IE950954A1 - A combination product. - Google Patents

Abstract

A combination of nitazoxanide with an anti-ulcer agent, especially ranitidine has a synergistic therapeutic profile in prophylaxis or treatment of H. pylori related infections. The product may also contain, as an antibacterial agent, bismuth salts such as bismuth subsalicylate or bismuth citrate.

Description

INTRODUCTION The invention relates to a novel combination product of nitazoxanide as well as to pharmaceutical compositions containing them and their therapeutic use. Nitazoxanide is the accepted name for 2-(acetolyloxy)-N-(S-Nitro-2thiazolye benzamide). It is used to treat a broad range of parasitic infections.

STATEMENTS OF INVENTION It has now been surprisingly found that a combination 10 product of nitazoxanide and an anti-ulcer agent shows a synergistic therapeutical profile.

The combined product has the potent activity of an antiulcer agent and the anti-parasitic activity associated with nitazoxanide.

In one embodiment of the invention the anti-ulcer agent is a histamine Hz receptor antagonist. In this case the antiulcer agent may be selected from cimetidine, ranitidine, famotidine, nizatidine and pharmaceutically acceptable salts thereof.

Particularly preferred are ranitidine hydrochloride as Form I or Form II which are potent histamine H2antagonists, and may be introduced for therapeutical use to reduce hyperacidity in the stomach.

In another embodiment of the invention the anti-ulcer agent is a gastric proton pump inhibitor such as omeprazole and pharmaceutically acceptable salts thereof.

OPEN TO PUBLIC INSPECTION UNDER SECTION 26 AND RULE 23 JNL. No..../..^·.....0F../W^ - 2 In recent years it has been realised that Helicobacter pylori is associated with histologically related gastritis and hyperchlorhydria. Helicobacter pylori is particularly sensitive to the combination product of the invention.

In one embodiment of the invention the weight ratio of nitazoxanide to anti-ulcer agent, particularly ranitidine hydrochloride is from 2:1 to 5:1, preferably from 3:1 to 4:1, most preferably approximately 10:3.

In one embodiment of the invention the combination product includes bismuth salts which have been used extensively as antacids for the treatment of hyperacidity and dyspepsia. Such bismuth salts are described in British Pharmaceutical Codex (1949) and include bismuth citrate, bismuth - and ammonium citrate, sodium bismuthyl tartarate, acidic bismuth sodium tartarate, an acidic solution of bismuth a concentrated solution of bismuth; and solutions of bismuth - and ammonium citrate.

In one embodiment of the invention the bismuth compound is selected from bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth nitrate, bismuth galate, dibismuth trietraoxidialuminate and hydrate thereof.

In a particularly preferred embodiment of the invention the bismuth compound is bismuth subsalicylate.

According to another preferred embodiment of the invention the bismuth compound is bismuth citrate.

The combination product has improved antibacterial activity against Helicobacter pylori. Nitazoxanide may be administered at the same time as the anti-ulcer agent or separately. In the case of a concurrent administration *950954 - 3 the combination product may be provided in a single formulation, especially for oral administration as a capsule or tablet. The pharmaceutical composition may contain suitable excipients and/or vehicles which are conventionally used in galenical pharmacy.

The combination product may be used in treating gastrointestinal disorders or prophylactically. 850954 DETAILED DESCRIPTION EXAMPLE 1 A batch of tablets was prepared by direct compression from the following ingredients: Active Ingredients Unit Formula (mg/tablet) Nitazoxanide Ranitidine Hydrochloride Form I Non Active Ingredients 500mg 150mg Unit Formula (mg/tablet) Function Maize Starch 80mg diluent/disintegrant Pregelatinised Maize Starch 90mg binder/disintegrant Hydroxypropylmethylcellulose 7mg binder Sucrose 40mg sweetener Sodium Starch Glycollate SOmg disintegrant Talc lOmg glidant Magnesium stearate 9mg lubricant Coating Materials.

Opaglos clear - 0.013ml Opaglos 6000 white - 0.013ml Sucrose 0.130mg - 5 The new combinations can be formulated in any suitable galenical forms particularly for oral administration, especially as tablets or capsules.

The preferable dosage of the present invention is 650mg to 2g, preferably 1.3g per day. Preferably two separate doses, each of 650mg are administered in a twenty four hour period.

The combination products described above have the potent anti-ulcer activity of anti-ulcer agents such as ranitidine hydrochloride combined with the antibiotic activity associated with nitazoxanide.

The product may include bismuth salts such as bismuth subsalicylate, bismuth nitrate, bismuth subcitrate, bismuth galate, bismuth salicylate, dibismuth trietraoxidialuminate and hydrate thereof and especially bismuth citrate.

Where present, the bismuth salts provide a synergistic antibacterial activity.

Many variations on the specific embodiments of the invention described will be readily apparent and accordingly the invention is not limited to the embodiments described which may be varied in detail.

Claims (12)

1. A combination product comprising nitazoxanide and an anti-ulcer agent.

2. A combination product as claimed in claim 1 5 wherein the anti-ulcer agent is a histamine H z receptor antagonist.

3. A combination product as claimed in claim 1 or 2 wherein the anti-ulcer agent is selected from cimetidine, ranitidine, famotidine, nizatidine and 10 pharmaceutically acceptable salts thereof.

4. A combination product as claimed in any of claims 1 to 3 wherein the anti-ulcer agent is ranitidine.

5. A combination product as claimed in any preceding claim wherein the anti-ulcer agent is ranitidine 15 hydrochloride - Form II.

6. A combination product as claimed in any of claims 1 to 4 wherein the anti-ulcer agent is ranitidine hydrochloride - Form I.

7. A combination product as claimed in any preceding 20 claim wherein the weight ratio of nitazoxanide to anti-ulcer agent is from 2:1 to 5:1.

8. A combination product as claimed in claim 7 wherein the weight ratio is from 3:1 to 4:1.

9. A combination product as claimed in claim 7 or 8 25 wherein the weight ratio is approximately 10:3. - 7 10. A combination product as claimed in claim 1 or any of claims 7 to 9 wherein the anti-ulcer agent is a gastric proton pump inhibitor. 11. A combination product as claimed in claim 1 or any of claims 7 to 10 wherein the anti-ulcer agent is omeprazole and pharmaceutically acceptable salts thereof. 12. A combination product as claimed in any preceding claim including a bismuth compound. 13. A combination product as claimed in claim 12 wherein the bismuth compound is selected from bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth nitrate, bismuth galate, dibismuth trietraoxidialuminate and hydrate thereof. 14. A combination product as claimed in claim 12 or 13 wherein the bismuth compound is bismuth subsalicylate. 15. A combination product as claimed in claim 12 or 13 wherein the bismuth compound is bismuth citrate. 16. A combination product substantially as hereinbefore described with reference to the example. 17. A pharmaceutical composition for oral administration incorporating a combination product as claimed in any preceding claim. 18. A composition as claimed in claim 17 in the form of a tablet. - 8 19. A composition as claimed in claim 17 in the form of a capsule. 20. A pharmaceutical composition for oral administration comprising nitazoxanide and 5 ranitidine hydrochloride. 21. A pharmaceutical composition for oral administration comprising nitazoxanide and ranitidine hydrochloride in a weight ratio of approximately 10:3.

10. 22. A pharmaceutical composition substantially as hereinbefore described with reference to the example. 23. Use of a combination product as claimed in any of claims 1 to 16 for the prophylaxis or treatment of

11. 15 H. pylori related infections. 24. Use of a combination product substantially as hereinbefore described with reference to the example. 25. A method of prophylaxis or treatment of H. pylori

12. 20 related infections comprising administering combination product as claimed in any of claims 1 to 16 .