GB2324724A

GB2324724A - A Concentrated Aqueous Sodium Alginate Composition

Info

Publication number: GB2324724A
Application number: GB9808522A
Authority: GB
Inventors: Ian Gordon Jolliffe; Paul Frederick Field; Edvar Jarle Onsoyen; Ase Hanne Kristensen; Peter William Dettmar
Original assignee: Reckitt and Colman Products Ltd
Current assignee: Reckitt Benckiser Healthcare UK Ltd
Priority date: 1997-04-30
Filing date: 1998-04-22
Publication date: 1998-11-04
Anticipated expiration: 2018-04-22
Also published as: GB2324724B; HUP0002238A3; GB9808522D0; HUP0002238A2; GB9708772D0

Abstract

A high concentration, liquid, pourable pharmaceutical composition comprises a particular form of sodium alginate and an alkali metal bicarbonate. The sodium alginate used is of comparatively high mannuronic acid:glucoronic acid (M/G) residue ratio (> 6:10) than those of previous liquid products. The composition is nonetheless, suitable for use in the treatment of reflux oesophagitis, gastritis, dyspepsia and peptic ulceration and enables a smaller dosage volume than conventionally used.

Description

ORGANIC COMPOSITIONS This invention relates to the preparation of pourable liquid sodium alginate compositions and in particular to the preparation of such compositions for the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration, or for use as sustained releasing or targeted delivery compositions.

Reflux oesophagitis occurs when small amounts of gastric juice, food and/or bile acids pass into the lower part of the oesophagus and cause oesophageal inflammation accompanied by pain which may manifest itself in the form of heartburn.

One approach to the problem of reflux oesophagitis has been to administer a preparation which on contact with gastric acid generates a carbonated gelatinous foam or raft which floats on the stomach contents.

When reflux occurs it is this raft which precedes the stomach contents into the oesophagus, thus protecting the mucosa from further irritation. Known preparations of this type include solid preparations in the form of powder or tablets containing alginic acid, sodium bicarbonate and antacid materials; or liquid preparations containing sodium alginate, sodium bicarbonate and calcium carbonate marketed under the name GAVISCON (TM Reckitt & Colman Products Lid) . In our British Patent No. 1524740 we describe such liquid preparations.

A current problem with liquid alginate products of the above type is the size of the dose which must be taken (up to 20 ml four times daily). This results in large volumes of products which are not conveniently portable and which take up a lot of space in pharmacies, warehouses etc.

It is therefore an aim of the invention to provide more concentrated products thereby reducing the relative dosage volume.

On the one hand, we have found that merely doubling the concentration of all ingredients in conventional sodium alginate compositions leads to compositions which are too thick to dispense from a bottle and may even be too thick to comfortably swallow.

On the other hand, we have found that partially reducing the sodium bicarbonate concentrations in such products will reduce the initial viscosity to apparently acceptable levels at which pouring may be achieved. However if the bicarbonate concentrations are reduced too far there will be inadequate carbon dioxide production in the stomach, which will lead to inadequate raft formation.

We have found moreover that compositions having high concentrations of conventional sodium alginates and low concentrations of sodium bicarbonate have a second serious defect, i.e. their pouring properties are irreversibly lost if storage temperatures drop too low. Specifically, if such compositions are stored at below 5"C for 48 hours or more they will remain too thick to pour, even after being restored to room temperature and vigorously shaken. Temperatures of 5"C or lower are commonly encountered when commercial products are stored for long periods in warehouses or transported over long distances.

We have now unexpectedly found that these thickening problems 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. 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.

Specifically 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.

According to the invention there is therefore 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 composition 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 50C 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.

Alginic acids 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.

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, 100"C for 1 hour followed by pH 3.8, 100" C for 1 hour.

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 200C, 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.

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.

The compositions of the invention may be used in the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration. They may also be used as carriers of other active ingredients and so act as sustained release compositions, or compositions delivering the actives specifically to the stomach (targeted delivery).

Further according to the 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 the 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.

Where the compositions of the invention comprise a suspending agent it may suitably be selected from 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.

However, It is a feature of 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 invention.

There is therefore 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 i55;i 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.

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 (eg sodium saccharin), flavours or pH adjusting agents (eg monopotassium phosphate or dipotassium phosphate). Preferably such ingredients are present in an amount of 0.01 to 1 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 or anticholinergic agents.

The invention will now be illustrated by reference to the following examples.

Example 1 A composition containing Sodium alginate LFR 5/60 RB 100g (M:G ratio 0.9:1, Pronova Biopolymer) Sodium bicarbonate 26g Calcium carbonate 32g Monopotassium phosphate 0.6g Dipotassium phosphate 5.4g Ethyl parahydroxybenzoate 2g Butyl parahydroxybenzoate 0.2g Sodium saccharin ig Flavour 0.7g Deionised water to 1 litre is made up as follows 1. 917ml of deionised water are dispensed into a mixing vessel and cooled to approximately 20"C.

2. The monopotassium phosphate and dipotassium phosphate are added and stirred until dissolved.

3. The preservatives, carbonates and sweetener are added to the mixture and stirred for 5 minutes.

4. The alginate is added with stirring over a period of 3 minutes.

5. The mixture is stirred for 30 minutes (the flavour being added after 10 minutes).

6. The temperature is controlled during manufacture to 22"C (plus or minus 5"C).

Examples 2 to 6 The following examples are all produced according to the method of Example 1 using the amounts of components as set out in the table below.

TABLE EXAMPLE 2 3 4 5 6 Sodium alginate LFR 5/60 25g 25g 25g 25g 25g (M to G ratio 0.45:1 Pronova Biopolymer) Sodium alginate LFR 5/60RB 75g 75g 75g 75g 75g (M to G ratio 1.1:1 Pronova Biopolymer) Sodium Bicarbonate 26g 26g 26g 16g 20g Calcium carbonate 32g 16g 60g 32g 32g Potassium phosphate 0.6g 0.6g 0.6g 0.6g 0.6g Dipotassium phosphate 5.4g 5.4g 5.4g 5.4g 5.4g Ethyl parahydroxybenzoate 2.0g 2.0g 2.0g 2.0g 2.0g Butyl parahydroxybenzoate 0.2g 0.2g 0.2g 0.2g 0.2g Sodium saccharin 1.0g l.0g l.0g 1.0g 1.0g Flavour 0.7g 0.7g 0.7g 0.7g 0.7g Deionised water to lltr lltr lltr lltr lltr

Claims

CLAIMS 1. 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.
2. A composition as claimed in claim 1 wherein at least 50% of the sodium alginate has a mannuronic to guluronic acid residue ratio of greater than 0.8:1.
3. A composition as claimed in claim 1 or claim 2 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.
4. 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.
5. 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
6. A method of treating reflux oesophagitis, gastritis, dyspepsia or peptic ulceration which comprises administration of an orally 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.
7. Use of a sodium alginate having an average mannuronic acid residue to guluronic acid residue ratio of at least 0.6:1 for the manufacture of a pharmaceutical composition for the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration.
8. A pharmaceutical composition, substantially as herein described with reference to any one of the Examples.
9. A pharmaceutical composition according to the invention whenever supplied with instructions for the use thereof in the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration.
10. A composition as claimed in claim 9 when the instructions are in printed or written form.
11. A composition as claimed in claim 10 supplied in a package or container having the said instructions provided therein or thereon.