CZ380899A3 - Liquid alginate preparations - Google Patents

Abstract

Liquid liquid compositions containing high concentration of sodium alginate and bicarbonate an alkali metal in which the alginate is average the ratio of mannuronic acid residues to acid residues guloronic (M / G) at least 0.6: 1. Further, alginate or alginic acid for the preparation of a medicament for forming a protective coating on the gastrointestinal mucosal tissue, its use and the means containing it.

Description

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Liquid alginate compositions

Technical field

The present invention relates to compositions containing alginates or alginic acid, to a process for their preparation, and in particular to the use of such compositions for the treatment of reflux esophagitis, gastritis, dyspepsia or ulcer, as well as the use of such compositions as targeted delivery and / or sustained release formulations.

The present invention further relates to the preparation of liquid liquid sodium alginate compositions and in particular to the preparation of such compositions for the treatment of reflux esophagitis, gastritis, dyspepsia or ulcer, or for use as sustained release or targeted delivery.

BACKGROUND OF THE INVENTION

Alginates can be found and isolated from various species, especially from algae belonging to the order Phaeophyceae and from soil bacteria such as Azotobacter vinelandii and Azotobacter crococcum and several strains of Pseudomonas. Common algal sources of alginates include Laminaria digitata, Ecklonia maxima, Macrocystis pyrifera, Lessonia nigrescens, Ascophyllum nodosum, Laminaria japonica, Durvillea antartica, Durvillea potatorum and Laminaria hyperborea.

Alginates are salts of alginic acid, which is a direct heteropolysaccharide containing β-Dmannuronic acid units (called M units) and α-L-guluronic acid units (called G units).

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The alginic acid and alginates may comprise homopolymeric mannuronic acid sequences known as M blocks, homopolymeric guluronic acid sequences known as G blocks, and mixed sequences from mannuronic and guluronic acid units known as MG or alternating blocks. A hypothetical schematic example of the structure of a typical alginate chain is given below:

GMMMMMMMGGGGGGGGGMGMGMGMGMGMGGGGGGGGM

M block G block MG block G block

Alginates typically contain all three different blocks and each block contains about three to about twenty monomeric (M or G) units. The distribution of M, G and MG blocks as well as the relative amount of M and G units vary depending on the species from which the alginate is isolated and, in the case of larger plants, depending on the part of the plant (eg stem or leaf) from which the alginate is isolated .

Alginates are also used in various other products, such as food, dental products and cosmetics. The alginates are particularly suitable in these cases as gelling, thickening, stabilizing, swelling and viscosity delivery compositions. The particular alginates used may be selected based on their particular properties, which may depend on the distribution of M blocks, G blocks and MG blocks, and the relative amounts of M and G monomer units.

Reflux esophagitis occurs when small amounts of gastric juice, food and / or bile acids penetrate into the lower sections of the esophagus and cause inflammation

accompanied by pain, which can manifest as heartburn.

One approach to the problem of reflux esophagitis is by administering a preparation which upon contact with stomach acid produces a gelatinous carbonated foam or a layer that floats on the stomach contents. If reflux occurs, it is the layer that enters the esophagus from the stomach contents, thereby protecting the mucosa from further irritation. Known compositions of this type include solid compositions in powder or tablet form containing alginic acid, sodium bicarbonate and antacids; or liquid formulations containing sodium alginate, sodium bicarbonate and calcium carbonate, commercially available under the tradename GAVISCON (TM Reckitt & Colman Products Ltd.) In our British Patent No. 1,524,740, these liquid formulations are described.

A current problem with liquid alginate compositions of the above type is the size of the dose to be administered (up to 20 ml four times a day). This means large amounts of means that cannot be conveniently transported and which take up a lot of space in pharmacies, warehouses, etc.

It is therefore an object of the present invention to provide more concentrated products and thereby reduce the relative dose volume.

SUMMARY OF THE INVENTION

From one point of view, we have found that simply doubling the concentration of all components in conventional sodium alginate formulations leads to formulations that are:

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9 499 9 · 9 4 9 9 f 9 9 9 9 9 9 9 «99 * 49 499 94 99 too dense to be dispensed from the bottle and may even be too dense to be swallowed comfortably.

On the other hand, we have found that a partial decrease in sodium bicarbonate concentrations in these products will reduce the initial viscosity to apparently acceptable levels at which fluidity is achieved. However, if sodium bicarbonate concentrations are too low, the stomach will produce disproportionate production of carbon dioxide and disproportionate layer formation.

In addition, we have found that formulations with high concentrations of conventional sodium alginates and low sodium bicarbonate concentrations have a second serious defect, i.e. if their storage temperatures fall too low, their fluid properties are irreversibly lost. Specifically, when stored at temperatures below 5 ° C for 48 hours or longer, they will remain too dense for pouring, even after warming to room temperature and vigorous shaking. Temperatures of 5 ° C and below are commonly used for long-term storage of commercial products in warehouses or for long-distance transport.

Another approach proposed for the treatment of oesophageal or gastric diseases is the use of a substance that provides a protective layer on the mucus or mucosa of the gastrointestinal tract.

Substances designed as such mucoprotectives or bioadhesives include antacid sucralfate and various polymers such as polyacrylates, cross-linked polyacrylates (e.g., Carbopols and Polycarbophil from B.F. Goodrich), sodium carboxymethylcellulose and chitosans.

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Alginates have generally not been accepted as bioadhesives, which may be due to either the many methods used for bioadhesives or, as the present inventors believe, due to the use of poorly characterized alginates.

Consequently, in view of the purpose of the present invention to provide more concentrated products and thereby reduce the relative batch volume, there is a need for an aqueous liquid liquid composition containing a high concentration of sodium alginates and an alkali metal bicarbonate to provide a more concentrated product having a reduced relative batch volume.

In view of the bioadhesivity of alginates, there is further a need for alginates or alginic acid to form an effective protective coating of the gastrointestinal mucosa when it comes into contact with it, which has not been achievable so far.

The present inventors have now unexpectedly found that thickening problems related to liquid formulations can be overcome by using certain forms of sodium alginates.

In particular, sodium alginate includes the sodium salt of alginic acid, which is a mixture of polyuronic acids composed of residues of D-mannuronic acid and L-guluronic acid as described above. It can be obtained from algae belonging to the order Phaeophycae.

In general, alginates with high ratios of guluronic acid residues have been preferred in previously used liquid alginate products. Generally, substances with ratios of mannuronic acid to guluronic acid ratios of about 0.4: 1 are used (i.e., 4 mannuronic acid residues per 10 guluronic acid residues).

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In the above-described compositions for the treatment of reflux esophagitis, it has been considered important to form a carbonated gelatinous foam or layer of the highest possible thickness. An important factor for the layer thickness is the crosslinking of alginates in the presence of a polyvalent ion, for example, by including calcium carbonate in the composition described above.

Crosslinking by a polyvalent ion occurs most among the guluronic acid residues in the alginate chains, and for this reason they comprise a layer forming agent of the type described above, rich in G units. These are also known as G-rich alginates (similarly M-rich alginates are also known as M-rich alginates).

Typically, G-rich alginates have a ratio of mannuronic acid residues to guluronic acid residues (hereinafter M / G values) of 2/3 or less.

The present inventors have now surprisingly found that the above-described concentration problems can be overcome by using sodium alginates having higher ratios of mannuronic acid residues to guluronic acid residues than those previously used in liquid products.

Accordingly, in accordance with a first aspect of the present invention, there is provided an aqueous liquid liquid composition comprising a high concentration of sodium alginates and an alkali metal bicarbonate, wherein the sodium aiginate has a ratio of mannuronic acid residues to guluronic acid residues of at least 0.6: 1. These compositions are preferably suitable for use as pharmaceutical compositions.

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These compositions are liquid at room temperature and further regain this property upon heating, which is followed by prolonged storage at temperatures below 5 ° C for 6 weeks or more (although adequate shaking may be necessary).

It is contemplated by the liquid that the compositions of the present invention will flow evenly at room temperature (optionally after adequate shaking vigorously) so that its doses, for example 5 ml, can be measured with reasonable accuracy. For example, reproducible doses as low as 5 ml can be dispensed from screw cap bottles with a neck diameter of 1.5 cm, or from plastic displaceable bottles having a dispensing opening as small as 5 mm over.

It is known that increasing the content of mannuronic acid residues in sodium alginate can lead to a reduction in the coherence of the layers formed by the layer-forming agent on contact with stomach acid. Therefore, it is preferable to establish a balance between increasing the content of mannuronic acid residues in sodium alginate to reduce thickening problems, but not to increase it to such an extent that the stomach does not subsequently form effective layers.

Therefore, in the compositions of the present invention, the average ratio of mannuronic acid residues to guluronic acid residues in 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 present invention may contain substances from a single source, 9, 9, 9, 9, 9 and 9.

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999-99-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9-9 all of approximately the same ratios of mannuronic acid residues to guluronic acid residues, or preferably a mixture of substances with different ratios of mannuronic acid residues to guluronic acid residues. Preferably at least 50% of sodium alginate has a ratio of mannuronic acid to guluronic acid residues of greater than 0.8:

1.

Most preferably, at least 70% of the sodium alginate has a ratio of mannuronic acid residues to guluronic acid residues greater than 0.9: 1.

Particularly preferred are compositions of the present invention comprising a mixture of sodium alginates wherein up to 80% sodium alginate has a ratio of mannuronic acid residues to guluronic acid residues of from 0.9: 1 to 1.2: 1 and up to 20% sodium alginate has an acid residue ratio mannuronic acid to guluronic acid residues from 0.35: 1 to 0.5: 1.

Alginates having average ratios of mannuronic acid to guluronic acid residues greater than 0.6: 1 can be extracted from many sources, for example, from Laminaria digitata, Ecklonia maxima, Macrocystis pyrifera, Lessonia nigrescens, Ascophillum nodosum, Laminaria japonica, Durvillea antartica, Durvillea potatorum and from Laminaria hyperborea leaves.

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The compositions of the present invention preferably comprise sodium alginates derived from Laminaria hyperborea.

Sources of alginates having suitable ratios of mannuronic acid residues to guluronic acid residues for carrying out the present invention can be obtained, for example, from Pronova Biopolymer. The company supplies different grades of alginates, which differ among others in molecular weight and viscosity.

Sodium alginate with a low degree of viscosity is preferably used to prepare the compositions of the present invention.

They are those of sodium alginates whose viscosity of a 10% w / v aqueous solution, when determined on a Brookfield RVT viscometer at speed 3 at 20 rpm at 20 ° C, falls within the range of 200 to 1500 mPa · s.

The concentration of sodium alginates in the compositions of the present invention should be higher than in conventional compositions, for example at least 8% w / v. Preferably, the concentration is 9-20%, more preferably 10-15% w / v, and most preferably 10-11% w / v, and especially about 10% w / v.

Further, according to this aspect of the present invention, there is provided a method of treating reflux esophagitis, gastritis, dyspepsia or gastric ulcer, comprising administering a pharmacologically effective amount of an aqueous liquid liquid composition comprising:

(a) 8% to 15% w / v of sodium alginates in which this is toto to toto ♦ ♦ ♦ toto toto toto toto toto toto toto to to to to to to to An average ratio of mannuronic acid residues to guluronic acid residues of at least 0.6: 1, and (b) 0.1 to 8% by weight / volume of alkali metal bicarbonate.

Further according to this aspect of the present invention there is provided a pharmaceutical composition for the treatment of reflux esophagitis, gastritis, dyspepsia or gastric ulcer or for use as a sustained release or targeted delivery composition in the form of an aqueous liquid liquid comprising:

(a) 8-15% w / v of a low viscosity sodium alginate in which the ratio of mannuronic acid residues to guluronic acid residues is at least 0.6: 1; and (b) 0.1 to 8% w / v alkali metal bicarbonate.

Further provided is a pharmaceutical composition for the treatment of reflux esophagitis, gastritis, dyspepsia or gastric ulcer or for use as a sustained release or targeted delivery composition in the form of an aqueous liquid liquid comprising:

(a) 8-15% w / v of a low viscosity sodium alginate in which the ratio of mannuronic acid residues to guluronic acid residues is at least 0.6: 1; and (b) 0.1 to 8% w / v alkali metal bicarbonate; and 9 9 9 99

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(C) substantially no additional suspending agent (suspension stabilizer).

Regarding the need for alginate or alginic acid to form an effective protective coating on the mucosa of the gastrointestinal tract in contact therewith, it has now surprisingly been found that certain grades or types of alginates may interact more effectively than others with mucus components of the gastrointestinal tract to form a mucoadhesive coating. . More specifically, these alginate species have been found to interact with mucin, a glycoprotein, which is a major component of the saliva and mucus of the gastrointestinal tract. The interaction of these alginates with mucus effectively enhances the gel-like mucus structure, providing an effective mucoadhesive coating.

Accordingly, in a second aspect of the present invention, an alginate or alginic acid having a ratio of mannuronic acid to guluronic acid (MG) residues of at least 1 (one) is provided to form a protective layer on gastrointestinal mucosal tissue in contact therewith, particularly for use in the treatment of reflux esophagitis, gastritis, dyspepsia or gastric ulcer and / or as a sustained release or targeted delivery device.

According to a further aspect of the present invention there is provided a pharmaceutical composition for forming a protective coating on gastrointestinal mucosal tissue, in particular for use in the treatment of reflux esophagitis, gastritis, dyspepsia or gastric ulcer and / or for use as a sustained release or targeted delivery composition. alginate or alginic acid, wherein the ratio of mannuronic acid residues to residues

guluronic acid of at least 1, (M / G), to form a protective coating on the gastroinestinal mucosal tissue in contact therewith, and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier may be, for example, water, preferably deionized water.

Preferably, the composition according to this aspect of the present invention should also be capable of forming a carbonated gelatinous foam or a layer that floats on the stomach contents together with the formation of a protective coating on the mucosa of the gastrointestinal tract.

Subsequently, there is provided a pharmaceutical composition for forming a protective coating on gastroinestinal mucosal tissue, preferably for use in the treatment of reflux esophagitis, gastritis, dyspepsia or gastric ulcer and / or as a sustained release or targeted delivery composition comprising:

(a) alginate or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) is at least 1 to form a protective coating on the gastroinestinal mucosal tissue in contact therewith; and (b) an alkali metal bicarbonate.

The composition preferably further comprises a polyvalent metal ion as a crosslinker, in particular calcium or aluminum, most preferably calcium.

In a preferred embodiment of this aspect of the present invention, the composition of the present invention comprises at least one high M alginate that is effective

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4 9 4 9 4 4 4 4 4 4 4 9 9 49 99 99 in forming a protective coating of the esophageal mucosa and at least one high G alginate to provide a gelatinous layer or a dense carbonated foam.

Therefore, in an embodiment of this aspect of the present invention there is provided a liquid liquid composition comprising:

i) a total of 1 to 10% (preferably 2.0 to 10%, more preferably

2.5 to 8%, in particular 4 to 6%) of two or more alginates, of which 10 to 90% comprise alginate or alginic acid in which the ratio of mannuronic acid residues to guluronic acid residues (M / G) is at least 1, for forming a protective coating of gastrointestinal mucosal tissue in contact therewith, and 90-10% comprises alginate or alginic acid in which the ratio of mannuronic acid residues to guluronic acid residues (M / G) is not more than 2/3 to give a dense gelatinous layer or foam, and (ii) an alkali metal bicarbonate.

The composition of this embodiment of the present invention preferably further comprises a polyvalent metal ion (e.g., calcium, aluminum, and especially calcium) as a crosslinker.

One of ordinary skill in the art will recognize that its viscosity should not be too high in order to prepare a liquid liquid formulation. Thus, a suitable liquid composition may, for example, comprise a relatively small amount of high M viscous (high molecular weight) alginates and a relatively large amount of low G viscous (lower molecular weight) alginates. Similarly, the composition may suitably contain relatively high levels of less viscous (lower molecular weight) alginates with a high M content and a relatively small amount of high viscosity (high molecular weight) alginate with a high G content. Even formulations that do not meet the above limits may be appropriate, for example, those containing approximately equal amounts of low M viscosity high M alginates and low viscosity High G alginates (wherein the M / G value is at least 1).

Where the liquid composition of the present invention is not required to be liquid, a higher total amount of alginate (e.g. up to 20%) may be included.

In yet another embodiment of this aspect, the compositions of the present invention may also be provided in the form of a tablet or other solid unit dosage form.

Therefore, in accordance with this aspect of the present invention, there is provided a composition in solid unit dosage form, comprising:

i) a total of 10 to 30% (preferably 15 to 25%, especially 20%) of two or more alginates, of which 10 to 90% comprises alginate or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) ) of at least 1, in order to form a protective coating on the gastrointestinal mucosa in contact with it, and wherein 90 to 10% comprises alginate or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) is not more than 2/3 to provide a dense gelatinous layer or dense carbonated foam; and ii) an alkali metal bicarbonate.

In another aspect of the present invention is fcfcfc

A method of forming a protective coating on the gastrointestinal mucosa for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulcer comprising administering an orally effective amount of a composition comprising at least one aiginate having a ratio of mannuronic acid residues guluronic acid residues (M / G) of at least 1, to form a protective coating on the gastrointestinal mucosa upon contact with it.

In a preferred embodiment of this aspect of the present invention, the composition further comprises an alkali metal bicarbonate and preferably a polyvalent metal ion as a crosslinker. The multivalent ion is preferably calcium or aluminum, most preferably calcium.

In another preferred embodiment of this aspect of the present invention, the composition comprises:

(i) a total of 1 to 10% (preferably 2.0 to 10%, more preferably 2.5 to 8%, particularly preferably 4 to 6%) of two or more alginates, of which 10 to 90% comprise aiginate or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) is at least 1, and to form a protective coating on the gastrointestinal mucosa upon contact therewith, and up to 90 to 10% comprises aiginate or alginic acid in which the ratio of mannuronic acid residues to acid residues The guluronic (M / G) is not more than 2/3 to provide a dense gelatinous layer or carbonated foam and (ii) an alkali metal bicarbonate.

In yet another aspect of the present invention, there is provided the use of alginates or alginic acid having a ratio of mannuronic acid to acid residues 9 9 9 9 9 9 9 9 9 9 9 9 99 99

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999 9 99 999 99 99 guluronic (M / G) of at least 1, for forming a protective coating on the gastrointestinal mucosa upon contact thereof, preferably for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulcer and / or for sustained release or targeted delivery active substances.

In yet another aspect of the present invention there is provided the use of alginate or alginic acid having a ratio of mannuronic acid residues to guluronic acid residues (M / G) of at least 1, for the preparation of a medicament for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulcer. mucous membrane in contact with it.

The interaction of alginates with mucin can be rheologically demonstrated by comparing the modulus of elasticity of mucin (G '), or accumulation, with that of the mixture of mucin and alginate.

Table 1 shows the modulus of elasticity (G ^z ) of a series of sodium alginates with different viscosities (and hence different molecular weights) and different M: G ratios in 2% aqueous solution. Also shown is the modulus of elasticity of a 2% aqueous solution of these alginates containing 15% partially purified porcine gastric mucin (type III Sigma Chemicals).

G 'values are determined using a Carri-med CSL 500 rheometer equipped with a 60 mm base cone and a 1.59 degree plate from frequency scans (0.01 to 10.0 Hz) at 25 ° C. The values are within the linear viscoelastic region of the samples and are those obtained at a frequency of 5.3 Hz using a set shift of 7.0 χ 10 ^-4 rad.

· · »· •

The viscosity (Brookfield RVT viscometer at 3 rpm at 20 rpm at 20 ° C) of a 1% solution of these alginates at the M: G ratio of each alginate is shown in Table 2.

Table 1

Modulus of elasticity of alginates and alginate / mucin mixtures (G 'for 15% mucin as such was 36)

Sodium alginate Species G '(2% solution) G '(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

Viscosity and M: G ratios of alginate species

Sodium alginate Species 1% solution Viscosity (mPa.s) M: G 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

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Tables 1 and 2 show that the modulus of elasticity G '

15% of the mucin (G '= 36) synergistically increase when mixed with each alginate, but that the effect is higher for alginates with an M / G value greater than 1 (alginate with a high M content). The effect is also significantly enhanced at higher viscosity, for high M content alginates, while the effect is almost independent of viscosity for high G alginates.

Therefore, it is apparent that alginates with a higher M content can interact more effectively with the mucin of the gastrointestinal mucosa, and that the resulting gel-like substance will form an effective protective coating on the gastrointestinal, especially esophageal and gastric mucosa.

This formation of an effective protective coating on the esophageal mucosa of high M-containing alginates is illustrated below.

Table 3 shows the percentage of accumulated alginates recovered after washing the esophageal mucosa with artificial saliva.

The values given in Table 3 are obtained after the pig's esophagus (substrate) has been obtained from the slaughterhouse and cut into 15 mm wide and 90 mm long pieces. Then, the substrate is well attached to the inclined support with an adjustable tilt angle.

2% solutions of different alginate species are fluorescently labeled. Then approximately 0.5 g of the alginate solution is applied to a substrate which is fixed at an angle of 180 ° (i.e. horizontally) and left for 5 minutes.

The alginate coated substrate is then tilted at a selected angle (76 °) for 1 minute and any excess alginate solution is allowed to drain from the inclined, fixed substrate.

The substrate and alginate solution were then washed with an artificial saliva solution (0.27% porcine mucin type III, Sigma Chemicals, and various salts) at a rate of 1 ml per minute and the eluent collected at 3-minute intervals for a 30-minute period.

The substrate and associated equipment is constantly maintained under constant conditions, i.e., a relative humidity of 90% and a temperature of 37 ° C.

The collected eluate fractions are then analyzed for alginate content using a fluorescence spectrophotometer. The percentage of regenerated accumulated alginate solution may be used as an indicator of the bioadhesive nature of alginate provided that a higher percentage of accumulated alginate indicates weaker adhesion and vice versa.

Table 3 below clearly indicates that the three alginate solutions that show the lowest percentage of accumulative regeneration (i.e., show the highest bioadhesiveness) are those having an M: G ratio of at least 1. (M: G ratios are shown in Table 2) .

Table 3

Percentage of cumulative alginate regenerated after washing with artificial saliva · »· · o

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Sodium alginate Species Percent regenerated solution of alginates Evaluation SF / LF140 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

(η = 11)

Particularly preferred mucoadhesive coatings may be achieved using high viscosity high M alginates. Therefore, preferred formulations of the present invention may contain a relatively small amount of high viscosity high M alginates to provide good coating efficiency, and a relatively large amount of low M alginates ( high G) to provide the desired layer density while at the same time providing a composition that is fluid. These formulations may preferably comprise 10 to 30% (of the total alginates) of at least one alginate with an M / G value of at least 1 and 90 to 70% (of the total alginates) of at least one alginate with an M / G value of no greater than 2/3.

In a liquid composition, good layer density can also be achieved by using a relatively small amount of high G viscosity high G alginates and a relatively large amount of low M viscosity high M alginates to achieve good coating efficiency. Therefore, other preferred compositions of the present invention may comprise 70 to 90% (of the total alginates) of at least one alginate with an M / G value of at least 1 and from 30 to 10% (of the total alginates) of at least one alginate with a M / G value not greater than 2/3.

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Where a high M alginate and a high G alginate, both of relatively low viscosity, are used, the amount of each alginate (of the total alginate in the composition) may preferably be from 40% to 60% and from 60% to 40% .

Further, if a composition containing high M alginate is used to form an effective coating on the gastrointestinal mucosa, pharmaceutically active agents can be included in the composition to achieve targeted delivery and / or sustained release of the pharmaceutically active agent by absorption of the gastrointestinal mucosa.

Accordingly, in the sense of the present invention, it is possible to provide compositions which are capable of forming protective coatings on the mucosa of the esophagus and stomach and further capable of forming a gelatinous carbonated layer or foam which prevents reflux of gastric contents into the esophagus. Because of their mucoadhesive properties, the compositions of the present invention are able to form a protective coating of the esophagus, both when passing down through the esophagus immediately after ingestion and also when penetrating from the stomach to the esophagus during reflux. The compositions may also be effective in strengthening an already formed coating or re-forming the esophageal coating at reflux.

Usability

The compositions of the present invention can be used as vehicles for the targeted delivery of pharmaceutically active compounds due to their mucoadhesive properties which allow them to form effective coatings on the esophagus or gastric mucosa. They can be compounds,

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They act systemically and are absorbed by the mucosa, for example the esophagus mucosa, the gastric mucosa, and in particular the small intestine mucosa. Particular active ingredients suitable for targeted delivery to or through the stomach include, for example, topical antimicrobials, H2-antagonists, prokinetics (e.g. cisapride), carbenoxolone, sucralfate, local anesthetics, proton pump inhibitors or anticholinergics. Other compounds particularly suitable for targeted delivery within the meaning of the compositions of the present invention may include compounds effective in the treatment of gastric disorders, for example compounds effective in the treatment of gastric disorders.

The mucoadhesive properties of the compounds of the present invention may also render these compositions suitable for use as sustained release formulations, in particular for sustained release of pharmaceutically active ingredients via the gastric mucosa. Incorporating active ingredients suitable for uninterrupted administration through the mucosa of the stomach into the compositions of the present invention, the mucoadhesive coating (and gelatin foam or carbonated layer) formed by the composition may function as a reservoir of active ingredient from which the uninterrupted administration takes place.

The supply of alginates having suitable ratios of mannuronic acid residues to guluronic acid residues for carrying out the present invention can be obtained, for example, from Pronova Biopolymer.

A suitable procedure for determining the ratio of mannuronic acid residues to guluronic acid residues in alginic acids is nuclear magnetic resonance spectroscopy. This method is described in Hans Grasdalen et al., 4, 4, 4, 4, and 4. φ · Φ Φ Φ Φ Φ * * «« · · · ·

Carbohydrate Research 68, 2331 (1979). It should be noted that the hydrolysis method mentioned in this work can be replaced by a two-step hydrolysis performed at pH 5.4, 100 ° C for 1 hour followed by pH 3.8, 100 ° C for 1 hour.

The concentration of the alkali metal bicarbonate in the compositions of the present 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% weight / volume. 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 present invention include a suspending agent, this may suitably be selected from xanthan gum, carageenates, hypromellose, tragacanth gum, pectin, pregelatinized potato starch, sodium starch glycolate, carbomer (eg, Carbopol 934P or Carbopol 974P, BF Goodrich) or mixtures thereof. In cases where a suspending agent is used, it is used from 0.01 to 1% w / v. When a carbomer is used as the suspending agent, preferably a further basic component is included in the composition to neutralize the suspending agent and thereby increase its effectiveness. The base component, for example sodium hydroxide, is preferably included in a 1: 1 (w / w) ratio with the carbomer.

However, a feature of the first aspect of the present invention is that stable formulations can be prepared without the use of a suspending agent, so it is preferable not to add

• • · 9 9 • 9 9 9 9 9 · • · 9 9 9 · 9 9 9 9 9 9 9 • 9 • 9 • • • 9 9 • 9 • • 9 · ♦ »9 • 9 9 9, 9 9 »

no suspending agent for the compositions of the first aspect of the present invention.

As mentioned previously, the compositions of the present invention preferably further comprise a source of divalent or trivalent metal ions to enhance the stomach layer. Preferably, these metal ions are released when the compositions reach the stomach, but must not be released earlier (as the composition would gel prematurely). Suitable metal ions are aluminum and preferably calcium ions. Most preferably, the compositions comprise calcium carbonate.

Therefore, the compositions of the present invention further preferably comprise 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 of microorganisms. Examples of suitable preservatives include ethyl and butyl para-hydroxybenzoate and salts thereof, which are preferably used in combination.

Preferred concentrations of preservatives are 0.01 to 0.5% w / v.

The compositions of the present invention may also contain one or more of the following: colorants, sweeteners (e.g., saccharin sodium), flavorings or pH adjusting agents (e.g., potassium dihydrogen phosphate or potassium hydrogen phosphate). These components are preferably present in an amount of 0.01 to 1% w / v.

To to * to to to f f f f f f f f f f f f f f f f f f f to ··

The compositions of the present invention may also contain conventional antacids including aluminum hydroxide, calcium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium carbonate, and magnesium trisilicates. Preferably, these components 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 contemplated as sustained release compositions, they will also contain active ingredients suitable for continuous gastric delivery.

Where the compositions of the present invention are intended to be targeted delivery devices, they will also contain active ingredients suitable for specific gastric delivery, e.g. anticholinergics and / or prokinetics.

The dosage regimen for the compositions of the present invention will generally be up to 1000 mg alginate a total of four times a day. For a liquid composition containing a total of 5% alginate, this means 20 ml four times a day. For a tablet formulation, the tablet may conveniently contain a total of 500 mg alginate and the dosage will suitably be one to two tablets up to four times a day.

The percentages given herein are% w / v for liquid components and% w / w. for solids, unless otherwise specified.

4444

The invention is further illustrated by reference to the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Device containing:

Sodium alginate LFR 5/60 RBG 100 g (M: G ratio 0.9: 1, Pronova Biopolymer) Sodium bicarbonate 26 g Calcium carbonate 32 g Potassium dihydrogen phosphate 0.6 g Potassium hydrogen phosphate 5,4 g Ethyl para-hydroxybenzoate 2 g Butyl-para-hydroxybenzoate 0.2 g Saccharin sodium 1 g Flavoring 0.7 g Deionized water is processed as follows: ad 1 liter

1. Separate 917 ml of deionized water into a mixing vessel and cool to approximately 20 ° C.

2. Add potassium dihydrogen phosphate and potassium hydrogen phosphate and stir until dissolved.

3. Add preservatives, carbonates and sweetener to the mixture and mix for 5 minutes.

4. Alginate is added over 3 minutes with stirring.

• 0 · 0 • * 0 · · 0 · · 0 · 000 · 000 000 «000« 0 000 0000 · 000 00 00000 «* ·· 0 0« 00 000 »

000 r 00 000 0 * 0 0

5. Stir for 30 minutes (add flavoring after 10 minutes).

6. Maintain a temperature of 22 ° C (plus / minus 5 ° C) during preparation.

Examples 2 to 6

The following examples were prepared in the same manner as in Example 1, using as many components as shown in the table below:

Table

EXAMPLE 2 3 4 5 6 Sodium alginate LFR 5/60 (M: G ratio 0.45: 1 Pronova Biopolymer) 25 g 25 g 25 g 25 g 25g Sodium alginate LFR 5 / 60RB (M: G ratio 1.1: 1 Pronova Biopolymer) 75 g 75 g 75 g 75 g 75 g Sodium bicarbonate 26 g 26 g 26 g 16 g 20 g Calcium carbonate 32 g 16 g 60 g 32 g 32 g Dihydrogenphosphate Potassium 0.6 g 0.6 g 0.6 g 0.6 g 0.6 g Hydrogen phosphate Potassium 5,4 g 5,4 g 5,4 g 5,4 g 5,4 g Ethy1-para-hydroxy- benzoat 2,0 g 2,0 g 2,0 g 2,0 g 2,0 g Buthyl-para-hydroxy- benzoat 0.2 g 0.2 g 0.2 g 0.2 g 0.2 g Saccharin sodium 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g Flavoring 0.7 g 0.7 g 0.7 g 0.7 g 0.7 g Deionized water etc. 1 liter 1 liter 1 liter 1 liter 1 liter

• 4 4 4 4 4 4 4 4 4 4 4 • · · 4 4 • 4 ♦ 4 4 « 4 4 • 4 • • 4 4 4 4 4 * 4 • 4 4 4 4 • 44 4 • 4 4 4 4 4 4 • 4

Example 7

The following means are prepared:

Sodium alginate LFR 5/60 25,0 g (viscosity 1% = 6 mPa.s, M content 36%) Sodium alginate LF 10L 25,0 g (viscosity 1% = 9.5 mPa.s, M content 57%) Calcium carbonate 16,0 g Sodium bicarbonate 26,7 g Methyl para-hydroxybenzoate 4.0 g Propyl para-hydroxybenzoate 0.6 g Karbopol 974P 6,5 g Sodium hydroxide 3,0 g Saccharin sodium 1.0 g Flavoring 0.2 g Deionized water ad 1 liter

The method of preparation is as follows:

1. Carbopol 97 4P is dispersed in 450 ml of deionized water and neutralized with sodium hydroxide.

2. Mix sodium bicarbonate, calcium carbonate, parahydroxybenzoates and saccharin in a second separate vessel with 450 ml deionized water.

3. Slowly add sodium alginates to the second vessel and stir until completely dissolved.

4. Add the contents of the second vessel to the Carbopol 974P phase and stir until fully dispersed.

5. Add flavor and mix.

• · · · · M 9 • a and 9 * · · 9 * and a ♦ • and • • · 9 • and »» and and « « • a 9 • and « and and and • * 9 * * ♦ * a · «· ♦ «

6. Adjust the volume to 1 liter by adding an additional amount of deionized water and stir until the water is completely dispersed.

Example 8

The following composition was prepared using the method of Example 1:

Sodium alginate LFR 5/60 40.0 g (viscosity 1% = 6 mPa.s, content M 36%)

Sodium alginate SF60L 10.0 g (viscosity 1% = 368 mPa.s, M content 56%) Sodium bicarbonate 26.7 g

Calcium carbonate 16.0 g

Methyl para-hydroxybenzoate 4.0 g

Propyl para-hydroxybenzoate 0.6 g

Carbopol 974P 1.0 g

Sodium hydroxide 0.46 g

Saccharin sodium 1.0 g

Flavoring 0.7 g

Deionized water up to 1 liter

Example 9

The following composition was prepared using the method of Example 1:

Sodium alginate LFR 5/60 30.0 g (viscosity 1% = 6 mPa.s, content M 36%)

Sodium alginate LF120L 20.0 g (viscosity 1% = 121 mPa.s, M content 56%)

Potassium bicarbonate 20.0 g

30 9 · · · • · · • · · • · »· • 9 · • ® · Φ · «· ♦ Φ · Φ • φφφφ • · Φ 9 4 * · · » Calcium carbonate 10, 0 g Methyl para-hydroxybenzoate 4.0 G Propyl para-hydroxybenzoate 0.6 G Karbopol 974P 2,0 G Sodium hydroxide 0.92 g Saccharin sodium 1.0 G Flavoring 0.7 G Deionized water ad 1 liter

Example 10 The following means are prepared: Sodium alginate LF10 / 60 10, o g (viscosity 1% = 54 mPa.s, M content 29%) Sodium alginate SF60L 15, 0 g (viscosity 1% = 368 mPa.s, M content 56%) Sodium bicarbonate 13, 3 g Calcium carbonate 8.0 G Ethyl para-hydroxybenzoate 2,0 G Butyl para-hydroxybenzoate 0.2 G Xanthan gum 4.0 G Potassium dihydrogen phosphate 0, 6 G Potassium hydrogen phosphate 5.4 G Saccharin sodium 1.0 G Flavoring 0.2 G Deionized water ad 1 liter

The method of preparation is as follows:

1. Dissolve the phosphates in 900 ml of deionized water with stirring.

· · ·

* * * * * 4 4 4 4 4 4 4 4 4 4 · · · · · · · · · · · · · · · · · ·

2. Add sodium bicarbonate, preservatives and saccharin sodium and disperse with stirring.

3. Slowly add xanthan gum and disperse over 20 minutes.

4. Alginates are slowly added and dispersed with stirring for an additional 20 minutes.

5. Add calcium carbonate and mix to disperse.

6. Add flavor and mix to disperse.

7. Adjust the volume to 1 liter by adding additional deionized water and stir until the water is completely dispersed.

Example 11

The following means are prepared:

Sodium alginate LFR5 / 60 40,0 g (viscosity 1% = 6 mPa.s, M content 36%) Sodium alginate SF60L 10,0 g (viscosity 1% = 368 mPa.s, M content 56%) Aluminum hydroxide (as 10% gel) 100.0 g Xanthan gum 4.0 g Sodium bicarbonate 26,7 g Potassium dihydrogen phosphate 0.6 g Potassium hydrogen phosphate 5,4 g Ethyl para-hydroxybenzoate 2,0 g Butyl para-hydroxybenzoate 0.2 g Saccharin sodium 1.0 g Flavoring 0.7 g

fc ···· fcfc fc fcfc fct fcfc fc «fcfcfc fcfc ·· • · fc fc · fcfcfcfc • · fcfcfc fc fcfcfc fc fc • fc fcfcfc fcfc ·· • fcfcfc fcfcfc

Deionized water up to 1 liter

The method of preparation is as follows:

1. Dissolve phosphates, sodium bicarbonate, saccharin sodium and paraben preservatives in 800 ml deionized water.

2. Slowly add xanthan gum and disperse over 20 minutes.

3. Slowly add alginates and disperse with stirring for an additional 20 minutes

4. Add the aluminum hydroxide gel and mix.

5. Add flavor and mix.

6. Adjust the volume to 1 liter by adding additional deionized water and stir until the water is completely dispersed.

· · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

999 9 99 999 99 99? / X / W -

Claims (16)

PATENT CLAIMS An aqueous liquid liquid composition comprising sodium alginate in high concentration and an alkali metal bicarbonate, characterized in that the sodium alginate has an average ratio of mannuronic acid residues to guluronic acid residues of at least 0.6: 1. 2. The composition of claim 1 wherein at least 50% of sodium alginate has a ratio of mannuronic acid to guluronic acid residues of greater than 0.8: 1. • Composition according to claim 1 or 2, characterized in that: 70 to 80% of sodium alginate has a ratio of mannuronic acid residues to guluronic acid residues of from 0.9: 1 to 1.2: 1; and 30 to 20% of sodium alginate has a ratio of mannuronic acid residues to guluronic acid residues of from 0.35: 1 to 0.5: 1. 4. A pharmaceutical composition for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulcer or for use as a sustained release composition or as a targeted delivery composition in the form of an aqueous liquid liquid, comprising: (a) 8 to 15% w / v low viscosity sodium alginate having an average acid residue ratio 9 99 99 ·· ♦ 98 9 9 9 9 9 9 9 9 9 9 9 9 • 9 9 9 9 9 β • 9 mannuronic acid to guluronic acid residues of at least 0.6: 1; and b) 0.1 to 8% w / v alkali metal bicarbonate, the composition preferably containing no further suspending agents. 5. A method of treating reflux esophagitis, gastritis, dyspepsia or peptic ulcer, comprising administering an orally effective amount of an aqueous liquid liquid composition comprising: (a) 8 to 15% w / v of low viscosity sodium alginate having an average ratio of mannuronic acid residues to guluronic acid residues of at least 0.6: 1; and b) 0.1 to 8% w / v alkali metal bicarbonate An alginate or alginic acid having a ratio of mannuronic acid residues to guluronic acid residues (M / G) of at least 1, to form a protective coating on the gastrointestinal mucosal tissue in contact therewith. A pharmaceutical composition for forming a protective coating on gastrointestinal mucosal tissue, comprising alginate or alginic acid having a ratio of mannuronic acid to guluronic acid (M / G) residues of at least 1, for forming a protective coating on gastrointestinal mucosal tissue upon contact with it and a pharmaceutically acceptable carrier. • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · A composition according to claim 7, characterized in that it is capable of forming a gelatinous foam or carbonated layer that floats on the stomach contents in conjunction with the formation of a protective coating on the gastrointestinal mucosa. The composition of any one of claims 6 to 8, further comprising one or more of the following: i) an alkali metal bicarbonate; ii) a polyvalent metal ion as a crosslinker, preferably calcium or aluminum, most preferably calcium; and (iii) an alginate or alginic acid in which the ratio of mannuronic acid residues to guluronic acid residues (M / G) is not more than 2/3 to provide a gelatinous layer or carbonated foam of high concentration. Composition according to any one of claims 6 to 9, characterized in that it comprises i) a total of i to 10% (preferably 2.0 to 10%, more preferably 2.5 to 8%, especially 4 to 6%) of one or two alginates, of which 10 to 90% are alginate or alginic acid, wherein the ratio is residues of mannuronic acid to residues of guluronic acid (M / G) is at least 1, to form a protective coating on the gastrointestinal mucosal tissue in contact therewith, and from 90% to 10% are alginate or alginic acid where there is no ratio of residues of mannuronic acid to residues guluronic acid (M / G) greater than 2/3 to provide a dense gelatinous layer or carbonated foam; ii) an alkali metal bicarbonate; and preferably * iii) poylvalent a metal ion crosslinker, preferably calcium or aluminum, most preferably calcium. Composition according to any one of claims 6 to 9, characterized in that it is provided in the form of tablets or other solid unit dosage form. 12. A pharmaceutical composition in solid unit dosage form comprising i) a total of 10 to 30% (preferably 15 to 25%, in particular 20%) of one or two alginates, of which 10 to 90% are alginate or alginic acid, with a ratio of mannuronic acid to guluronic acid (M / G) residues at least 1, to form a protective coating on the gastro-intestinal mucosal tissue in contact therewith, and from 90% to 10% form alginate or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) is not more than 2 / 3 to provide a dense gelatinous layer or carbonated foam; ii) an alkali metal bicarbonate. 13. A method of preparing a protective coating on oral mucosa tissue for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulcer, comprising administering an orally effective amount of a composition comprising: i) alginate or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) is at least 1; the composition optionally further comprising: ii) an alkali metal bicarbonate; and (iii) a polyvalent metal ion crosslinker, preferably calcium or aluminum, most preferably calcium. The method of claim 13, wherein the composition comprises i) a total of 1 to 10% (preferably 2.0 to 10%, more preferably 2.5 to 8%, especially 4 to 6%) of one or two alginates, of which 10 to 90% are alginate or alginic acid, wherein the ratio is residues of mannuronic acid to residues of guluronic acid (M / G) is at least 1, to form a protective coating on the gastrointestinal mucosal tissue in contact therewith, and from 90% to 10% are alginate or alginic acid where there is no ratio of residues of mannuronic acid to residues guluronic acid (M / G) greater than 2/3 to provide a dense gelatinous layer or carbonated foam; ii) an alkali metal bicarbonate. Use of alginates or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) is at least 1, to form a protective coating on gastrointestinal mucosal tissue in contact therewith. Use of alginates or alginic acid, wherein the ratio of mannuronic acid residues to guluronic acid residues (M / G) is at least 1, for the preparation of a medicament for forming a protective coating on gastrointestinal mucosal tissue for treating reflux esophagitis, gastritis, dyspepsia or peptic ulcers or use for sustained release or targeted delivery of the active ingredient.