HK1034897B - A double capsule for the administration of active principles in multiple therapies - Google Patents

Description

Double-layer capsule for administering active ingredients in combination therapy

Technical Field

The invention relates to a pharmaceutical form consisting of a double-layer capsule (double capsule) for administering active ingredients in combination therapy. The double-layered capsule consists of a capsule placed in another capsule.

Background

Treatments for the administration of more than one active ingredient simultaneously or at short intervals are known. The most common pharmaceutical dosage forms consist of tablets of different active ingredients with a coating to allow the compounds to be released separately.

In such treatments, it is most common that the digestive system is affected by the presence of the microorganism helicobacter pylori, such as gastritis and gastroduodenal ulcers, which may, where appropriate, cause tumor formation. Helicobacter pylori is known as the latest name for Campylobacter pylori.

US5196205 describes a method for treating these pathological agents comprising the administration of a bismuth compound, an antibiotic belonging to the penicillin and tetracycline class and a second antibiotic, such as metronidazole. The relevant treatment consists of administering three tablets (one for each active ingredient) several times a day.

Therefore, the treatment is extremely complicated.

The treatment described in US5196205 is further improved by the addition of a fourth active ingredient, omeprazole, which reduces gastric secretion by inhibiting the irreversible inhibitory enzyme H +/K + ATP. Omeprazole must be administered from the above active ingredients at different times, which will be determined by the physician depending on the severity of the disease, age and other factors that may affect the efficacy of the patient.

Thus, it can be stated with certainty that treatment requiring complex doses, such as combination therapy, is misleading and may adversely affect the outcome of the treatment itself.

Other patents and patent applications describing single or multiple treatment for eradication of helicobacter pylori are known, for example, from US5472695, US5560912, US5582837, WO92/11848 and WO 96/02237. None of these earlier patents and patent applications address the problem of interaction between active ingredients in a simpler and more flexible manner than proposed by the present invention.

US5310555 and US5501857 teach the use of bilayer capsules to deliver nutritional supplements to animals.

Japanese patent 60-193917 refers to a soft capsule containing several small soft capsules.

DE patent 2,729,068 refers to standard hard gelatin capsules having additional hard gelatin capsules therein and having the same or different dissolution characteristics.

FR patent 2,524,311 refers to double and triple capsules.

FR patent 1,454,013 refers to a double capsule in which the inner capsule has a delayed release characteristic.

GB patent 2,013,564 refers to a capsule combination for oral prophylactic agents, characterised by a frangible outer capsule and an inner edible capsule, with an air space between them, which the user can bite into the outer capsule and thereby swallow the entire inner capsule.

In the combined treatment for eradicating helicobacter pylori, the following combinations of effective ingredients were tested for human bodies and have been published:

1. amoxicillin, metronidazole and furazolidone;

2. bismuth subsalicylate, lansoprazole, and clarithromycin;

3. bismuth subsalicylate, roxithromycin, metronidazole, and ranitidine;

4. clarithromycin, colloidal bismuth subcitrate, and furazoline;

5. colloidal bismuth subcitrate, amoxicillin and metronidazole;

6. ethidium bromide, amoxicillin and metronidazole;

7. lansoprazole, amoxicillin and azithromycin;

8. lansoprazole, amoxicillin;

9. lansoprazole, amoxicillin and rebalance and cladribate;

10. lansoprazole, clarithromycin, and furazoline;

11. lansoprazole, azithromycin, and metronidazole;

12. lansoprazole, miconazole and amoxicillin;

13. lansoprazole and norfloxacin;

14. metronidazole and dirithromycin;

15. omeprazole, amoxicillin and azithromycin;

16. omeprazole, amoxicillin, clarithromycin and metronidazole;

17. omeprazole, amoxicillin, metronidazole and bismuth;

18. omeprazole, amoxicillin and rebamipide;

19. omeprazole, amoxicillin and tinidazole;

20. omeprazole and amoxicillin;

21. omeprazole and azithromycin;

22. omeprazole, bismuth and ciprofloxacin;

23. omeprazole, bismuth and clarithromycin;

24. omeprazole, clarithromycin, and tinidazole;

25. omeprazole and dirithromycin;

26. omeprazole, lansoprazole, and rebamipide;

27. omeprazole, metronidazole and amoxicillin;

28. omeprazole, metronidazole and azithromycin;

29. omeprazole, metronidazole, and clarithromycin;

30. omeprazole and norfloxacin;

31. omeprazole, gastric ulcer, metronidazole and tetracycline;

32. omeprazole, clarithromycin, and tinidazole;

33. pantoprazole, clarithromycin, and amoxicillin;

34. pantoprazole and clarithromycin;

35. ranitidine bismuth citrate, clarithromycin, and tetracycline;

36. ranitidine bismuth citrate and clarithromycin;

37. ranitidine bismuth citrate, metronidazole and clarithromycin;

38. ranitidine bismuth citrate and cefuroxime;

39. rifaximin and erythromycin;

40. omeprazole, bismuth, tetracycline and metronidazole;

41. omeprazole, bismuth subcitrate, tetracycline and metronidazole;

42. bismuth subcitrate, tetracycline and metronidazole.

Disclosure of Invention

The object of the present invention is to treat the microorganism helicobacter pylori with a pharmaceutical dosage form that is active in multiple therapies, comprising two capsules, placed one inside the other.

According to the invention, the object of the invention is achieved as follows: soluble salts of bismuth, a first antibiotic and a second antibiotic are used for the preparation of a pharmaceutical dosage form for the ternary treatment of the microorganism helicobacter pylori, comprising two capsules, placed one inside the other, wherein the outer capsule comprises the soluble salts of bismuth and the first antibiotic and the inner capsule comprises the second antibiotic.

The object of the invention can also be achieved as follows: mixing soluble salts of bismuth, a first antibiotic and a second antibiotic, and K⁺/Na⁺ATPase inhibitors or anti-H₂The agent is used for preparing a pharmaceutical dosage form for the quaternary treatment of the microorganism helicobacter pylori, comprising two capsules, one placed inside the other, wherein the outer capsule comprises a soluble salt of bismuth and a first antibiotic, and the inner capsule comprises a second antibiotic and K⁺/Na⁺ATPase inhibitors or anti-H₂And (3) preparing.

The object of the invention can be further achieved as follows: mixing soluble salts of bismuth, a first antibiotic and a second antibiotic, and K⁺/Na⁺ATPase inhibitors or anti-H₂The agent is used for preparing a pharmaceutical dosage form for the quaternary treatment of the microorganism helicobacter pylori, comprising two capsules, one placed inside the other, wherein the outer capsule comprises a soluble salt of bismuth, a first antibiotic and K⁺/Na⁺ATPase inhibitors or anti-H₂Preparation: the inner capsule includes a second antibiotic.

The object of the invention can be further achieved as follows: mixing a soluble salt of bismuth, a first antibiotic, a second antibiotic and K⁺/Na⁺ATPase inhibitors or anti-H₂The preparation is used for preparing a first drug dosage form and a second drug dosage form for quaternary treatment of microorganism helicobacter pylori, wherein the first drug dosage form comprises two capsulesOne inside the other, wherein the outer capsule comprises a soluble salt of bismuth and a first antibiotic and the inner capsule comprises a second antibiotic; the second pharmaceutical dosage form comprises K⁺/Na⁺ATPase inhibitors or anti-H₂And (3) preparing.

The pharmaceutical dosage form of the present invention has the advantage of being used in combination therapy, which is simple and safe.

One of the main advantages of the pharmaceutical dosage form of the present invention is that it overcomes the problems associated with the interaction of the active ingredients by means of a physical barrier.

The features and advantages of the present invention will be better understood after reading the following non-limiting description.

Double-layer capsule

The invention provides a pharmaceutical dosage form for the administration of active principles in combination therapy, characterized in that two capsules are present, one placed inside the other and each comprising one or several active principles. The pharmaceutical dosage form is referred to as a double-layer capsule, and the two capsules are referred to as an inner capsule and an outer capsule, respectively.

Both the inner and outer capsules are preferably made of hard gelatin. If desired, the inner capsule may be made of gelatin treated so as to render it gastro-resistant or slow-releasing.

Capsules are available on the market, identified by a numerical value or letter depending on their size (length, diameter and thickness), as described in table 1 (CAPSUGEL multiple FILE, 2 ° Ed.).

Table 1: size of the jelly Capsule

Capsule type	Type of capsule	Total capsule length (nm +/-0.3nm)	Outer diameter (nm)	Wall thickness (nm)
					CONI-SNAPSNAP-FIT
000	26.14	9.55	-
				00		23.3	8.18	0.231
0+	23.8	7.36	0.224
				0		21.2	7.33	0.212
1	19.0	6.63	0.216
				2		17.5	6.07	0.211
3	15.6	5.57	0.203
				4		13.9	5.05	0.198
5	11.0	4.64	0.173
				CONI-SNAPSUPRO
A	18.00	8.18	0.231
					B	14.20	8.18	0.231
C	13.50	7.33	0.224
					D	12.60	6.63	0.216
E	11.60	6.07	0.211
					LICAPS
0	21.70	7.33	0.224
				1		19.70	6.6 3	0.216
2	17.90	6.07	0.211

According to the present invention, the inner capsule of the double-layered capsule is smaller than the outer capsule, since all combinations in table 1 can be any type of capsule except for the combination of the type 0+ outer capsule and the type a or O inner capsule according to this principle. These combinations are convenient for the patient and are selected according to the quantity of substance to be introduced into the two capsules. In fact, the volume between the two capsules and the volume of the inner capsule should be suitable to allow insertion of the quantity predicted by the therapeutic dose. The inner capsule should preferably be of type 2 or 3, while the outer capsule should be of type 0+ or 1, respectively. According to a preferred embodiment of the invention, the inner capsule, model 3, is inserted into the outer capsule, model 0 +.

The pharmaceutical dosage form is achieved by feeding powder, pills, tablets or filled capsules to empty capsules by means of an intermittent or continuous motion capsule filling machine equipped with a doser. Examples of such capsule filling machines are Zanazi 40 by IMA corporation in bolgna and Futura level 02 by MG2 corporation in bolgna. Alternatively, the novel double-layer capsule can be realized by means of the manual mechanical type Zuma 150 or 300 and the Parke-Davis/Capsule type.

Furthermore, it must be considered that even the capsule movements caused by the capsule filling machine, either automatically or manually, and the simple act of inserting the inner capsule are sufficient to form a powder layer between the two capsules that separates them.

Triple therapy

The pharmaceutical dosage form is particularly suitable for use in a triple therapy for the eradication of the pathological agent helicobacter pylori (also known as Campylobacter pylori), comprising the administration of three active principles of a soluble salt of bismuth, a first antibiotic and a second antibiotic. The inner and outer capsules contain one or more active ingredients.

The bismuth salt is preferably selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate, and bismuth vanadium tetraoxide. The bismuth salts can be used in the form of complexes. For example, bismuth dicalcium citrate is in the form of a complex of bismuth subcitrate.

The first antibiotic is selected from the group consisting of nitroimidazoles. The nitroimidazole is preferably selected from the group consisting of metronidazole, aprazole, nitromycin, metronidazole, dimetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ornidazole and tinidazole. Preferably, the first antibiotic is metronidazole.

The second antibiotic is selected from the group consisting of macrolides and compounds of the tetracycline family. The macrolide is preferably selected from the group consisting of azithromycin, clarithromycin and erythromycin. The compound of the tetracycline family is preferably selected from the group consisting of tetracycline, chlorotetracycline, doxycycline, glycycycline, guanmecycline, lymecycline, methacycline, and sancycline. As is known in the art, tetracycline corresponds to tetracycline hydrochloride.

According to a preferred embodiment of the invention, the outer capsule contains bismuth subcitrate and metronidazole and the inner capsule contains tetracycline.

While the outer capsule preferably contains bismuth subcitrate and metronidazole in the form of a complex, it allows the complex bismuth to form a gastric level drug gel. After a certain time, the inner capsule is shown to dissolve and release tetracycline, according to treatment, which also acts at a gastroeffective concentration.

Triple therapies as described above generally consist of administering two identical double-layer capsules several times a day, without particular care being taken with regard to the consumption and the operating sequence of said double-layer capsules. It is preferred to ingest the capsule before meals and before snacks are eaten while sleeping.

Quadruple therapy

A further way of carrying out the invention consists in coupling, for example, K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂The fourth active ingredient of (1) is administered together with the above-mentioned double-layer capsule. In this case, the double-layered capsule as would be known from the present invention is intended to be used in a four-tuple therapy to affect the digestive system. K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Selected from the group consisting of pumaprazole, cimetidine, ethiozoitin, statine, famotidine, flunarizine, N- [1- (4-amidobutyl) -1H-pyrazol-3-yl)]-N' - (2, 2, 2-trifluoroethyl) guanidine, lansoprazole, thiamethoxam, prochloraz,Mitotane, nipetidine, nizatidine, omeprazole, ormetidine, pantoprazole, rabeprazole, ranitidine, ritanserin, roxatidine hydrochloride, ropinatidine, 1-amino-2- [3- (3-piperidinomethylphenoxy) propylamino]-1-cyclobutene-3, 4-dione, sulbactidine, thiotidine, (+/-) -2- [ (4-methoxy-6, 7, 8, 9-tetrahydro-5H-cyclohepta [ b ] c]Pyridin-9-yl) sulfinyl]-1H-benzimidazole sodium salt, N- (2- (((5-dimethylamino) methyl) -2-furyl) methyl) thio) ethyl) thieno (3, 4-d) isothiazol-3-amine-1, 1-dioxide and zoltidine. Preferably, omeprazole is used as K⁺/Na⁺Inhibitors of ATP-enzymes.

Can be combined with K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Adding into outer capsule, inner capsule or adding in single medicine form. Due to the need of K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Reach the small intestine and can therefore be implanted resistant to gastric coating tablets, composite pellets or single pellet delivery. In view of K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Must be administered according to standards other than those foreseen for triple therapy, without K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Can be selectively administered to K-containing capsules⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Depending on the severity of the disease and the health of the patient, the treatment regimen described by the physician is performed.

According to another preferred embodiment of the present invention, the outer capsule contains bismuth subcitrate and metronidazole and the inner capsule contains tetracycline and omeprazole.

Features of the invention

Preferably, both capsules contain excipients. These excipients are selected from the group consisting of magnesium stearate, talc, cellulose and its derivatives, silica and its derivatives, sugars, polyethylene glycol, waxes, mono-, di-and tri-glycerides of hydrogenated fatty acids, high molecular weight alcohols and acids and related mixtures thereof.

The inner and outer capsules containing the above-mentioned effective ingredients are stable at a temperature of 5-50 deg.C and a humidity of 35-65%.

Preferred embodiments of the present invention for triple and quadruple therapy to eradicate H.pylori are described above. Although these embodiments are preferred for these treatments, it is to be understood that the bilayer capsule may contain other active ingredients in accordance with the present invention. Thus, the combinations of active ingredients listed above in the background of the invention may be used in the claimed pharmaceutical dosage forms without departing from the scope of the invention as claimed. For example, using the combination No. 34 listed above, a double-layered capsule with an outer capsule containing clarithromycin and an anti-gastric capsule containing pantoprazole would fall within the scope of the claimed invention.

The following are examples of stability and dissolution tests and of bilayer capsules contemplated for carrying out, illustrating the present invention, but are not intended to be limiting.

Stability test

Two products were analyzed, wherein the single capsule contained coated tetracycline hydrochloride, dicalcium bismuth citrate, metronidazole, the double-layered capsule of the invention contained uncoated tetracycline in the inner capsule and dicalcium bismuth citrate and metronidazole in the outer capsule.

Samples of each product to be analyzed have been incubated at room temperature, 37 ℃ and 44 ℃ for 1 month. At the beginning and end of the culture (1 month), the product was subjected to macroscopic characterization.

At the beginning

Single capsule

And (3) outer capsule: white colour

Content (2): white powder mixture: (bismuth Dicalcium citrate) and yellow

Powder (tetracycline hydrochloride)

Double-layer capsule

And (3) outer capsule: white colour

And (3) inner capsule: brown colour

Content of outer capsule: white powder (dicalcium citrate bismuth, metronidazole)

Content of inner capsule: yellow powder (tetracycline hydrochloride)

TABLE 2

After 1 month
				Single capsule	At room temperature	37℃	44℃
External capsule	Slightly yellow	White colour	White colour
				Content(s) therein	Mixture of white and yellow powders	Mixture of white and beige powders	Mixture of white and beige powders
Double-layer capsule	At room temperature	37℃	44℃
				External capsule	White colour	White colour	White colour
Inner capsule	Brown colour	Brown colour	Brown colour
				Content of outer capsule	White powder	White powder	White powder
Content of inner capsule	Yellow powder	Yellow powder	Yellow powder

As can be seen from table 2, the contents of the coated single capsules formed beige-colored products at temperatures of 37 ℃ and 44 ℃, whereas the double-layered capsules of the present invention did not form any degradation products. The physical barrier presented by the coating of the inner capsule that does not allow tetracycline to escape supports this effect.

Dissolution test

From one batch 5 double-layer capsules were taken for testing, all 5 having the same characteristics as follows:

the model number of the external capsule is 0+

Comprises

215mg of dicalcium citrate

Metronidazole 125mg

Type 3 of inner capsule

Comprises

Tetracycline hydrochloride 125mg

These capsules were each analyzed under the same conditions according to the united states pharmacopeia standard USP 23 ed for dissolution testing.

The purpose of the test is to check whether the correct amount of tetracycline hydrochloride contained in the inner capsule is dissolved (as described in the above pharmacopoeia, which is in accordance with all other pharmacopoeias). In this case, the presence of the outer capsule and its components should not affect the amount of dissolved substance and the time taken to release the active ingredient tetracycline hydrochloride.

The pharmacopoeia states that the amount of substance to be dissolved in 60 minutes must not be less than 80% of the amount present in the capsule according to the above definition.

For this bilayer capsule, the following percent dissolution results were obtained:

dissolution minimum: 81.4 percent

Maximum dissolution: 107.9 percent

Average value: 100.0 percent

RSD 9.7% (RSD relative standard deviation)

It is clear from the results obtained that the bilayer capsules according to the invention meet the predicted dissolution profile.

Detailed Description

Example 1

Type 3 capsules were prepared with the following contents:

tetracycline hydrochloride 125mg

Stomach-protecting omeprazole 5mg

Magnesium stearate 5mg

Talcum powder 5mg

Type O + capsules were prepared with the following contents:

215mg of dicalcium citrate (equivalent to 53.7mg of bismuth)

Metronidazole 125mg

Magnesium stearate 5mg

Talcum powder 5mg

The capsules O + are not completely sealed so that they can be reopened by hand machine (Zuma) and inserted into a pre-prepared capsule of type 3.

The capsules were then sealed and subjected to controls relating to time to deagglomeration, average weight of contents, sealing treatment, single component evaluation and microbial purity as described in the pharmacopoeia.

Although preferred embodiments of the present invention have been described herein in detail, it is to be understood that the invention is not limited to the precise embodiments, and that various changes and modifications may be effected therein without departing from the scope or spirit of the invention.

Claims (36)

1. Use of a soluble salt of bismuth, a first antibiotic and a second antibiotic for the preparation of a pharmaceutical dosage form for the ternary treatment of the microorganism helicobacter pylori, comprising two capsules, placed one inside the other, wherein the outer capsule comprises the soluble salt of bismuth and the first antibiotic and the inner capsule comprises the second antibiotic.

2. The use of claim 1, wherein the pharmaceutical dosage form further comprises K⁺/Na⁺ATPase inhibitors or anti-H₂Agent, wherein the external glueThe capsule comprises a soluble salt of bismuth and a first antibiotic, and the inner capsule comprises a second antibiotic and K⁺/Na⁺ATPase inhibitors or anti-H₂And (3) preparing.

3. The use of claim 2, wherein the outer capsule comprises a soluble salt of bismuth, a first antibiotic and K⁺/Na⁺ATPase inhibitors or anti-H₂Preparation: the inner capsule includes a second antibiotic.

4. Soluble salts of bismuth, a first antibiotic, a second antibiotic and K⁺/Na⁺ATPase inhibitors or anti-H₂Use of the agent for the preparation of a first pharmaceutical dosage form and a second pharmaceutical dosage form for the quaternary treatment of the microorganism helicobacter pylori, the first pharmaceutical dosage form comprising two capsules, one placed inside the other, wherein the outer capsule comprises a soluble salt of bismuth and a first antibiotic and the inner capsule comprises a second antibiotic; the second pharmaceutical dosage form comprises K⁺/Na⁺ATPase inhibitors or anti-H₂And (3) preparing.

5. Use according to one of claims 1 to 4, wherein the bismuth salt is selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate and bismuth vanadium tetraoxide.

6. Use according to claim 5, wherein the bismuth salt is bismuth subcitrate.

7. Use according to one of claims 1 to 4, wherein the first antibiotic is selected from the group consisting of nitroimidazoles.

8. The use as claimed in claim 7, wherein the nitroimidazole is selected from the group consisting of metronidazole, aprazole, nitromycin, metronidazole, dimetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, pannidazole, ronidazole and tinidazole.

9. Use according to claim 8, wherein the nitroimidazole is metronidazole.

10. Use according to any one of claims 1 to 4, wherein the second antibiotic is selected from the group consisting of macrolides and compounds of the tetracycline family.

11. Use according to claim 10, wherein the macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin.

12. Use according to claim 10, wherein the compound of the tetracycline family is selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycylcycline, guanmecycline, lymecycline, methacycline, and sancycline.

13. The use of claim 12, wherein the second antibiotic is tetracycline.

14. Use according to any one of claims 2 to 4, wherein K is⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Selected from the group consisting of pumaprazole, cimetidine, ethidium bromide, statine, famotidine, flunarizine, and N- [ 1-4-amidobutyl-]-1H-pyrazol-3-yl]]-N' - (2, 2, 2-trifluoroethyl) guanidine, lansoprazole, thiamethoxam, mifepridine, niperidine, nizatidine, omeprazole, pantoprazole, rabeprazole, rassotidine, ranitidine, ritanserin, roxatidine hydrochloride, ropinetidine, 1-amino-2- [3- (3-piperidinomethylphenoxy) propylamino]-1-cyclobutene-3, 4-dione, sulbactidine, thiotidine, (+/-) -2- [ (4-methoxy-6, 7, 8, 9-tetrahydro-5H-cyclohepta [ b ] c]Pyridin-9-yl) sulfinyl]-1H-benzimidazole sodium salt, N- (2- (((5-dimethylamino) methyl) -2-furyl) methyl) thioethyl) thieno (3, 4-d) isothiazol-3-amine-1, 1-dioxide and zoltidine.

15. The use as claimed in claim 14, wherein k is⁺/Na⁺ATP-enzyme inhibitors or anti-H₂The agent is selected from omeprazole.

16. Use according to any one of claims 1 to 4, wherein the inner and outer capsules are stable at a temperature of 5 to 50 ℃ and a humidity of 35 to 65%.

17. Use according to one of claims 1 to 4, wherein both the inner and outer capsules are made of hard gelatin.

18. Use according to any one of claims 1 to 4, wherein the inner capsule has a size of 2 or 3 and the outer capsule has a size of 0+ or 1.

19. The use of claim 18, wherein the outer capsule has a size of 0+ and the inner capsule has a size of 3.

20. Pharmaceutical dosage form for the ternary treatment of the microorganism helicobacter pylori, comprising two capsules, placed one inside the other, wherein the outer capsule comprises a soluble salt of bismuth and a first antibiotic and the inner capsule comprises a second antibiotic.

21. A pharmaceutical dosage form as claimed in claim 20 wherein the inner capsule further comprises k⁺/Na⁺ATPase inhibitors or anti-H₂An inhibitor, whereby the pharmaceutical dosage form is for oral quaternary therapy.

22. A pharmaceutical dosage form as claimed in claim 20 wherein the outer capsule further comprises k⁺/Na⁺ATPase inhibitors or anti-H₂An inhibitor, whereby the pharmaceutical dosage form is for oral quaternary therapy.

23. A pharmaceutical dosage form as claimed in claim 20 wherein:

the bismuth salt is selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate, and bismuth vanadium tetraoxide;

the first antibiotic is selected from the group consisting of nitroimidazoles; and

the second antibiotic is selected from the group consisting of macrolides and compounds of the tetracycline family.

24. A pharmaceutical dosage form as claimed in claim 23 wherein:

the nitroimidazole is selected from the group consisting of metronidazole, aprazole, nitromycin, metronidazole, dimetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ornidazole and tinidazole;

the macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin; and

the compound of the tetracycline family is selected from the group consisting of tetracycline, chlorotetracycline, doxycycline, glycycycline, guanmecycline, lymecycline, methacycline, and sancycline.

25. A pharmaceutical dosage form as claimed in claim 24 wherein:

the bismuth salt is bismuth subcitrate;

the first antibiotic is metronidazole; and

the second antibiotic is tetracycline.

26. A pharmaceutical dosage form as claimed in claim 21 wherein:

the bismuth salt is selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate, and bismuth vanadium tetraoxide;

the first antibiotic is selected from the group consisting of nitroimidazoles;

the second antibiotic is selected from the group consisting of macrolides and compounds of the tetracycline family; and

K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Selected from the group consisting of pumaprazole, cimetidine, ethidium bromide, statine, famotidine, flunarizine, and N- [ 1-4-amidobutyl-]-1H-pyrazol-3-yl]]-N' - (2, 2, 2-trifluoroethyl) guanidine, lansoprazole, thiamethoxam, mifepridine, niperidine, nizatidine, omeprazole, pantoprazole, rabeprazole, rassotidine, ranitidine, ritanserin, roxatidine hydrochloride, ropinetidine, 1-amino-2- [3- (3-piperidinomethylphenoxy) propylamino]-1-cyclobutene-3, 4-dione, sulbactidine, thiotidine, (+/-) -2- [ (4-methoxy-6, 7, 8, 9-tetrahydro-5H-cyclohepta [ b ] c]Pyridin-9-yl) sulfinyl]-1H-benzimidazole sodium salt, N- (2- (((5-dimethylamino) methyl) -2-furyl) methyl) thioethyl) thieno (3, 4-d) isothiazol-3-amine-1, 1-dioxide and zoltidine.

27. A pharmaceutical dosage form as claimed in claim 26 wherein:

the nitroimidazole is selected from the group consisting of metronidazole, aprazole, nitromycin, metronidazole, dimetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ornidazole and tinidazole;

the macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin; and

the compound of the tetracycline family is selected from the group consisting of tetracycline, chlorotetracycline, doxycycline, glycycycline, guanmecycline, lymecycline, methacycline, and sancycline.

28. A pharmaceutical dosage form as claimed in claim 27 wherein:

the bismuth salt is bismuth subcitrate;

the first antibiotic is metronidazole;

the second antibiotic is tetracycline; and

k+/Na⁺ATP-enzyme inhibitors or anti-H₂The agent is selected from omeprazole.

29. A pharmaceutical dosage form as claimed in claim 22 wherein:

the bismuth salt is selected from the group consisting of bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate, and bismuth vanadium tetraoxide;

the first antibiotic is selected from the group consisting of nitroimidazoles;

the second antibiotic is selected from the group consisting of macrolides and compounds of the tetracycline family; and

K⁺/Na⁺ATP-enzyme inhibitors or anti-H₂Selected from the group consisting of pumaprazole, cimetidine, ethidium bromide, statine, famotidine, flunarizine, and N- [ 1-4-amidobutyl-]-1H-pyrazol-3-yl]]-N' - (2, 2, 2-trifluoroethyl) guanidine, lansoprazole, thiamethoxam, mifepridine, niperidine, nizatidine, omeprazole, pantoprazole, rabeprazole, rassotidine, ranitidine, ritanserin, roxatidine hydrochloride, ropinetidine, 1-amino-2- [3- (3-piperidinomethylphenoxy) propylamino]-1-cyclobutene-3, 4-dione, sulbactidine, thiotidine, (+/-) -2- [ (4-methoxy-6, 7, 8, 9-tetrahydro-5H-cyclohepta [ b ] c]Pyridin-9-yl) sulfinyl]-1H-benzimidazole sodium salt, N- (2- (((5-dimethylamino) methyl) -2-furyl) methyl) thioethyl) thieno (3, 4-d) isothiazol-3-amine-1, 1-dioxide and zoltidine.

30. A pharmaceutical dosage form as claimed in claim 29 wherein:

the nitroimidazole is selected from the group consisting of metronidazole, aprazole, nitromycin, metronidazole, dimetridazole, etanidazole, flunidazole, misonidazole, nimorazole, ornidazole, panidazole, ornidazole and tinidazole;

the macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin; and

the compound of the tetracycline family is selected from the group consisting of tetracycline, chlorotetracycline, doxycycline, glycycycline, guanmecycline, lymecycline, methacycline, and sancycline.

31. A pharmaceutical dosage form as claimed in claim 30 wherein:

the bismuth salt is bismuth subcitrate;

the first antibiotic is metronidazole;

the second antibiotic is tetracycline; and

k+/Na⁺ATP-enzyme inhibitors or anti-H₂The agent is selected from omeprazole.

32. A pharmaceutical dosage form as claimed in claim 20 wherein the inner capsule has a size of 2 or 3 and the outer capsule has a size of 0+ or 1.

33. A pharmaceutical dosage form as claimed in claim 32 wherein the outer capsule has a size of 0+ and the inner capsule has a size of 3.

34. A pharmaceutical dosage form as claimed in claim 20 wherein both the inner and outer capsules are made of hard gelatin.

35. A pharmaceutical dosage form as claimed in claim 20 wherein the inner and outer capsules contain one or more excipients separately and independently.

36. A pharmaceutical dosage form as claimed in claim 35 wherein the excipients are selected from magnesium stearate; talc; cellulose and derivatives thereof; silica or a derivative thereof; a sugar; polyethylene glycol; a wax; mono-, di-and tri-glycerides of hydrogenated fatty acids; high molecular weight alcohols and acids; and their corresponding mixtures.