharmaceutical compositions.
Such compositions are pourable at room temperatures, and furthermore this property is regained upon warming following prolonged storage below 5oC. for up to six weeks or more (although reasonably vigorous shaking may be required).
By pourable we mean that the compositions of the invention will flow evenly at room temperature (possibly following reasonably vigorous shaking) such that doses of, for example, 5 ml may be measured out with reasonable accuracy. For example reproducible doses of as low as 5 ml may be dispensed from screw cap bottles having neck diameters of 1.5 cm, or from squeezable plastic bottles having dispensing outlets as small as 5 mm diameter.
It is known that increasing the mannuronic acid residue content of sodium alginate may cause a reduction in the coherence of the rafts produced by raft forming preparations on contact with gastric acid. Therefore a balance must preferably be struck between increasing the mannuronic acid residue content of the sodium alginate to reduce the thickening problems, but not increasing it to such an extent that effective rafts are not produced in the stomach.
Therefore in the compositions of the invention the average ratio of mannuronic acid residues to guluronic acid residues in the sodium alginate is preferably 0.65:1 to 3:1, more preferably 0.65:1 to 1.5:1, most preferably 0.7:1 to 1.3:1 and especially 0.75:1 to 1.1:1.
The sodium alginate used in the compositions of the invention may comprise materials from the same source all having approximately the same mannuronic to guluronic acid residue ratios or, preferably, it is a blend of materials having different mannuronic to guluronic acid residue ratios. Preferably at least 50% of the sodium alginate has a mannuronic to guluronic acid residue ratio of greater than 0.8:1.
Most preferably at least 70% of the sodium alginate has a mannuronic to guluronic acid residue ratio greater than 0.9:1.
Especially preferred are compositions of the invention which comprise a mixture of sodium alginates wherein
70 to 80% of the sodium alginate has a mannuronic to guluronic acid residue ratio of from 0.9:1 to 1.2:1, and
30 to 20% of the sodium alginate has a mannuronic to guluronic acid residue ratio of from 0.35:1 to 0.5:1.
Alginates having average mannuronic to guluronic acid residues ratios of greater than 0.6:1 may be extracted from many sources, for example from Laminaria digitata, Ecklonia maxima, Macrocystis pyrifera, Lessonia nigrescens, Ascophillum nodosum, Laminaria japonica, Durvillea antarctica, Durvillea potatorum and from the leaves of Laminaria hyperborea.
Preferably the compositions of the invention comprise Sodium alginates derived from Laminaria hyperborea.
Supplies of alginates having suitable mannuronic acid residue to guluronic acid residue ratios for carrying out the invention may be obtained from, for example, Pronova Biopolymer. Such a company supplies different grades of alginate which vary in, inter alia, molecular weight and viscosity.
Preferably, low viscosity grade sodium alginate is used to prepare the compositions of the invention. These are grades of sodium alginate for which the viscosity of a 10% weight/volume aqueous solution, when determined on a Brookfield RVT viscometer using spindle number 3 at 20 r.p.m. at 20oC., falls within the range 200-1500 cps.
The concentration of sodium alginate in the compositions of the invention should be higher than in conventional compositions, i.e. at least 8% w/v. Preferably the concentration is 9 to 20% w/v, more preferably 10 to 15% w/v and most preferably 10 to 11% w/v, especially around 10% w/v.
Further according to this aspect to the present invention there is provided a method of treating reflux oesophagitis, gastritis, dyspepsia or peptic ulceration which comprises the administration of a pharmacologically effective amount of an aqueous pourable liquid composition, comprising
a) 8 to 15% w/v low viscosity sodium alginate, wherein the average mannuronic acid residue to guluronic acid residue ratio is at least 0.6:1; and
b) 0.1 to 8% w/v alkali metal bicarbonate.
Further according to this aspect to the present invention there is provided a pharmaceutical composition for the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration, or for use as a sustained releasing or targeted delivery composition, in the form of an aqueous pourable liquid comprising
a) 8 to 15% w/v low viscosity grade sodium alginate, wherein the average mannuronic acid residue to guluronic acid residue ratio is at least 0.6:1; and
b) 0.1 to 8% w/v alkali metal bicarbonate.
There is further provided a pharmaceutical composition for the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration, or for use as a sustained releasing or targeted delivery composition, in the form of an aqueous pourable liquid comprising;
a) 8 to 15% w/v low viscosity grade sodium alginate, wherein the average mannuronic acid residue to guluronic acid residue ratio is at least 0.6:1;
b) 0.1 to 8% w/v alkali metal bicarbonate; and
c) substantially no other suspending agents.
Turning now to the need for an alginate or alginic acid for forming an effective protective coating on gastrointestinal mucosa when brought into contact with same, it has now surprisingly been found that particular grades or types of alginates are able to interact much more effectively than others with components of the mucus of the gastrointestinal tract in order to provide a mucoadhesive coating. More especially, it has been found that these grades or types of alginate interact with mucin, a glycoprotein which is a major component of saliva and gastrointestinal mucus. The interaction of these alginates with mucin effectively strengthens the gel-like structure of the mucin thereby providing an effective mucoadhesive coating.
Therefore, according to a second aspect of the present invention there is provided an alginate or alginic acid having a mannuronic acid residue to guluronic acid residue ratio (M/G) of at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same, preferably for use in the treatment of reflux oesophagitis, gastritis, dyspesia or peptic ulceration, and/or in sustained release or targeted delivery of an active.
According to a further aspect of the present invention there is provided a pharmaceutical composition for forming a protective coating on gastrointestinal mucosal tissue, preferably for use in the treatment of reflux oesophagitis, gastritis, dyspesia or peptic ulceration, and/or for as a sustained releasing or targeted delivery composition, the composition comprising an alginate or alginic acid having a mannuronic acid residue to guluronic acid residue ratio (M/G) of at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same and a pharmaceutically acceptable carrier.
The pharmacetically acceptable carrier may, for example, be water, preferably deionised water.
Preferably, the composition of this aspect to the invention is also able to form a carbonated gelatinous foam or raft which floats on the stomach contents, in addition to forming a protective coating on the gastrointestinal mucosa.
Accordingly, there is provided a pharmaceutical composition for forming a protective coating on gastrointestinal mucosal tissue, preferably for use in the treatment of oesophagitis, gastritis, dyspepsia or peptic ulceration, and/or as a sustained releasing or targeted delivery composition comprising
a) an alginate or alginic acid wherein the ratio of the mannuronic acid residues to the guluronic acid residues (M/G) is at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same, and
b) an alkali metal bicarbonate.
Advantageously, the composition further includes a polyvalent metal ion as a cross-linking agent, especially calcium or aluminium, most preferably calcium.
In a preferred embodiment of this aspect of the invention, the composition of the invention includes at least one high M alginate which is effective in forming a protective coating on the oesophageal mucosa and also at least one high G alginate in order to provide a carbonated gelatinous raft or foam of high strength.
Thus, in an embodiment of this aspect of the invention, there is provided a pourable liquid composition comprising
i) from 1% to 10% (preferably 2.0% to 10%, more preferably 2.5% to 8%, especially 4% to 6%) in total of two or more alginates, of which from 10% to 90% comprises an alginate or alginic acid wherein the ratio of the mannuronic acid residues to the guluronic acid residues (M/G) is at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same, and from 90% to 10% comprises an alginate or alginic acid wherein the ratio of the mannuronic acid residues to the guluronic acid residues (M/G) is not more than 2/3 in order to provide a carbonated gelatinous raft or foam of high strength, and
ii) an alkali metal bicarbonate.
Preferably, the composition of this embodiment of the invention further comprises a polyvalent metal ion, (in particular calcium or aluminium and especially calcium) as a cross-linking agent.
It will be apparent to the person skilled in the art that in order to produce a pourable liquid composition the viscosity of the composition should not be too high. A suitable pourable composition may thus, for example include a relatively low amount of a viscous (high molecular weight) high M alginate and a relatively high amount of a less viscous (lower molecular weight) high G alginate. Similarly, a composition may suitably include a relatively high amount of a less viscous (lower molecular weight) high M alginate and a relatively low amount of a more viscous (higher molecular weight) high G alginate. Compositions not tending towards the above noted limits may also be suitable, such as for example a composition including approximately equal amounts of low viscosity high M and low viscosity high G alginates (provided that the M/G value is at least 1)
Where a liquid composition of the invention is not required to be pourable, a higher amount of total alginate (for example up to 20%) may be included.
In still another embodiment of this aspect of the invention, the compositions of the invention may also be provided in tablet or other solid unit dosage form. Thus according to this aspect of the invention there is provided a composition in solid unit dosage form comprising
i) from 10% to 30% (preferably 15% to 25%, especially 20%) in total of two or more alginates, of which from 10% to 90% comprises an alginate or alginic acid wherein the ratio of the mannuronic acid residues to the guluronic acid residues (M/G) is at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same, and from 90% to 10% comprises an alginate or alginic acid wherein the ratio of the mannuronic acid residues to the guluronic acid residues (M/G) is not more than 2/3 in order to provide a carbonated gelatinous raft or foam of high strength, and
ii) an alkali metal bicarbonate.
In a further aspect to the present invention, there is provided a method of forming a protective coating on gastrointestinal mucosal tissue for treating reflux oesophagitis, gastritis, dyspepsia or peptic ulceration which comprises administering an orally effective amount of a composition including at least one alginate having a ratio of the mannuronic acid residues to the guluronic acid residues (M/G) of at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same.
In a preferred embodiment of this aspect of the invention, the composition further comprises an alkali metal bicarbonate, and, advantageously, a polyvalent metal ion as a cross-linking agent. Preferably the polyvalent ion is calcium or aluminium, most preferably calcium.
In another preferred embodiment of this aspect of the invention, the composition comprises
i) from 1% to 10% (preferably 2.0% to 10%, more preferably 2.5% to 8%, especially 4% to 6%) in total of two or more alginates, of which from 10% to 90% comprises an alginate or alginic acid wherein the ratio of the mannuronic acid residues to the guluronic acid residues (M/G) is at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same, and from 90% to 10% comprises an alginate or alginic acid wherein the ratio of the mannuronic acid residues to the guluronic acid residues (M/G) is not more than 2/3 in order to provide a carbonated gelatinous raft or foam of high strength, and
ii) an alkali metal bicarbonate.
In still a further aspect to the present invention there is provided the use of an alginate or alginic acid having a mannuronic acid residue to guluronic acid residue ratio (M/G) of at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same, preferably for the treatment of reflux oesophagitis, gastritis, dyspesia or peptic ulceration, and/or for use in sustained release or targeted delivery of an active.
In a still further aspect of the invention there is provided the use of an alginate or alginic acid having a mannuronic acid residue to guluronic acid residue ratio (M/G) of at least 1 for the preparation of a medicament for the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration by forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same.
The interaction of alginates with mucin can be demonstrated Theologically by comparing the elastic, or storage, modulus (G') of the mucin with that of a mucin-alginate mixture.
Table 1 below shows the elastic modulus (G') of a range of sodium alginates of varying viscosity (and hence molecular weight) and varying M:G ratio in 2% aqueous solution. Also shown is the elastic modulus for a 2% aqueous solution of these alginates containing 15% partially purified porcine gastric mucin (type III Sigma Chemicals).
The G' values were determined using a Carri-med CSL 500 rheometer equipped with a 60 mm diameter cone and plate (angle 1.59 degrees) from frequency scans (0.01-10.0 Hz) at temperature 25oC. The values given are within the linear viscoelastic region of the samples and are those obtained at 5.3 Hz using a set displacement of 7.0x10-4 rad.
The viscosity (Brookfield RVT Viscometer with spindle number 3 at 20 rpm at 20oC.) of a 1% solution of these alginates and the M:G ratio of each alginate are shown in table 2.
TABLE 1
Elastic modulus of alginates and alginate/mucin mixtures
(G' for 15% mucin alone was 36)
Sodium G'
Alginate G' (2% Solution
Grade (2% Solution) with 15% Mucin)
SF120 144 642
SF/LF40 134 698
SF200 143 640
LF120L 243 747
SF60L 260 6,124
H120L 243 1,059
TABLE 2
Viscosities and M:G ratios of alginate grade
Sodium 1% Solution
Alginate Viscosity M:G
Grade (mpa.s) ratio
SF120 110 31:69
SF/LF40 410 37:63
SF200 990 31:69
LF120L 121 56:44
SF60L 368 56:44
H120L 950 54:46
It can be seen from tables 1 and 2 that the elastic modulus G' of 15% mucin (G'=36) is synergistically increased upon mixing with each alginate, but that the effect is increased in alginates with a M/G value of more than about 1 (high M). The effect is also increased greatly with higher viscosity, high M, alginates, whereas the effect is largely independent of the viscosity of high G alginates.
Thus, it is apparent the higher M alginates can interact more effectively with mucin in the gastrointestinal mucosa and that the resulting gel substance will form an effective protective coating on the gastrointestinal, in particular oesophageal and stomach, mucosa.
This formation of an effective protective coating on oesophageal mucosa by high M alginates is demonstrated as follows.
Table 3 shows the percentage cumulative alginate recovered after washing oesophageal mucosa with artificial saliva.
The values shown in Table 3 were arrived at by obtaining porcine oesophagus (the substrate) from an abattoir and cutting the substrate to a 15 mm width and a 90 mm length. Thereafter, the substrate was securely mounted on an inclined support, the angle of inclination of which was variable.
2% solutions of different grades of alginate were fluorescently labelled. Approximately 0.5 grams of the alginate solution was then applied to the substrate which was held at an angle of 180.degree. (i.e. horizontal) and left for 5 minutes.
The alginate coated substrate was then inclined at a selected angle (76.degree.) for 1 minute and any excess alginate solution allowed to flow off the inclined mounted substrate.
The substrate and alginate solution were then washed with an artificial saliva solution (0.27% porcine mucin type III (Sigma Chemicals) and a range of salts) at a rate of 1 ml per minute and the eluent collected at 3 minute intervals over a 30 minute period.
At all times the substrate and associated equipment were held under constant conditions of relative humidity (90%) and temperature (37.degree. C.).
The collected eluate fractions were then analysed for alginate content using a fluorescence spectrophotometer. The percentage cumulative alginate solution recovered can be used as an indicator of the bioadhesive nature of the alginate, given that a higher percentage cumulative alginate recovered implies a weaker adhesion and vice versa.
Table 3 below clearly indicates that the three alginate solutions showing the lowest percentage cumulative recovery (and therefore displaying the highest bioadhesion) are those having an M:G ratio of at least 1. (M:G ratios are given in Table 2)
TABLE 3
Percentage cumulative alginate recovered following
washings with artificial saliva.
Sodium Percentage
Alginate Alginate Solution
Grade Recovered (%) Ranking
SF/LF40 68.23+6.4 4
SF200 73.42+3.4 5
LF120L 12.49+1.8 1
SF60L 14.57+1.1 2
H120L 32.12+4.2 3
(n = 12)
Particularly advantageous mucoadhesive coatings can be achieved by using high viscosity, high M alginates. Thus, preferred formulations according to the invention can include a relatively small amount of a high viscosity high M alginate to provide good coating efficacy and a relatively large amount of a low M (high G) alginate to provide good raft strength, whilst also providing a composition which is pourable. Such formulations may preferably include from 10% to 30% (with respect to the total alginate) of at least one alginate having a M/G value of at least 1 and from 90% to 70% (with respect to the total alginate) of at least one alginate having a M/G value of not more than 2/3.
Also in a pourable composition, good raft strength may also be achieved by using a relatively small amount of a high viscosity high G alginate and a relatively large amount of low viscosity high M alginate may be used to achieve a good coating efficacy. Thus, further preferred compositions according to the invention may include from 70% to 90% (with respect to the total alginate) of at least one alginate having a M/G value of at least 1 and from 30% to 10% (with respect to the total alginate) of at least one alginate having a M/G value of not more than 2/3.
Where a high M alginate and a high G alginate are used each having a relatively lower viscosity, the amounts of each alginate (with respect to the total amount of alginate in the composition) may preferably be respectively from 40% to 60% and from 60% to 40%.
Furthermore, when a composition including a high M alginate is used to form an effective coating on the gastrointestinal mucosa, pharmaceutically active substances maybe incorporated in the composition, whereby targeted delivery and/or sustained release of the pharmaceutically active substance by absorption through the gastrointestinal mucosa can be achieved.
Thus, by means of the present invention there can be provided compositions able to form a protective coating on the mucosa of the oesophagus and stomach and further able to form a carbonated gelatinous raft or foam which, on reflux, precedes the stomach contents into the oesophagus. Because of their mucoadhesive properties, the compositions of the invention are able to form a protective coating on the oesophagus both when passing downwards through the oesophagus directly after ingestion and also when passing from the stomach in to the oesophagus on reflux. The compositions can also be effective in enhancing an existing coating, or re-coating the oesophagus, on reflux.
The compositions of the invention, because of their mucoadhesive properties which allow them to form an effective coating on the oesophageal or gastric mucosa, can be used as vehicles for targeted delivery of pharmaceutically active compounds. These may be compounds which act systemically and are absorbed into the body through the mucosa, such as the oesophageal mucosa, the stomach mucosa and in particular the intestinal mucosa. Particular active ingredients suitable for targeted delivery in or via the stomach include, for example, locally acting antimicrobial agents, H2-antagonists, pro-kinetic agents (such as cisapride), carbenoxolone, sucralfate, local anaesthetics, proton pump inhibitors or anticholinergic agents. Other compounds which are particularly suitable for targeted delivery by means of the compositions of the invention may include those beneficial in the treatment of gastric disorders, such as, for example compounds effective in the treatment of gastric lesions.
The mucoadhesive properties of the compositions of the present invention also render the compositions suitable for use as sustained releasing compositions, in particular for sustained release of pharmaceutically active ingredients through the stomach mucosa. By incorporation in the compositions of the invention of active ingredients suitable for sustained administration through the stomach mucosa, the mucoadhesive coating (and the carbonated gelatinous foam or raft) formed by the compositions may act as a reservoir of the active ingredient from which sustained release can occur.
Supplies of alginates having suitable mannuronic acid residue to guluronic acid residue ratios for carrying out the invention may be obtained from, for example, Pronova Biopolymer.
A suitable procedure to determine the ratio of mannuronic acid residues to guluronic acid residues in alginic acids is by nuclear magnetic resonance spectroscopy. Such a method is described in the paper by Hans Grasdalen et al (Carbohydrate Research 68 (1979) 2331). It should be noted that the hydrolysis method mentioned in that paper may be replaced by a two step hydrolysis carried out at pH 5.4, 100oC. for 1 hour followed by pH 3.8, 100oC. for 1 hour.
The concentration of alkali metal bicarbonate in the compositions of the invention is preferably 0.1 to 8% w/v, more preferably 0.5 to 5% w/v, even more preferably 1 to 3% w/v and most preferably 1.5 to 3% w/v. The alkali metal bicarbonate is preferably sodium or potassium bicarbonate or a mixture thereof. More preferably at least 90% (most preferably 100%) of the alkali metal bicarbonate is sodium bicarbonate.
Where the compositions of the invention comprise a suspending agent it may suitably be selected from xanthan gum, carageenans, hypromellose, tragacanth, pectin, pre-gelatinised potato starch, sodium starch glycolate, carbomer (eg Carbopol 934P or Carbopol 974P, BF Goodrich) or mixtures thereof. Where present the suspending agent is used in an amount of 0.01 to 1% w/v. When carbomer is used as a suspending agent, it is preferably to include a further basic ingredient in the composition to neutralise the suspending agent and to thereby increase its efficacy. Such a basic ingredient, for example, sodium hydroxide, is preferably included in a 1:1 (wt for wt) ratio with the carbomer.
However, it is a feature of the first aspect to the present invention that stable compositions may be prepared without the use of suspending agents. Thus it is preferred that no suspending agent is added to the compositions of the first aspect to the present invention.
As mentioned earlier, the compositions of the present invention preferably further comprise a source of divalent or trivalent metal ions to strengthen the raft formed in the stomach. These metal ions preferably become available when the compositions reach the stomach but must not be available before then (as the compositions will gel too early). Suitable metal ions are aluminium and, preferably, calcium ions. Most preferably the compositions comprise calcium carbonate.
The compositions of the present invention therefore preferably further comprise from 0.1 to 5% w/v calcium ions, more preferably 0.5 to 3.5% w/v calcium carbonate, most preferably 1.5 to 3% w/v.
The compositions of the present invention may further comprise preservatives to prevent contamination and subsequent deterioration by micro-organisms. Examples of suitable preservatives are ethyl and butyl para-hydroxybenzoates and their salts, which are preferably used in combination.
Preferred concentrations for the preservatives are 0.01 to 0.5% w/v.
The compositions of the present invention may also include one or more of the following ingredients, colours, sweeteners (e.g. sodium saccharin), flavours or pH adjusting agents (e.g. monopotassium phosphate or dipotassium phosphate). Preferably such ingredients are present in an amount of 0.01 to 1% w/v.
The compositions according the present invention may also contain conventional antacids including aluminium hydroxide, calcium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium carbonate and magnesium trisilicate. Preferably such ingredients are present in an amount of from 1 to 15% w/v, preferably 2 to 8% w/v.
Where the compositions of the present invention are intended for use as sustained releasing compositions they will also contain active ingredients suitable for sustained administration in the stomach.
Where the compositions of the present invention are intended for use as targeted delivery compositions they will also contain active ingredients suitable for specific delivery to the stomach, for example locally acting antimicrobial agents, H2-antagonists, carbenoxolone, sucralfate, local anaesthetics, proton pump inhibitors, anticholinergic agents and/or prokinetic agents.
The dosage regime for the compositions of the invention will generally be up to 1000 mg total alginate up to four times daily. For a liquid composition comprising 5% total alginate, this equates to a regime of 20 ml four times daily. For a composition in tablet form, the tablet may suitably include 500 mg total alginate and the dosage will suitably be one to two tablets up to four times daily.
Claim 1 of 19 Claims
What is claimed is:
1. An aqueous pourable liquid composition comprising from 8 to 15% w/v of
sodium alginate and an alkali metal bicarbonate, wherein the sodium
alginate has an average mannuronic acid residue to guluronic acid residue
ratio of 0.7:1 to 1.3:1.
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