Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Patent
1993-01-21
1998-12-01
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
514152, 514394, 514395, 514925, 514926, A61K 3324, A61K 3165, A61K 31415
Patent
active
058434828
DESCRIPTION:
BRIEF SUMMARY
This invention relates to products and processes for the treatment of the alimentary canal, the use of bismuth and novel complexes thereof for treating conditions of the alimentary canal.
Bismuth compounds have been used medically for over 150 years, originally being used in the treatment of treponeme infection, e.g. syphilis, and latterly as dusting powders, antacids, astringents and in the treatment/prophylaxis of traveller's diarrhoea. More recently, bismuth salts have been used in the treatment of gastric and duodenal ulcers. However, it is likely that such salts are precipitated in the low pH environment of the stomach and thereby will be less likely to be biologically active further along the gut. It has also been known to use suppositories and ointments containing bismuth to treat haemorrhoids.
There has been a need to improve the pharmacological effectiveness of bismuth while minimising its absorption from the gut. The desired action of bismuth is local, and absorption leads to unwanted side-effects which may limit the duration, dosage or intensity of treatment.
We have discovered that bismuth forms a water soluble complex with polyacrylates and that the soluble complexes are particularly useful in treatment of conditions of the alimentary canal. Moreover, they have the advantage of being very poorly absorbed from the gut.
One aspect of our invention provides a water soluble complex of bismuth with a polyacrylate.
We surmise that bismuth complexes with the anionic carboxyl groups of the polyacrylate and does not readily precipitate at acid pH, although our invention is founded on empirical evidence and not on any theory of action.
Preferably, the polyacrylate is a carbomer, such as those described in the British Pharmacopoeia and defined in CAS 54182-57-9, which generally consists of a polymer of acrylic acid cross-linked with allylsucrose, and contains 56 to 68% carboxylic acid groups. Preferred carbomers are carbopol 934P and 974P (available from Goodrich UK).
Until recently, carbomer has been used in the pharmaceutical and cosmetic fields as stabilisers, binding agents, emulsifiers and gel-forming excipients. In GB 2,220,855 (Reckitt & Coleman) polyacrylates of the carbomer type are suggested for use alone in the treatment of inflammatory bowel disease.
It is noted that carbomer has been reacted with basic drugs, such as ephedrine, but it has not been suggested previously that polyacrylates might form a soluble complex with heavy metal ions like bismuth and thereby modify their pharmacological effect and metabolic fate.
We prefer to use a bismuth salt to prepare the complex and prefer salts with weak inorganic acids or organic carboxylic acids, e.g. selected from bismuth citrate, bismuth carbonate, bismuth subsalicylate and bismuth subgallate. Bismuth hydroxide may also be used. Other salts, such as bismuth subnitrate, and bismuthates, such as tripotassium dicitrato bismuthate, may be used. The complex preferably comprises carbopol 934P and bismuth derived from bismuth citrate.
It is also possible to use bismuth combined with ligands, such as coordinating ligands, and ligands or cations from the salts mentioned above may become incorporated into the complex. It is clear therefore that the cation or ligand used must be carefully selected since it may be released from the complex in use.
The complex may be prepared by reacting a suitable bismuth compound, e.g. a salt with a weak acid, preferably with an aliphatic or aromatic carboxylic acid, with a dispersion of the carbomer. If desired an acid acceptor may be present or preferably may be added subsequently to combine with the acid liberated from said salt and produce a final pH e.g. in the range 5 to 8. For example, bismuth citrate and bismuth subsalicylate may be used as said bismuth compound; in the case of bismuth citrate, it is desirable to add sodium hydroxide or other acid acceptor at the end of the reaction to increase the water solubility of the carbomer-bismuth complex, neutralise the citric acid liberated and maintain the pH necessary t
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Hutton et al., "Mucolysis Of The Colonic Mucus Barrier By Faecal Proteinases: Inhibition By Interacting Polyacrylate", Clinical Science, 1990, vol. 78, pp. 265-271.
"Methylcellulose And Stabilising And Suspending Agents--5409-w Carbomer", p. 950, Martindale, 28th Edition, 1982.
Derwent Abstract 10879 B/06--JP-A-53148538, entitled "Anti-anaemia Compositions For Warm-Blooded Animals--Contains Iron Salts And Sodium Polyacrylate".
Evans Brian Kenneth
Rhodes John
Tillotts Pharma AG
Weddington Kevin E.
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