Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Carbonate
Reexamination Certificate
1999-12-17
2002-05-28
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Carbonate
C424S722000, C514S054000, C514S769000, C514S779000, C514S925000, C514S927000
Reexamination Certificate
active
06395307
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions including alginates or alginic acid, to their preparation and in particular to the use of such compositions for the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration and also to the use of such compositions as targeted delivery and/or sustained release compositions.
The present invention further 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.
BACKGROUND OF THE INVENTION
Alginates may be found in and isolated from various species, in particular from algae belonging to the order Phaeophyceae and soil bacteria such as
Azotobacter vinelandii
and
Azotobacter crococcum
and from several strains of Pseudomonas bacteria. 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 linear hetero-polysaccharide comprising units of &bgr;-D-mannuronic acid (denominated M units) and &agr;-L-guluronic acid (denominated G units).
Alginic acid and alginates may comprise homopolymeric sequences of mannuronic acid, known as M blocks, homopolymeric sequences of guluronic acid, known as G blocks and mixed sequences of mannuronic acid and guluronic acid units, known as MG blocks or alternating blocks. A hypothetical schematic representation of the structure of a typical alginate chain is represented below:
GMMMMMMMGGGGGGGGGMGMGMGMGMGMGGGGGGGGM
M block G block MG block G block
Usually, alginates will contain all three different blocks and each block will contain from about three to about twenty monomer (M or G) units. The distribution of the M, G and MG blocks and also the relative quantity of the M and G units varies according to the species from which the alginate is isolated and in the case of larger plants, on the part of the plant (e.g. stem or leaf) from which the alginate is isolated.
Alginates are also used in various other products such as, for example, food, dental products and cosmetics. The alginates are particularly useful in these areas as gelling, thickening, stabilising, swelling and viscosity imparting agents. The particular alginates used can be selected according to their particular properties which can depend on the distribution of the M blocks, G blocks and MG blocks and the relative quantities of the M and G monomer units.
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™ (Reckitt & Colman Products Ltd). 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 present 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.
Another approach proposed for the treatment of oesophageal and gastric disorders has been to use a material which provides a protective coating on the mucus or mucosa of the gastrointestinal tract.
Materials proposed as such mucoprotectants or bioadhesives have included the antacid sucralfate and various polymers such as polyacrylates, cross linked polyacrylates (for example, the Carbopols and Polycarbophil from the B. F. Goodrich company), sodium carboxymethylcellulose and chitosans.
Alginates have not been generally accepted as bioadhesives and this may be due either to the many different methods employed for bioadhesion or, as the present inventors now believe, to the use of poorly characterised alginates.
Accordingly, with respect to the aim of the present invention to provide more concentrated products thereby reducing the relative dosage volume, a need exists for an aqueous pourable liquid composition comprising a high concentration of sodium alginate and an alkali metal bicarbonate, to thereby provide a more concentrated product having a reduced relative dosage volume.
With respect to the bioadhesion of alginates, a further need exists for an alginate or alginic acid for forming an effective protective coating on gastrointestinal mucosa when brought into contact with same, which has hereto before not been achievable.
SUMMARY AND DETAILED DISCLOSURE OF THE INVENTION
The 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 com
Banning Douglas
Craig Duncan Quinell MacKenzie
Dettmar Peter William
Field Paul Frederick
Hampson Frank Chadwick
Choi Frank
Dees Jose′ G.
Fish & Richardson P.C.
Reckitt Benckiser (UK) Limited
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