GB2236479A - Preparation of orally administrable bismuth ammonium citrate solutions - Google Patents

Abstract

A process for the manufacture of an aqueous solution of bismuth ammonium citrate complex for use in a pharmaceutical formulation having activity against gastrointestinal ulcers, comprises the step-wise addition of an aqueous ammonia solution to a mixture of bismuth citrate powder in water and continuing such addition until the mixture substantially clarifies, indicating substantial solubilisation of the bismuth citrate and the formation of the desired complex. The pharmaceutical formulation comprises the resulting aqueous solution, optionally with flavouring and preservatives.

Description

PREPARATION OF ORALLY ADMINISTRABLE LIQUIDS OF USE Rees This invention relates to orally administrable bismuth salt formulations for use in the treatment of disorders of the gastrointestinal tract. More particularly, the invention relates to a process for the preparation of a liquid bismuth ammonium citrate complex formulation with good organoleptic properties for use in such disorders.

Various bismuth compounds have been used inter alia as antacids and anti-ulcer drugs. Thus, bismuth subcitrate, formerly called tripotassium dicitrato bismuthate, is used to treat both duodenal and gastric ulcers, and in these uses it has been found to be as effective as the H2-antagonists cimetidine and ranitidine.

As indicated in Martindale The Extra Pharmacopoeia (29th edition) studies have shown that bismuth subcitrate is capable of producing initial healing comparable with cimetidine or ranitidine in patients with duodenal ulcer or gastric ulcer. Also these studies demonstrated on follow-up that after the initial therapy was discontinued the relapse rate was significantly lower in the bismuthate-treated patients than in those given an H2-antagonist. Bismuth subcitrate has a strong affinity for mucosal glycoproteins, especially in the necrotic tissue in ulcer craters. Bismuth salts have antibacterial properties, and bismuth subcitrate has been found to be bactericidal to Camoylobacter pylori which colonises the gastric epithelium.In a recent study cimetidine has been found to have no effect on C pylori whereas colloidal bismuth subcitrate eradicated r L;ylorl in 45% of patients.

A liquid tripotassium dicitrato bismuthate for oral adminstration is marketed by Gist-Brocades under the Trade Mark DE-NOL. This product has poor organoleptic properties which cannot be masked by conventional flavouring and sweetening agents and thus it is poorly tolerated. The poor organoleptic properties of DE-NOL are attributed to the presence of ammonia.

DE-NOL comprises tri-potassium dicitrato bismuth calculated as Bi203 120 mg per 5ml.

It is an object of the present invention to provide a bismuth subcitrate solution for oral administration with good organoleptic properties.

The present invention provides a process for the manufacture of an aqueous solution of bismuth ammonium citrate complex, which process comprises the step-wise addition of an ammonia solution to a stirred mixture of bismuth citrate powder in an amount of water corresponding to approximately 20% of the final volume of the solution to be prepared1 the bismuth citrate being present at a concentration in the range 20-27% w/v, and continuing such addition until the mixture substantially clarifies, indicating substantial solubilisation of the bismuth citrate and the formation of the desired complex.

Preferably, the ammonia solution is added in metered amounts such that the ratio of ammonia solution to water is approximately 6% v/v.

Further, preferably the amount of bismuth citrate used is of the order of 23.5% w/v of final solution.

The solution as prepared is substantially odourless and tasteless.

For the preparation of volumes of bismuth ammonium citrate solution of up to approximately 50 1 the bismuth citrate is suitably added to approximately 20% of the total volume of water in a stainless steel vessel and stirred. Half the ammonia solution is added, the tank is covered and the mixture left for approximately 5 min. The mixture is then stirred and the remainder of the ammonia solution added, covered and left for approximately 10 to 15 min., whereupon the solution clarifies and a substantially odourless and tasteless solution is obtained. For larger volumes of approximately 100 1 or greater it is preferable to add the ammonia solution gradually as hereinafter described in the Example.

The solution obtained according to the process of the invention may be used as a basis for a liquid formulation for oral administration by adding conventional auxiliaries thereto and adjusting to said final volume.

A preferred formulation includes one or more flavouring agent(s) and/or sweetening agent(s) and one or more preservatives secundem artem.

According to one embodiment of the invention a sucrose syrup prepared using approximately 20% of the water contained in the final solution and sucrose at a concentration of approximately 200% w/v and containing effective amounts of one or more flavouring agent(s) and one or more preservative(s) is added to the bismuth ammonium citrate solution followed by adjustment to the final volume of solution to be prepared.

In an alternative embodiment the water (20% of the final volume) may be added directly to the bismuth citrate solution followed by the sucrose, flavouring agent(s) and preservative(s).

A preferred orally administrable solution prepared in accordance with the invention has the following composition per 5 ml: Bismuth citrate 235.0 mg as Bismuth ammonium citrate complex calculated as bismuth trioxide (Bi2O3) 137.5 mg Sucrose 2.016 g Ammonia solution 'AnalaR' sp. gr.

0.88 0.063 ml Wild cherry concentrate 1 - 7 0.3355 ml Nipasept (Nipasept is a Trade Mark) sodium 6.25 mg Deionisedwater to 5.0 ml The above bismuth ammonium citrate solution is a clear brown solution which has excellent organoleptic properties and results in excellent patient compliance. A further advantage of the solution prepared in accordance with the invention is that it does not produce constipation, a side effect of DE-NOL.

The solution in accordance with the invention is suitable for use in the treatment of gastric and duodenal ulcers and is especially suitable for the treatment of ulcers and other disorders of the gastrointestinal tract characterised by the presence of Campylobacter pylori.

The solution prepared in accordance with the invention is also effective in the treatment of non-ulcerative dyspepsia. A recent study has shown that patients who have symptoms of peptic ulcer but in whom no lesion is seen at endoscopy and in whom the possibility of gall bladder, pancreatic and oesphageal reflux diseases have been excluded and may thus be defined as having non-ulcerative dyspepsia, 60% of such patients may harbour L pylori and have evidence of microscopic gastritis. Furthermore, in such patients symptoms resolve if P pylori is cleared.

The invention will be further illustrated by the following EXAMPLE Preoaration of bismuth ammonium citrate complex solution for oral administration A batch (500 1) of bismuth ammonium citrate solution is prepared having the following composition: Batch size 500.000 1 Bismuth citrate 23.500 kg Sucrose 201.600 kg Ammonia solution 'AnalaR' sp. gr.

0.88 (35%) 6.300 1 Wild Cherry Syrup (concentrated 1 - 7) 33.550 1 Nipasept Sodium 0.625 kg Water (deionised) to 500.000 1 The bismuth citrate is added to approximately 20% (100 1) of the total volume of water in a stainless steel vessel and dissolved using a "Lightening" (Lightening is a Trade Mark) stirrer.

The ammonia solution (BDH) is added gradually and the mixture stirred constantly until the solution clarifies and a substantially odourless and tasteless solution is obtained. The preparation of the bismuth ammonium citrate solution is carried out at room temperature. The addition of ammonia is highly exothermic with significant generation of heat.

The sucrose is separately dissolved in approximately 20% of the total volume of water using a 10 h.p. Silverson (Silverson is a Trade Mark) stirrer in a main manufacturing vessel and the wild cherry syrup concentrate (William Ransom & Son) added thereto with constant stirring.

A solution of the Nipasept Sodium (Nipa Laboratories) in 2 1 of water is prepared by dissolving the Nipasept Sodium in a stainless steel container using hand mixing and then added to the sucrose/cherry solution. The bismuth ammonium citrate solution is then added to the main manufacturing vessel with constant stirring. The volume is adjusted to 500 1 with the remainder of the deionised water. The final solution is mixed well for 10 min.

prior to sampling for analysis and then bottled under sterile conditions.

Nipasept sodium which is a water soluble mixture of the methyl, ethyl and propyl esters of p-hydroxybenzoic acid has been found to adequately preserve the product at a level of 0.125% wlv .

The bismuth citrate is present in the formulation in the form of a soluble chelated bismuth complex. Bismuth citrate is insoluble in water, however, it is soluble in diluted ammonia solution.

The solution prepared is a pleasant tasting mixture in contrast to other bismuth-containing pharmaceutical formulations such as DE-NOL and for this reason results in better patient compliance. The solution can be used as hereinbefore described in the treatment of the indicated disorders of the gastrointestinal tract.

Claims (10)

CLAIMS:

1. A process for the manufacture of an aqueous solution of bismuth ammonium citrate complex, which process comprises the step-wise addition of an ammonia solution to a stirred mixture of bismuth citrate powder in an amount of water corresponding to approximately 20% of the final volume of the solution to be prepared, the bismuth citrate being present at a concentration in the range 20-27% w/v, and continuing such addition until the mixture substantially clarifies, indicating substantial solubilisation of the bismuth citrate and the formation of the desired complex.

2. A process according to Claim 1, wherein the ammonia solution is added in metered amounts such that the ratio of ammonia solution to water is approximately 6% v/v.

3. A process according to Claim 1 or 2, wherein the amount of bismuth citrate used is of the order of 23.5% w/v of final solution.

4. A process according to any one of Claims 1-3, wherein conventional pharmaceutical auxiliaries are incorporated in the solution and the volume of the solution adjusted to said final volume.

5. A process according to Claim 4, wherein the auxiliaries are selected from flavouring agents, preservatives and sweetening agents.

6. A process according to any preceding claim, wherein the solution is added to a sucrose syrup and the volume of the solution thereby obtained adjusted to said final volume.

7. A process according to Claim 6, when dependent on Claim 4 or 5, wherein said auxiliaries are added to said sucrose syrup prior to the addition of the bismuth ammonium citrate complex solution.

8. A process according to any preceding claim for the manufacture of a pharmaceutical formulation for use in the treatment of disorders of the gastrointestinal tract.

9. A process according to any one of Claims 1-7, for the manufacture of a pharmaceutical formulation for use in the treatment of gastric and peptic ulcers, non-ulcerative dyspepsia and disorders of the gastrointestinal tract characterised by the present of Campylobacter pylori.

10. A process according to Claim 1, substantially as hereinbefore described and exemplified.