IE950090A1 - Pharmaceutical composition - Google Patents

Abstract

A combination product comprising Ranitidine hydrochloride Form 1 and a bismuth compound and solvates of the combination product. Ranitidine hydrochloride is the accepted name N-£2-£££5-£Dimethyl-amino)methyl|2-furany1|methyl|thio|ethyl for/-N'-methyl-2-n/itro-1, /1-ethenediamine-hydrochloride. It exists in two different crystalline forms, designated as Form I and Form II. The mixture contains 0,1425 mol of Ranitidine hydrochloride Form 1 and 0,046 mol bismuth subsalicylate. (molar ratio 1: 3:1 bismuth subsalicylate/Ranitidine hydrochloride Form 1).

Description

LODGED “FKarmaceutical Composition Introduction The invention relates to novel pharmaceutical combination products of Ranitidine hydrochloride (Form 1) which act on histamine receptors and against Helicobacter pylori as well as to pharmaceutical compositions containing them and their therapeutic use.

Ranitidine hydrochloride is the accepted name for N-[2[ [ [ 5 - [Dimethyl-amino)methyl]2-furany1]methyl]thio]ethyl]N'-methyl-2-nitro-1,1-ethenediamine-hydrochloride. It exists in two different crystalline forms, designated as Form I and Form II.

Statements of Invention It has now been surprisingly found that the combination of Ranitidine hydrochloride as Form 1 together with bismuth compounds shows a synergistic therapeutical profile.

The combined product has the potent histamine H2-antagonist activity of Ranitidine hydrochloride as Form 1 with the antibacterial activity associated with bismuth salts.

Ranitidine hydrochloride as Form 1 is a potent histamine H2-antagonist, which is introduced for therapeutical use to reduce hyperacidity in the stomach.

Bismuth salts have been used extensively as antacids for the treatment of hyperacidity and dyspepsia. Such bismuth salts are described, for example, in British Pharmaceutical Codex (1949) and include bismuth citrate, bismuth - and ammonium citrate, sodium bismuthyl tartrate, acidic bismuth sodium tartrate, aji.....^jc.id.ic, OPEN TO PUBLIC INSPECTION SECTION 28 AND RULE 23 JNL No..... - 2 bismuth, a concentrated solution of bismuth; and solutions of bismuth - and ammonium citrate.

In recent years it has been realised that Helicobacter pylori is associated with histologically related gastritis and hypochlorhydria. Helicobacter pylori is sensitive to bismuth compounds such as bismuth citrate, bismuth salicylate and bismuth nitrate.

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.

In one embodiment of the invention the weight ratio of Ranitidine hydrochloride Form 1 to bismuth subsalicylate is from 1:9 to 9:1, preferably approximately 1:1, corresponding to a molar ratio of approximately 3.1:1.

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

In this case the weight ratio of Ranitidine hydrochloride Form 1 to bismuth citrate is from 1:9 to 9:1, most preferably approximately 1:1.

In another aspect the combination product includes at least one antibiotic.

The antibiotic may be selected from nitroimidazole antibiotics, tetracyline antibiotics, cephalosporin antibiotics, macrolide antibiotics, penicillin 0 0 9 0' - 3 antibiotics, rifamycin antibiotics, quinolone antibiotics and lincosamide antibiotics. Most preferably the antibiotic is selected from metronidazole, nitazoxanide, tetracylin, amoxycillin and clindamycin.

When the combination product includes at least one antibiotic the product will have improved antibacterial activity against Helicobacter pylori. The antibiotic(s) may be administered at the same time as the Ranitidine hydrochloride Form 1 and bismuth salt or separately. In the case of a concurrent administration the combination product may be provided in a single formulation, for example as a capsule or tablet. The antibiotic(s) may also be administered separately either at the same time as or before or after the administration of the Ranitidine hydrochloride Form 1/bismuth salt.

The combination product may be used in treating gastrointestinal disorders or prophylactically.

In a preferred embodiment of the invention the weight ratio of the Ranitidine hydrochloride Form 1, the bismuth compound and the antibiotic is approximately 1:1:1.

The products may be provided in any suitable pharmaceutical composition including capsules; solutions; syrups; ointments; injectable preparations; aerosols; creams; powders and suspensions. The pharmaceutical composition may contain suitable excipients and/or vehicles which are conventionally used in galenical pharmacy.

In another aspect, the invention provides the use of a combination product comprising Ranitidine hydrochloride Form 1 and a bismuth compound or solvates thereof in the manufacture of a medicament for use in the treatment or 450090 prophylaxis of gastrointestinal disorders.

In a further aspect the invention provides the use of Ranitidine hydrochloride Form 1 - bismuth compound or solutes thereof and at least one antibiotic in the manufacture of a medicament for use in the prophylaxis or treatment of gastrointestinal disorders.

Detailed Description In one aspect, the present combinations of bismuth hydrochloride Form 1 and combinations. invention relates to new salts with Ranitidine the solvates of these Special Combinations Include : Ranitidine hydrochloride Form 1 with bismuth subsalicylate (stoichiometrically composed of 10-90% of Ranitidine hydrochloride Form 1 with 90%-10% of bismuth subsalicylate) preferably a mixture of 50% Ranitidine hydrochloride and 50% of bismuth subsalicylate.

The mixture contains 0,1425 mol of Ranitidine hydrochloride Form 1 and 0,046 mol bismuth subsalicylate. (molar ratio 1 : 3:1 bismuth subsalicylate/Ranitidine hydrochloride Form 1).

Structure Further examples are combinations of Ranitidine hydrochloride Form 1 with bismuth nitrate, bismuth subcitrate, bismuth galate, bismuth salicylate, dibismuth trietraoxodialuminate and hydrate thereof and especially bismuth citrate.

The advantages of combinations of Ranitidine hydrochloride Form 1 with bismuth salts is clearly related to the therapeutical use. This means the combination can be adjusted to the therapeutical use requirements.

The new combinations may be prepared by mixing Ranitidine hydrochloride Form 1 with the desired amount of bismuth salts at 20-40°C and dried at 20-40°C.

The new combinations and hydrate can be formulated in any suitable galenical forms such as tablets, effervescent tablets, capsules, syrups, and parenteral forms.

The preferable dosage of the present invention is 100 mg to lg, preferably 150-600 mg.

Example 1 Ranitidine hydrochloride Form 1 with bismuth subsalicylate. 50.0 g of Ranitidine hydrochloride Form 1 is added to 50.0 g of bismuth subsalicylate (1:1 weight ratio) at 20-40°C and homogenised. 100 g of this mixture contains 0.1425 Mol of Ranitidine hydrochloride Form 1 and 0.046 Mol of bismuth subsalicylate (i.e. a molar ratio of 1:3.1).

Melting points : 9SQ09O has a melting point of 133-134°C Ranitidine hydrochloride Form 1 Bismuth subsalicylate has a melting point of > 230°C Mixture of Ranitidine hydrochloride Form 1 with Bismuth subsalicylate has a melting point of 219-220°C The infra red spectrum for the mixture of Ranitidine 10 hydrochloride Form 1 with bismuth salicylate is plotted in Fig. 1.

Example 2 Ranitidine hydrochloride Form 1 with bismuth citrate. 21.6 g of Ranitidine hydrochloride Form 1 is added to 15 24.51 g of bismuth citrate (1:1.13 weight ratio) at 2040°C and homogenised. 100 g of this mixture contains 0.0615 Mol of Ranitidine hydrochloride Form 1 and 0.0615 Mol of bismuth citrate (i.e. a molar ratio of 1:1).

Melting points : Ranitidine hydrochloride Form 1 has a melting point of 133-134°C Bismuth citrate has a melting point of > 230°C Mixture of Ranitidine hydrochloride Form 1 with Bismuth subsalicylate has a melting point of 142-146°C.

The infra red spectrum for the mixture of Ranitidine hydrochloride Form 1 with Bismuth citrate is plotted in Fig. 2.

The combination products described above have the potent histamine H2 - antagonist activity of Ranitidine hydrochloride as Form 1 combined with the antibacterial activity associated with bismuth salts.

The product may also include one or more antibiotics to treat or prevent gastrointestinal disorders. The antibiotic (s) will inhibit Helicobacter pylori. The antibiotics may be selected from one or more of nitroimidazole, tetracyline, cephalosporin, macrolide, penicillin, rifamycin, quinolone and lincosamide For reasons of effectiveness and the fact may be readily formulated for oral administration the preferred antibiotics are metronidazole, nitazoxanide, tetracylin, amoxycillin and clindamycin. antibiotics that they The antibiotic(s) may be administered simultaneously or separately from the Ranitidine hydrochloride Form 1/bismuth salt. For concurrent administration the combination product may be presented as a single formulation, preferably for oral administration in the form of a tablet or capsule. The antibiotic(s) may also be administered separately. 910090 - 8 Many variations on the specific embodiments of invention described will be readily apparent accordingly the invention is not limited to embodiments described which may be varied in detail.

Claims (30)

1. A combination product comprising Ranitidine hydrochloride Form 1 and a bismuth compound and solvates of the combination product.

2 . A combination product as claimed in claim 1 wherein the bismuth compound is selected from bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth nitrate, bismuth galate, dibismuth trietraoxidialuminate and hydrate thereof.

3. A combination product as claimed in claim 1 or 2 wherein the bismuth compound is bismuth subsalicylate.

4. A combination product as claimed in claim 3 wherein the weight ratio of Ranitidine hydrochloride Form 1 to bismuth subsalicylate is from 1:9 to 9 :1.

5. A combination product as claimed in claim 4 wherein the weight ratio is approximately 1:1.

6. Ranitidine hydrochloride Form 1 bismuth subsalicylate.

7 . A combination product as claimed in claim 1 or 2 wherein the bismuth compound is bismuth citrate.

8. A combination product as claimed in claim 7 wherein the weight ratio of Ranitidine hydrochloride Form 1 to bismuth citrate is from 1:9 to 9:1. 950091 - 10

9. A combination product as claimed in claim 8 wherein the weight ratio is approximately 1:1.

10. A combination product as claimed in any preceding claim including at least one antibiotic.

11. A combination product as claimed in claim 10 wherein the antibiotic is selected from nitroimidazole antibiotics, tetracyline antibiotics, cephalosporin antibiotics, macrolide antibiotics, penicillin antibiotics, rifamycin antibiotics, quinolone antibiotics and lincosamide antibiotics.

12. A combination product as claimed in claim 10 or 11 wherein the antibiotic is selected from metronidazole, nitazoxanide, tetracylin, amoxycillin and clindamycin.

13. A combination product as claimed in any of claims 10 to 12 wherein the antibiotic is nitazoxanide.

14. A combination product as claimed in any of claims 10 to 13 wherein the weight ratio of the Ranitidine hydrochloride Form 1, the bismuth compound and the antibiotic is approximately 1:1:1.

15. A combination product substantially as hereinbefore described with reference to the examples.

16. A pharmaceutical composition comprising a combination product as claimed in any preceding claim together with a pharmaceutically acceptable carrier and/or vehicle.

Q * 0 fl Q β 17. 18. - 11 19. 20. 21. 22. 23.

A pharmaceutical composition substantially as hereinbefore described with reference to the examples .

Use of a combination product comprising Ranitidine hydrochloride Form 1 and a bismuth compound or solvates thereof in the manufacture of a medicament for use in the treatment or prophylaxis of gastrointestinal disorders.

Use as claimed in claim 18 wherein the bismuth compound is selected from bismuth citrate, bismuth subcitrate, bismuth salicylate, bismuth subsalicylate, bismuth nitrate, bismuth galate, dibismuth trietraoxidialuminate and hydrate thereof.

Use as claimed in claim 18 or 19 wherein the bismuth compound is bismuth salicylate.

Use as claimed in claim 20 wherein the weight ratio of Ranitidine hydrochloride Form 1 to bismuth subsalicylate is from 1:9 to 9:1.

Use as claimed in claim 21 wherein the weight ratio is approximately 1:1.

Use as claimed in claim 18 or 19 wherein the bismuth compound is bismuth citrate.

Use as claimed in claim 23 wherein the weight ratio of Ranitidine hydrochloride Form 1 to bismuth citrate is from 1:9 to 9:1. 24. - 12 25. Use as claimed in claim 24 wherein the weight ratio is approximately 1:1.

26. Use of Ranitidine hydrochloride Form 1 - bismuth compound or solvates thereof and at least one antibiotic in the manufacture of a medicament for use in the prophylaxis or treatment of gastrointestinal disorders.

27. Use as claimed in claim 26 wherein the antibiotic is selected from nitroimidazole antibiotics, tetracyline antibiotics, cephalosporin antibiotics, macrolide antibiotics, penicillin antibiotics, rifamycin antibiotics, quinolone antibiotics and lincosamide antibiotics.

28. Use as claimed in claim 26 or 27 wherein the antibiotic is selected from metronidazole, nitazoxanide, tetracylin, amoxycillin and clindamycin.

29. Use as claimed in claims 26 to 28 wherein the antibiotic is nitazoxanide.

30. Use as claimed in any of claims 26 to 29 wherein the weight ratio of the Ranitidine hydrochloride Form 1, the bismuth compound and the antibiotic is approximately 1:1:1.